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1.  Aripiprazole in the Maintenance Treatment of Bipolar Disorder: A Critical Review of the Evidence and Its Dissemination into the Scientific Literature 
PLoS Medicine  2011;8(5):e1000434.
A systematic search of the literature reveals limited evidence to support use of aripiprazole, a second-generation antipsychotic medication, in maintenance therapy of bipolar disorder, despite widespread use.
Background
Aripiprazole, a second-generation antipsychotic medication, has been increasingly used in the maintenance treatment of bipolar disorder and received approval from the U.S. Food and Drug Administration for this indication in 2005. Given its widespread use, we sought to critically review the evidence supporting the use of aripiprazole in the maintenance treatment of bipolar disorder and examine how that evidence has been disseminated in the scientific literature.
Methods and Findings
We systematically searched multiple databases to identify double-blind, randomized controlled trials of aripiprazole for the maintenance treatment of bipolar disorder while excluding other types of studies, such as open-label, acute, and adjunctive studies. We then used a citation search to identify articles that cited these trials and rated the quality of their citations. Our evidence search protocol identified only two publications, both describing the results of a single trial conducted by Keck et al., which met criteria for inclusion in this review. We describe four issues that limit the interpretation of that trial as supporting the use of aripiprazole for bipolar maintenance: (1) insufficient duration to demonstrate maintenance efficacy; (2) limited generalizability due to its enriched sample; (3) possible conflation of iatrogenic adverse effects of abrupt medication discontinuation with beneficial effects of treatment; and (4) a low overall completion rate. Our citation search protocol yielded 80 publications that cited the Keck et al. trial in discussing the use of aripiprazole for bipolar maintenance. Of these, only 24 (30%) mentioned adverse events reported and four (5%) mentioned study limitations.
Conclusions
A single trial by Keck et al. represents the entirety of the literature on the use of aripiprazole for the maintenance treatment of bipolar disorder. Although careful review identifies four critical limitations to the trial's interpretation and overall utility, the trial has been uncritically cited in the subsequent scientific literature.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Bipolar disorder (manic depression) is a serious, long-term mental illness that affects about 1% of adults at some time during their life. It usually develops in late adolescence or early adulthood and affects men and women from all backgrounds. People with bipolar disorder experience wild mood swings that interfere with daily life and damage relationships. During “manic” episodes, which can last several months if untreated, they may feel euphoric (“high”), energetic, or irritable. They may be full of ambitious plans, feel creative, and spend money recklessly. They can also have psychotic symptoms—they may see or hear things that are not there. During depressive episodes, affected individuals may feel helpless, worthless, and suicidal. Treatments for bipolar disorder include drugs to stabilize mood swings (for example, lithium and anticonvulsant medications), antidepressants to treat depressive episodes, and antipsychotic drugs to treat manic episodes. Psychotherapy can also help and patients can be taught to recognize the signs of approaching manic or depressive episodes and the triggers for these episodes.
Why Was This Study Done?
Treatment of bipolar disorder is divided into three phases: acute treatment lasting about 2 months to achieve remission, continuance treatment lasting from months 2 through 6 to prevent relapse, and long-term maintenance treatment to prevent recurrence. Second-generation (atypical) antipsychotics are widely used for acute treatment of manic episodes but are also used for maintenance treatment. For example, the atypical antipsychotic aripiprazole, which gained US approval for this indication in 2005, is now a popular choice among clinicians for treating bipolar disorder. But how much evidence is there to support aripiprazole's use in the maintenance treatment of bipolar disorder? Here, the researchers systematically search the published literature for double-blind randomized controlled trials of aripiprazole for this indication, critically analyze the quality of these trials, and undertake a citation search to investigate how the results of these trials have been disseminated in the scientific literature. In double-blind randomized controlled trials, patients are randomly assigned to receive a test drug or a control (generally, placebo), and the effects of these drugs compared; patients in the trial, and physicians administering treatments, would not know who is receiving the test drug or control until the trial is completed.
What Did the Researchers Do and Find?
The researchers' search for reports of double-blind randomized controlled trials of aripiprazole for the maintenance treatment of bipolar disorder using predefined criteria identified only two publications, both describing a single trial—the Keck trial. Critical review of this trial identified four issues that limit its interpretation for supporting aripiprazole as a maintenance therapy: the trial was too short to demonstrate maintenance efficacy; all the trial participants had responded well to aripiprazole as an acute treatment so the generalizability of the trial's results was limited; the trial design meant that some of the apparent beneficial treatment results could have reflected the adverse effects of abrupt medication discontinuation in the control group; and the trial had a low completion rate. The researchers' citation search identified 80 publications that cited the Keck trial in discussions of the use of aripiprazole for maintenance treatment of bipolar disorder. Only a quarter of these papers presented any numerical data from the trial, only a third mentioned any of the reported adverse events, and only four papers mentioned the trial's limitations.
What Do These Findings Mean?
This evaluation of the evidence base supporting the use of aripiprazole for the maintenance treatment of bipolar disorder shows that the justification for this practice relies on the results of one published trial. Moreover, the methodology and reporting of this trial mean that its results cannot easily be generalized to inform the treatment of most patients with bipolar disorder. Worryingly, the researchers' citation search indicates that the Keck trial has been cited uncritically in the ensuing scientific literature. Although the unique features of bipolar disorder make it hard to undertake controlled studies of treatment options, the researchers express concern that “the publication and apparently uncritical acceptance of this trial may be diverting patients away from more effective treatments”.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000434.
The US National Institute of Mental Health has detailed information on bipolar disorder, including an Easy to Read booklet (in English and Spanish)
The UK National Health Service Choices website provides information on all aspects of bipolar disorder
The UK charity Mind has information on bipolar disorder and provides links to other useful organizations
MedlinePlus has links to further information on bipolar disorder (in English and Spanish)
doi:10.1371/journal.pmed.1000434
PMCID: PMC3086871  PMID: 21559324
2.  Home Telehealth for Patients With Chronic Obstructive Pulmonary Disease (COPD) 
Executive Summary
In July 2010, the Medical Advisory Secretariat (MAS) began work on a Chronic Obstructive Pulmonary Disease (COPD) evidentiary framework, an evidence-based review of the literature surrounding treatment strategies for patients with COPD. This project emerged from a request by the Health System Strategy Division of the Ministry of Health and Long-Term Care that MAS provide them with an evidentiary platform on the effectiveness and cost-effectiveness of COPD interventions.
After an initial review of health technology assessments and systematic reviews of COPD literature, and consultation with experts, MAS identified the following topics for analysis: vaccinations (influenza and pneumococcal), smoking cessation, multidisciplinary care, pulmonary rehabilitation, long-term oxygen therapy, noninvasive positive pressure ventilation for acute and chronic respiratory failure, hospital-at-home for acute exacerbations of COPD, and telehealth (including telemonitoring and telephone support). Evidence-based analyses were prepared for each of these topics. For each technology, an economic analysis was also completed where appropriate. In addition, a review of the qualitative literature on patient, caregiver, and provider perspectives on living and dying with COPD was conducted, as were reviews of the qualitative literature on each of the technologies included in these analyses.
The Chronic Obstructive Pulmonary Disease Mega-Analysis series is made up of the following reports, which can be publicly accessed at the MAS website at: http://www.hqontario.ca/en/mas/mas_ohtas_mn.html.
Chronic Obstructive Pulmonary Disease (COPD) Evidentiary Framework
Influenza and Pneumococcal Vaccinations for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Smoking Cessation for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Community-Based Multidisciplinary Care for Patients With Stable Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Pulmonary Rehabilitation for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Long-term Oxygen Therapy for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Noninvasive Positive Pressure Ventilation for Acute Respiratory Failure Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Noninvasive Positive Pressure Ventilation for Chronic Respiratory Failure Patients With Stable Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Hospital-at-Home Programs for Patients With Acute Exacerbations of Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Home Telehealth for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Cost-Effectiveness of Interventions for Chronic Obstructive Pulmonary Disease Using an Ontario Policy Model
Experiences of Living and Dying With COPD: A Systematic Review and Synthesis of the Qualitative Empirical Literature
For more information on the qualitative review, please contact Mita Giacomini at: http://fhs.mcmaster.ca/ceb/faculty_member_giacomini.htm.
For more information on the economic analysis, please visit the PATH website: http://www.path-hta.ca/About-Us/Contact-Us.aspx.
The Toronto Health Economics and Technology Assessment (THETA) collaborative has produced an associated report on patient preference for mechanical ventilation. For more information, please visit the THETA website: http://theta.utoronto.ca/static/contact.
Objective
The objective of this analysis was to conduct an evidence-based assessment of home telehealth technologies for patients with chronic obstructive pulmonary disease (COPD) in order to inform recommendations regarding the access and provision of these services in Ontario. This analysis was one of several analyses undertaken to evaluate interventions for COPD. The perspective of this assessment was that of the Ontario Ministry of Health and Long-Term Care, a provincial payer of medically necessary health care services.
Clinical Need: Condition and Target Population
Canada is facing an increase in chronic respiratory diseases due in part to its aging demographic. The projected increase in COPD will put a strain on health care payers and providers. There is therefore an increasing demand for telehealth services that improve access to health care services while maintaining or improving quality and equality of care. Many telehealth technologies however are in the early stages of development or diffusion and thus require study to define their application and potential harms or benefits. The Medical Advisory Secretariat (MAS) therefore sought to evaluate telehealth technologies for COPD.
Technology
Telemedicine (or telehealth) refers to using advanced information and communication technologies and electronic medical devices to support the delivery of clinical care, professional education, and health-related administrative services.
Generally there are 4 broad functions of home telehealth interventions for COPD:
to monitor vital signs or biological health data (e.g., oxygen saturation),
to monitor symptoms, medication, or other non-biologic endpoints (e.g., exercise adherence),
to provide information (education) and/or other support services (such as reminders to exercise or positive reinforcement), and
to establish a communication link between patient and provider.
These functions often require distinct technologies, although some devices can perform a number of these diverse functions. For the purposes of this review, MAS focused on home telemonitoring and telephone only support technologies.
Telemonitoring (or remote monitoring) refers to the use of medical devices to remotely collect a patient’s vital signs and/or other biologic health data and the transmission of those data to a monitoring station for interpretation by a health care provider.
Telephone only support refers to disease/disorder management support provided by a health care provider to a patient who is at home via telephone or videoconferencing technology in the absence of transmission of patient biologic data.
Research Questions
What is the effectiveness, cost-effectiveness, and safety of home telemonitoring compared with usual care for patients with COPD?
What is the effectiveness, cost-effectiveness, and safety of telephone only support programs compared with usual care for patients with COPD?
Research Methods
Literature Search
Search Strategy
A literature search was performed on November 3, 2010 using OVID MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, EMBASE, the Cumulative Index to Nursing & Allied Health Literature (CINAHL), the Cochrane Library, and the International Agency for Health Technology Assessment (INAHTA) for studies published from January 1, 2000 until November 3, 2010. Abstracts were reviewed by a single reviewer and, for those studies meeting the eligibility criteria, full-text articles were obtained. Reference lists were also examined for any additional relevant studies not identified through the search. Articles with unknown eligibility were reviewed with a second clinical epidemiologist, and then a group of epidemiologists until consensus was established. The quality of evidence was assessed as high, moderate, low, or very low according to GRADE methodology.
Inclusion Criteria – Question #1
frequent transmission of a patient’s physiological data collected at home and without a health care professional physically present to health care professionals for routine monitoring through the use of a communication technology;
monitoring combined with a coordinated management and feedback system based on transmitted data;
telemonitoring as a key component of the intervention (subjective determination);
usual care as provided by the usual care provider for the control group;
randomized controlled trials (RCTs), controlled clinical trials (CCTs), systematic reviews, and/or meta-analyses;
published between January 1, 2000 and November 3, 2010.
Inclusion Criteria – Question #2
scheduled or frequent contact between patient and a health care professional via telephone or videoconferencing technology in the absence of transmission of patient physiological data;
monitoring combined with a coordinated management and feedback system based on transmitted data;
telephone support as a key component of the intervention (subjective determination);
usual care as provided by the usual care provider for the control group;
RCTs, CCTs, systematic reviews, and/or meta-analyses;
published between January 1, 2000 and November 3, 2010.
Exclusion Criteria
published in a language other than English;
intervention group (and not control) receiving some form of home visits by a medical professional, typically a nurse (i.e., telenursing) beyond initial technology set-up and education, to collect physiological data, or to somehow manage or treat the patient;
not recording patient or health system outcomes (e.g., technical reports testing accuracy, reliability or other development-related outcomes of a device, acceptability/feasibility studies, etc.);
not using an independent control group that received usual care (e.g., studies employing historical or periodic controls).
Outcomes of Interest
hospitalizations (primary outcome)
mortality
emergency department visits
length of stay
quality of life
other […]
Subgroup Analyses (a priori)
length of intervention (primary)
severity of COPD (primary)
Quality of Evidence
The quality of evidence assigned to individual studies was determined using a modified CONSORT Statement Checklist for Randomized Controlled Trials. (1) The CONSORT Statement was adapted to include 3 additional quality measures: the adequacy of control group description, significant differential loss to follow-up between groups, and greater than or equal to 30% study attrition. Individual study quality was defined based on total scores according to the CONSORT Statement checklist: very low (0 to < 40%), low (≥ 40 to < 60%), moderate (≥ 60 to < 80%), and high (≥ 80 to 100%).
The quality of the body of evidence was assessed as high, moderate, low, or very low according to the GRADE Working Group criteria. The following definitions of quality were used in grading the quality of the evidence:
Summary of Findings
Six publications, representing 5 independent trials, met the eligibility criteria for Research Question #1. Three trials were RCTs reported across 4 publications, whereby patients were randomized to home telemonitoring or usual care, and 2 trials were CCTs, whereby patients or health care centers were nonrandomly assigned to intervention or usual care.
A total of 310 participants were studied across the 5 included trials. The mean age of study participants in the included trials ranged from 61.2 to 74.5 years for the intervention group and 61.1 to 74.5 years for the usual care group. The percentage of men ranged from 40% to 64% in the intervention group and 46% to 72% in the control group.
All 5 trials were performed in a moderate to severe COPD patient population. Three trials initiated the intervention following discharge from hospital. One trial initiated the intervention following a pulmonary rehabilitation program. The final trial initiated the intervention during management of patients at an outpatient clinic.
Four of the 5 trials included oxygen saturation (i.e., pulse oximetry) as one of the biological patient parameters being monitored. Additional parameters monitored included forced expiratory volume in one second, peak expiratory flow, and temperature.
There was considerable clinical heterogeneity between trials in study design, methods, and intervention/control. In relation to the telemonitoring intervention, 3 of the 5 included studies used an electronic health hub that performed multiple functions beyond the monitoring of biological parameters. One study used only a pulse oximeter device alone with modem capabilities. Finally, in 1 study, patients measured and then forwarded biological data to a nurse during a televideo consultation. Usual care varied considerably between studies.
Only one trial met the eligibility criteria for Research Question #2. The included trial was an RCT that randomized 60 patients to nurse telephone follow-up or usual care (no telephone follow-up). Participants were recruited from the medical department of an acute-care hospital in Hong Kong and began receiving follow-up after discharge from the hospital with a diagnosis of COPD (no severity restriction). The intervention itself consisted of only two 10-to 20-minute telephone calls, once between days 3 to 7 and once between days 14 to 20, involving a structured, individualized educational and supportive programme led by a nurse that focused on 3 components: assessment, management options, and evaluation.
Regarding Research Question #1:
Low to very low quality evidence (according to GRADE) finds non-significant effects or conflicting effects (of significant or non-significant benefit) for all outcomes examined when comparing home telemonitoring to usual care.
There is a trend towards significant increase in time free of hospitalization and use of other health care services with home telemonitoring, but these findings need to be confirmed further in randomized trials of high quality.
There is severe clinical heterogeneity between studies that limits summary conclusions.
The economic impact of home telemonitoring is uncertain and requires further study.
Home telemonitoring is largely dependent on local information technologies, infrastructure, and personnel, and thus the generalizability of external findings may be low. Jurisdictions wishing to replicate home telemonitoring interventions should likely test those interventions within their jurisdictional framework before adoption, or should focus on home-grown interventions that are subjected to appropriate evaluation and proven effective.
Regarding Research Question #2:
Low quality evidence finds significant benefit in favour of telephone-only support for self-efficacy and emergency department visits when compared to usual care, but non-significant results for hospitalizations and hospital length of stay.
There are very serious issues with the generalizability of the evidence and thus additional research is required.
PMCID: PMC3384362  PMID: 23074421
3.  Pulmonary Rehabilitation for Patients With Chronic Pulmonary Disease (COPD) 
Executive Summary
In July 2010, the Medical Advisory Secretariat (MAS) began work on a Chronic Obstructive Pulmonary Disease (COPD) evidentiary framework, an evidence-based review of the literature surrounding treatment strategies for patients with COPD. This project emerged from a request by the Health System Strategy Division of the Ministry of Health and Long-Term Care that MAS provide them with an evidentiary platform on the effectiveness and cost-effectiveness of COPD interventions.
After an initial review of health technology assessments and systematic reviews of COPD literature, and consultation with experts, MAS identified the following topics for analysis: vaccinations (influenza and pneumococcal), smoking cessation, multidisciplinary care, pulmonary rehabilitation, long-term oxygen therapy, noninvasive positive pressure ventilation for acute and chronic respiratory failure, hospital-at-home for acute exacerbations of COPD, and telehealth (including telemonitoring and telephone support). Evidence-based analyses were prepared for each of these topics. For each technology, an economic analysis was also completed where appropriate. In addition, a review of the qualitative literature on patient, caregiver, and provider perspectives on living and dying with COPD was conducted, as were reviews of the qualitative literature on each of the technologies included in these analyses.
The Chronic Obstructive Pulmonary Disease Mega-Analysis series is made up of the following reports, which can be publicly accessed at the MAS website at: http://www.hqontario.ca/en/mas/mas_ohtas_mn.html.
Chronic Obstructive Pulmonary Disease (COPD) Evidentiary Framework
Influenza and Pneumococcal Vaccinations for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Smoking Cessation for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Community-Based Multidisciplinary Care for Patients With Stable Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Pulmonary Rehabilitation for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Long-term Oxygen Therapy for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Noninvasive Positive Pressure Ventilation for Acute Respiratory Failure Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Noninvasive Positive Pressure Ventilation for Chronic Respiratory Failure Patients With Stable Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Hospital-at-Home Programs for Patients With Acute Exacerbations of Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Home Telehealth for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Cost-Effectiveness of Interventions for Chronic Obstructive Pulmonary Disease Using an Ontario Policy Model
Experiences of Living and Dying With COPD: A Systematic Review and Synthesis of the Qualitative Empirical Literature
For more information on the qualitative review, please contact Mita Giacomini at: http://fhs.mcmaster.ca/ceb/faculty member_giacomini.htm.
For more information on the economic analysis, please visit the PATH website: http://www.path-hta.ca/About-Us/Contact-Us.aspx.
The Toronto Health Economics and Technology Assessment (THETA) collaborative has produced an associated report on patient preference for mechanical ventilation. For more information, please visit the THETA website: http://theta.utoronto.ca/static/contact.
Objective
The objective of this evidence-based review was to determine the effectiveness and cost-effectiveness of pulmonary rehabilitation in the management of chronic obstructive pulmonary disease (COPD).
Technology
Pulmonary rehabilitation refers to a multidisciplinary program of care for patients with chronic respiratory impairment that is individually tailored and designed to optimize physical and social performance and autonomy. Exercise training is the cornerstone of pulmonary rehabilitation programs, though they may also include components such as patient education and psychological support. Pulmonary rehabilitation is recommended as the standard of care in the treatment and rehabilitation of patients with COPD who remain symptomatic despite treatment with bronchodilators.
For the purpose of this review, the Medical Advisory Secretariat focused on pulmonary rehabilitation programs as defined by the Cochrane Collaboration—that is, any inpatient, outpatient, or home-based rehabilitation program lasting at least 4 weeks that includes exercise therapy with or without any form of education and/or psychological support delivered to patients with exercise limitations attributable to COPD.
Research Questions
What is the effectiveness and cost-effectiveness of pulmonary rehabilitation compared with usual care (UC) for patients with stable COPD?
Does early pulmonary rehabilitation (within 1 month of hospital discharge) in patients who had an acute exacerbation of COPD improve outcomes compared with UC (or no rehabilitation)?
Do maintenance or postrehabilitation programs for patients with COPD who have completed a pulmonary rehabilitation program improve outcomes compared with UC?
Research Methods
Literature Search
Search Strategy
For Research Questions 1and 2, a literature search was performed on August 10, 2010 for studies published from January 1, 2004 to July 31, 2010. For Research Question 3, a literature search was performed on February 3, 2011 for studies published from January 1, 2000 to February 3, 2011. Abstracts were reviewed by a single reviewer and, for those studies meeting the eligibility criteria, full-text articles were obtained. Reference lists and health technology assessment websites were also examined for any additional relevant studies not identified through the systematic search.
Inclusion Criteria
Research questions 1 and 2:
published between January 1, 2004 and July 31, 2010
randomized controlled trials, systematic reviews, and meta-analyses
COPD study population
studies comparing pulmonary rehabilitation with UC (no pulmonary rehabilitation)
duration of pulmonary rehabilitation program ≥ 6 weeks
pulmonary rehabilitation program had to include at minimum exercise training
Research question 3:
published between January 1, 2000 and February 3, 2011
randomized controlled trials, systematic reviews, and meta-analyses
COPD study population
studies comparing a maintenance or postrehabilitation program with UC (standard follow-up)
duration of pulmonary rehabilitation program ≥ 6 weeks
initial pulmonary rehabilitation program had to include at minimum exercise training
Exclusion Criteria
Research questions 1, 2, and 3:
grey literature
duplicate publications
non-English language publications
study population ≤ 18 years of age
studies conducted in a palliative population
studies that did not report primary outcome of interest
Additional exclusion criteria for research question 3:
studies with ≤ 2 sessions/visits per month
Outcomes of Interest
The primary outcomes of interest for the stable COPD population were exercise capacity and health-related quality of life (HRQOL). For the COPD population following an exacerbation, the primary outcomes of interest were hospital readmissions and HRQOL. The primary outcomes of interest for the COPD population undertaking maintenance programs were functional exercise capacity and HRQOL.
Quality of Evidence
The quality of each included study was assessed taking into consideration allocation concealment, randomization, blinding, power/sample size, withdrawals/dropouts, and intention-to-treat analyses.
The quality of the body of evidence was assessed as high, moderate, low, or very low according to the GRADE Working Group criteria. The following definitions of quality were used in grading the quality of the evidence:
Summary of Findings
Research Question 1: Effect of Pulmonary Rehabilitation on Outcomes in Stable COPD
Seventeen randomized controlled trials met the inclusion criteria and were included in this review.
The following conclusions are based on moderate quality of evidence.
Pulmonary rehabilitation including at least 4 weeks of exercise training leads to clinically and statistically significant improvements in HRQOL in patients with COPD.1
Pulmonary rehabilitation also leads to a clinically and statistically significant improvement in functional exercise capacity2 (weighted mean difference, 54.83 m; 95% confidence interval, 35.63–74.03; P < 0.001).
Research Question 2: Effect of Pulmonary Rehabilitation on Outcomes Following an Acute Exacerbation of COPD
Five randomized controlled trials met the inclusion criteria and are included in this review. The following conclusion is based on moderate quality of evidence.
Pulmonary rehabilitation (within 1 month of hospital discharge) after acute exacerbation significantly reduces hospital readmissions (relative risk, 0.50; 95% confidence interval, 0.33–0.77; P = 0.001) and leads to a statistically and clinically significant improvement in HRQOL.3
Research Question 3: Effect of Pulmonary Rehabilitation Maintenance Programs on COPD Outcomes
Three randomized controlled trials met the inclusion criteria and are included in this review. The conclusions are based on a low quality of evidence and must therefore be considered with caution.
Maintenance programs have a nonsignificant effect on HRQOL and hospitalizations.
Maintenance programs have a statistically but not clinically significant effect on exercise capacity (P = 0.01). When subgrouped by intensity and quality of study, maintenance programs have a statistically and marginally clinically significant effect on exercise capacity.
PMCID: PMC3384375  PMID: 23074434
4.  Community-Based Multidisciplinary Care for Patients With Stable Chronic Obstructive Pulmonary Disease (COPD) 
Executive Summary
In July 2010, the Medical Advisory Secretariat (MAS) began work on a Chronic Obstructive Pulmonary Disease (COPD) evidentiary framework, an evidence-based review of the literature surrounding treatment strategies for patients with COPD. This project emerged from a request by the Health System Strategy Division of the Ministry of Health and Long-Term Care that MAS provide them with an evidentiary platform on the effectiveness and cost-effectiveness of COPD interventions.
After an initial review of health technology assessments and systematic reviews of COPD literature, and consultation with experts, MAS identified the following topics for analysis: vaccinations (influenza and pneumococcal), smoking cessation, multidisciplinary care, pulmonary rehabilitation, long-term oxygen therapy, noninvasive positive pressure ventilation for acute and chronic respiratory failure, hospital-at-home for acute exacerbations of COPD, and telehealth (including telemonitoring and telephone support). Evidence-based analyses were prepared for each of these topics. For each technology, an economic analysis was also completed where appropriate. In addition, a review of the qualitative literature on patient, caregiver, and provider perspectives on living and dying with COPD was conducted, as were reviews of the qualitative literature on each of the technologies included in these analyses.
The Chronic Obstructive Pulmonary Disease Mega-Analysis series is made up of the following reports, which can be publicly accessed at the MAS website at: http://www.hqontario.ca/en/mas/mas_ohtas_mn.html.
Chronic Obstructive Pulmonary Disease (COPD) Evidentiary Framework
Influenza and Pneumococcal Vaccinations for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Smoking Cessation for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Community-Based Multidisciplinary Care for Patients With Stable Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Pulmonary Rehabilitation for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Long-term Oxygen Therapy for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Noninvasive Positive Pressure Ventilation for Acute Respiratory Failure Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Noninvasive Positive Pressure Ventilation for Chronic Respiratory Failure Patients With Stable Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Hospital-at-Home Programs for Patients With Acute Exacerbations of Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Home Telehealth for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Cost-Effectiveness of Interventions for Chronic Obstructive Pulmonary Disease Using an Ontario Policy Model
Experiences of Living and Dying With COPD: A Systematic Review and Synthesis of the Qualitative Empirical Literature
For more information on the qualitative review, please contact Mita Giacomini at: http://fhs.mcmaster.ca/ceb/faculty_member_giacomini.htm.
For more information on the economic analysis, please visit the PATH website: http://www.path-hta.ca/About-Us/Contact-Us.aspx.
The Toronto Health Economics and Technology Assessment (THETA) collaborative has produced an associated report on patient preference for mechanical ventilation. For more information, please visit the THETA website: http://theta.utoronto.ca/static/contact.
Objective
The objective of this evidence-based analysis was to determine the effectiveness and cost-effectiveness of multidisciplinary care (MDC) compared with usual care (UC, single health care provider) for the treatment of stable chronic obstructive pulmonary disease (COPD).
Clinical Need: Condition and Target Population
Chronic obstructive pulmonary disease is a progressive disorder with episodes of acute exacerbations associated with significant morbidity and mortality. Cigarette smoking is linked causally to COPD in more than 80% of cases. Chronic obstructive pulmonary disease is among the most common chronic diseases worldwide and has an enormous impact on individuals, families, and societies through reduced quality of life and increased health resource utilization and mortality.
The estimated prevalence of COPD in Ontario in 2007 was 708,743 persons.
Technology
Multidisciplinary care involves professionals from a range of disciplines, working together to deliver comprehensive care that addresses as many of the patient’s health care and psychosocial needs as possible.
Two variables are inherent in the concept of a multidisciplinary team: i) the multidisciplinary components such as an enriched knowledge base and a range of clinical skills and experiences, and ii) the team components, which include but are not limited to, communication and support measures. However, the most effective number of team members and which disciplines should comprise the team for optimal effect is not yet known.
Research Question
What is the effectiveness and cost-effectiveness of MDC compared with UC (single health care provider) for the treatment of stable COPD?
Research Methods
Literature Search
Search Strategy
A literature search was performed on July 19, 2010 using OVID MEDLINE, OVID MEDLINE In-Process and Other Non-Indexed Citations, OVID EMBASE, EBSCO Cumulative Index to Nursing & Allied Health Literature (CINAHL), the Wiley Cochrane Library, and the Centre for Reviews and Dissemination database, for studies published from January 1, 1995 until July 2010. Abstracts were reviewed by a single reviewer and, for those studies meeting the eligibility criteria, full-text articles were obtained. Reference lists were also examined for any additional relevant studies not identified through the search.
Inclusion Criteria
health technology assessments, systematic reviews, or randomized controlled trials
studies published between January 1995 and July 2010;
COPD study population
studies comparing MDC (2 or more health care disciplines participating in care) compared with UC (single health care provider)
Exclusion Criteria
grey literature
duplicate publications
non-English language publications
study population less than 18 years of age
Outcomes of Interest
hospital admissions
emergency department (ED) visits
mortality
health-related quality of life
lung function
Quality of Evidence
The quality of each included study was assessed, taking into consideration allocation concealment, randomization, blinding, power/sample size, withdrawals/dropouts, and intention-to-treat analyses.
The quality of the body of evidence was assessed as high, moderate, low, or very low according to the GRADE Working Group criteria. The following definitions of quality were used in grading the quality of the evidence:
Summary of Findings
Six randomized controlled trials were obtained from the literature search. Four of the 6 studies were completed in the United States. The sample size of the 6 studies ranged from 40 to 743 participants, with a mean study sample between 66 and 71 years of age. Only 2 studies characterized the study sample in terms of the Global Initiative for Chronic Obstructive Lung Disease (GOLD) COPD stage criteria, and in general the description of the study population in the other 4 studies was limited. The mean percent predicted forced expiratory volume in 1 second (% predicted FEV1) among study populations was between 32% and 59%. Using this criterion, 3 studies included persons with severe COPD and 2 with moderate COPD. Information was not available to classify the population in the sixth study.
Four studies had MDC treatment groups which included a physician. All studies except 1 reported a respiratory specialist (i.e., respiratory therapist, specialist nurse, or physician) as part of the multidisciplinary team. The UC group was comprised of a single health care practitioner who may or may not have been a respiratory specialist.
A meta-analysis was completed for 5 of the 7 outcome measures of interest including:
health-related quality of life,
lung function,
all-cause hospitalization,
COPD-specific hospitalization, and
mortality.
There was only 1 study contributing to the outcome of all-cause and COPD-specific ED visits which precluded pooling data for these outcomes. Subgroup analyses were not completed either because heterogeneity was not significant or there were a small number of studies that were meta-analysed for the outcome.
Quality of Life
Three studies reported results of quality of life assessment based on the St. George’s Respiratory Questionnaire (SGRQ). A mean decrease in the SGRQ indicates an improvement in quality of life while a mean increase indicates deterioration in quality of life. In all studies the mean change score from baseline to the end time point in the MDC treatment group showed either an improvement compared with the control group or less deterioration compared with the control group. The mean difference in change scores between MDC and UC groups was statistically significant in all 3 studies. The pooled weighted mean difference in total SGRQ score was −4.05 (95% confidence interval [CI], −6.47 to 1.63; P = 0.001). The GRADE quality of evidence was assessed as low for this outcome.
Lung Function
Two studies reported results of the FEV1 % predicted as a measure of lung function. A negative change from baseline infers deterioration in lung function and a positive change from baseline infers an improvement in lung function. The MDC group showed a statistically significant improvement in lung function up to 12 months compared with the UC group (P = 0.01). However this effect is not maintained at 2-year follow-up (P = 0.24). The pooled weighted mean difference in FEV1 percent predicted was 2.78 (95% CI, −1.82 to −7.37). The GRADE quality of evidence was assessed as very low for this outcome indicating that an estimate of effect is uncertain.
Hospital Admissions
All-Cause
Four studies reported results of all-cause hospital admissions in terms of number of persons with at least 1 admission during the follow-up period. Estimates from these 4 studies were pooled to determine a summary estimate. There is a statistically significant 25% relative risk (RR) reduction in all-cause hospitalizations in the MDC group compared with the UC group (P < 0.001). The index of heterogeneity (I2) value is 0%, indicating no statistical heterogeneity between studies. The GRADE quality of evidence was assessed as moderate for this outcome, indicating that further research may change the estimate of effect.
COPD-Specific Hospitalization
Three studies reported results of COPD-specific hospital admissions in terms of number of persons with at least 1 admission during the follow-up period. Estimates from these 3 studies were pooled to determine a summary estimate. There is a statistically significant 33% RR reduction in all-cause hospitalizations in the MDC group compared with the UC group (P = 0.002). The I2 value is 0%, indicating no statistical heterogeneity between studies. The GRADE quality of evidence was assessed as moderate for this outcome, indicating that further research may change the estimate of effect.
Emergency Department Visits
All-Cause
Two studies reported results of all-cause ED visits in terms of number of persons with at least 1 visit during the follow-up period. There is a statistically nonsignificant reduction in all-cause ED visits when data from these 2 studies are pooled (RR, 0.64; 95% CI, 0.31 to −1.33; P = 0.24). The GRADE quality of evidence was assessed as very low for this outcome indicating that an estimate of effect is uncertain.
COPD-Specific
One study reported results of COPD-specific ED visits in terms of number of persons with at least 1 visit during the follow-up period. There is a statistically significant 41% reduction in COPD-specific ED visits when the data from these 2 studies are pooled (RR, 0.59; 95% CI, 0.43−0.81; P < 0.001). The GRADE quality of evidence was assessed as moderate for this outcome.
Mortality
Three studies reported the mortality during the study follow-up period. Estimates from these 3 studies were pooled to determine a summary estimate. There is a statistically nonsignificant reduction in mortality between treatment groups (RR, 0.81; 95% CI, 0.52−1.27; P = 0.36). The I2 value is 19%, indicating low statistical heterogeneity between studies. All studies had a 12-month follow-up period. The GRADE quality of evidence was assessed as low for this outcome.
Conclusions
Significant effect estimates with moderate quality of evidence were found for all-cause hospitalization, COPD-specific hospitalization, and COPD-specific ED visits (Table ES1). A significant estimate with low quality evidence was found for the outcome of quality of life (Table ES2). All other outcome measures were nonsignificant and supported by low or very low quality of evidence.
Summary of Dichotomous Data
Abbreviations: CI, confidence intervals; COPD, chronic obstructive pulmonary disease; n, number.
Summary of Continuous Data
Abbreviations: CI, confidence intervals; FEV1, forced expiratory volume in 1 second; n, number; SGRQ, St. George’s Respiratory Questionnaire.
PMCID: PMC3384374  PMID: 23074433
5.  Smoking Cessation for Patients With Chronic Obstructive Pulmonary Disease (COPD) 
Executive Summary
In July 2010, the Medical Advisory Secretariat (MAS) began work on a Chronic Obstructive Pulmonary Disease (COPD) evidentiary framework, an evidence-based review of the literature surrounding treatment strategies for patients with COPD. This project emerged from a request by the Health System Strategy Division of the Ministry of Health and Long-Term Care that MAS provide them with an evidentiary platform on the effectiveness and cost-effectiveness of COPD interventions.
After an initial review of health technology assessments and systematic reviews of COPD literature, and consultation with experts, MAS identified the following topics for analysis: vaccinations (influenza and pneumococcal), smoking cessation, multidisciplinary care, pulmonary rehabilitation, long-term oxygen therapy, noninvasive positive pressure ventilation for acute and chronic respiratory failure, hospital-at-home for acute exacerbations of COPD, and telehealth (including telemonitoring and telephone support). Evidence-based analyses were prepared for each of these topics. For each technology, an economic analysis was also completed where appropriate. In addition, a review of the qualitative literature on patient, caregiver, and provider perspectives on living and dying with COPD was conducted, as were reviews of the qualitative literature on each of the technologies included in these analyses.
The Chronic Obstructive Pulmonary Disease Mega-Analysis series is made up of the following reports, which can be publicly accessed at the MAS website at: http://www.hqontario.ca/en/mas/mas_ohtas_mn.html.
Chronic Obstructive Pulmonary Disease (COPD) Evidentiary Framework
Influenza and Pneumococcal Vaccinations for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Smoking Cessation for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Community-Based Multidisciplinary Care for Patients With Stable Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Pulmonary Rehabilitation for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Long-term Oxygen Therapy for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Noninvasive Positive Pressure Ventilation for Acute Respiratory Failure Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Noninvasive Positive Pressure Ventilation for Chronic Respiratory Failure Patients With Stable Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Hospital-at-Home Programs for Patients With Acute Exacerbations of Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Home Telehealth for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Cost-Effectiveness of Interventions for Chronic Obstructive Pulmonary Disease Using an Ontario Policy Model
Experiences of Living and Dying With COPD: A Systematic Review and Synthesis of the Qualitative Empirical Literature
For more information on the qualitative review, please contact Mita Giacomini at: http://fhs.mcmaster.ca/ceb/faculty member_giacomini.htm.
For more information on the economic analysis, please visit the PATH website: http://www.path-hta.ca/About-Us/Contact-Us.aspx.
The Toronto Health Economics and Technology Assessment (THETA) collaborative has produced an associated report on patient preference for mechanical ventilation. For more information, please visit the THETA website: http://theta.utoronto.ca/static/contact.
Objective
The objective of this evidence-based analysis was to determine the effectiveness and cost-effectiveness of smoking cessation interventions in the management of chronic obstructive pulmonary disease (COPD).
Clinical Need: Condition and Target Population
Tobacco smoking is the main risk factor for COPD. It is estimated that 50% of older smokers develop COPD and more than 80% of COPD-associated morbidity is attributed to tobacco smoking. According to the Canadian Community Health Survey, 38.5% of Ontarians who smoke have COPD. In patients with a significant history of smoking, COPD is usually present with symptoms of progressive dyspnea (shortness of breath), cough, and sputum production. Patients with COPD who smoke have a particularly high level of nicotine dependence, and about 30.4% to 43% of patients with moderate to severe COPD continue to smoke. Despite the severe symptoms that COPD patients suffer, the majority of patients with COPD are unable to quit smoking on their own; each year only about 1% of smokers succeed in quitting on their own initiative.
Technology
Smoking cessation is the process of discontinuing the practice of inhaling a smoked substance. Smoking cessation can help to slow or halt the progression of COPD. Smoking cessation programs mainly target tobacco smoking, but may also encompass other substances that can be difficult to stop smoking due to the development of strong physical addictions or psychological dependencies resulting from their habitual use.
Smoking cessation strategies include both pharmacological and nonpharmacological (behavioural or psychosocial) approaches. The basic components of smoking cessation interventions include simple advice, written self-help materials, individual and group behavioural support, telephone quit lines, nicotine replacement therapy (NRT), and antidepressants. As nicotine addiction is a chronic, relapsing condition that usually requires several attempts to overcome, cessation support is often tailored to individual needs, while recognizing that in general, the more intensive the support, the greater the chance of success. Success at quitting smoking decreases in relation to:
a lack of motivation to quit,
a history of smoking more than a pack of cigarettes a day for more than 10 years,
a lack of social support, such as from family and friends, and
the presence of mental health disorders (such as depression).
Research Question
What are the effectiveness and cost-effectiveness of smoking cessation interventions compared with usual care for patients with COPD?
Research Methods
Literature Search
Search Strategy
A literature search was performed on June 24, 2010 using OVID MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations (1950 to June Week 3 2010), EMBASE (1980 to 2010 Week 24), the Cumulative Index to Nursing and Allied Health Literature (CINAHL), the Cochrane Library, and the Centre for Reviews and Dissemination for studies published between 1950 and June 2010. A single reviewer reviewed the abstracts and obtained full-text articles for those studies meeting the eligibility criteria. Reference lists were also examined for any additional relevant studies not identified through the search. Data were extracted using a standardized data abstraction form.
Inclusion Criteria
English-language, full reports from 1950 to week 3 of June, 2010;
either randomized controlled trials (RCTs), systematic reviews and meta-analyses, or non-RCTs with controls;
a proven diagnosis of COPD;
adult patients (≥ 18 years);
a smoking cessation intervention that comprised at least one of the treatment arms;
≥ 6 months’ abstinence as an outcome; and
patients followed for ≥ 6 months.
Exclusion Criteria
case reports
case series
Outcomes of Interest
≥ 6 months’ abstinence
Quality of Evidence
The quality of each included study was assessed taking into consideration allocation concealment, randomization, blinding, power/sample size, withdrawals/dropouts, and intention-to-treat analyses.
The quality of the body of evidence was assessed as high, moderate, low, or very low according to the GRADE Working Group criteria. The following definitions of quality were used in grading the quality of the evidence:
Summary of Findings
Nine RCTs were identified from the literature search. The sample sizes ranged from 74 to 5,887 participants. A total of 8,291 participants were included in the nine studies. The mean age of the patients in the studies ranged from 54 to 64 years. The majority of studies used the Global Initiative for Chronic Obstructive Lung Disease (GOLD) COPD staging criteria to stage the disease in study subjects. Studies included patients with mild COPD (2 studies), mild-moderate COPD (3 studies), moderate–severe COPD (1 study) and severe–very severe COPD (1 study). One study included persons at risk of COPD in addition to those with mild, moderate, or severe COPD, and 1 study did not define the stages of COPD. The individual quality of the studies was high. Smoking cessation interventions varied across studies and included counselling or pharmacotherapy or a combination of both. Two studies were delivered in a hospital setting, whereas the remaining 7 studies were delivered in an outpatient setting. All studies reported a usual care group or a placebo-controlled group (for the drug-only trials). The follow-up periods ranged from 6 months to 5 years. Due to excessive clinical heterogeneity in the interventions, studies were first grouped into categories of similar interventions; statistical pooling was subsequently performed, where appropriate. When possible, pooled estimates using relative risks for abstinence rates with 95% confidence intervals were calculated. The remaining studies were reported separately.
Abstinence Rates
Table ES1 provides a summary of the pooled estimates for abstinence, at longest follow-up, from the trials included in this review. It also shows the respective GRADE qualities of evidence.
Summary of Results*
Abbreviations: CI, confidence interval; NRT, nicotine replacement therapy.
Statistically significant (P < 0.05).
One trial used in this comparison had 2 treatment arms each examining a different antidepressant.
Conclusions
Based on a moderate quality of evidence, compared with usual care, abstinence rates are significantly higher in COPD patients receiving intensive counselling or a combination of intensive counselling and NRT.
Based on limited and moderate quality of evidence, abstinence rates are significantly higher in COPD patients receiving NRT compared with placebo.
Based on a moderate quality of evidence, abstinence rates are significantly higher in COPD patients receiving the antidepressant bupropion compared to placebo.
PMCID: PMC3384371  PMID: 23074432
6.  Current status of boron neutron capture therapy of high grade gliomas and recurrent head and neck cancer 
Boron neutron capture therapy (BNCT) is a biochemically targeted radiotherapy based on the nuclear capture and fission reactions that occur when non-radioactive boron-10, which is a constituent of natural elemental boron, is irradiated with low energy thermal neutrons to yield high linear energy transfer alpha particles and recoiling lithium-7 nuclei. Clinical interest in BNCT has focused primarily on the treatment of high grade gliomas, recurrent cancers of the head and neck region and either primary or metastatic melanoma. Neutron sources for BNCT currently have been limited to specially modified nuclear reactors, which are or until the recent Japanese natural disaster, were available in Japan, the United States, Finland and several other European countries, Argentina and Taiwan. Accelerators producing epithermal neutron beams also could be used for BNCT and these are being developed in several countries. It is anticipated that the first Japanese accelerator will be available for therapeutic use in 2013. The major hurdle for the design and synthesis of boron delivery agents has been the requirement for selective tumor targeting to achieve boron concentrations in the range of 20 μg/g. This would be sufficient to deliver therapeutic doses of radiation with minimal normal tissue toxicity. Two boron drugs have been used clinically, a dihydroxyboryl derivative of phenylalanine, referred to as boronophenylalanine or “BPA”, and sodium borocaptate or “BSH” (Na2B12H11SH). In this report we will provide an overview of other boron delivery agents that currently are under evaluation, neutron sources in use or under development for BNCT, clinical dosimetry, treatment planning, and finally a summary of previous and on-going clinical studies for high grade gliomas and recurrent tumors of the head and neck region. Promising results have been obtained with both groups of patients but these outcomes must be more rigorously evaluated in larger, possibly randomized clinical trials. Finally, we will summarize the critical issues that must be addressed if BNCT is to become a more widely established clinical modality for the treatment of those malignancies for which there currently are no good treatment options.
doi:10.1186/1748-717X-7-146
PMCID: PMC3583064  PMID: 22929110
Boron neutron capture therapy; Gliomas; Head and neck cancer; Radiation therapy
7.  RESPONSE OF THE U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES IN PROTECTING CIVILIAN AMERICANS IN JAPAN DURING THE FUKUSHIMA NUCLEAR CRISIS 
Health physics  2012;102(5):10.1097/HP.0b013e31824c79e5.
Following the earthquake and tsunami in northern Japan on 11 March 2011, and the ensuing damage to the Fukushima Daiichi nuclear power plant complex, a request by the U.S. Ambassador to Japan to the U.S. Department of Health and Human Services (DHHS) Assistant Secretary for Preparedness and Response (ASPR) resulted in deployment of a five-person team of subject matter experts to the U.S. Embassy. The primary purpose of the deployment was to provide the U.S. Embassy in Tokyo with guidance on health and medical issues related to potential radiation exposure of U.S. citizens in Japan, including employees of the U.S. Department of State at consulates in Japan and American citizens living in or visiting Japan. At the request of the Government of Japan, the deployed health team also assisted Japanese experts in their public health response to the radiation incident. Over a three-week period in Japan and continuing for weeks after their return to the U.S., the team provided expertise in the areas of medical and radiation oncology, health physics, assessment of radiation dose and cancer risk, particularly to U.S. citizens living in Tokyo and the surrounding areas, food and water contamination and the acceptable limits, countermeasures to exposure such as potassium iodide (KI), the use of KI and an offered donation from the United States, evacuation and re-entry issues, and health/emergency-related communication strategies. This paper describes the various strategies used and observations made by the DHHS team during the first two months after the Fukushima crisis began.
doi:10.1097/HP.0b013e31824c79e5
PMCID: PMC3816381  PMID: 24198437
public heath; emergency response; radiation exposure; medical countermeasures; nuclear power plant
8.  Airway Clearance Devices for Cystic Fibrosis 
Executive Summary
Objective
The purpose of this evidence-based analysis is to examine the safety and efficacy of airway clearance devices (ACDs) for cystic fibrosis and attempt to differentiate between devices, where possible, on grounds of clinical efficacy, quality of life, safety and/or patient preference.
Background
Cystic fibrosis (CF) is a common, inherited, life-limiting disease that affects multiple systems of the human body. Respiratory dysfunction is the primary complication and leading cause of death due to CF. CF causes abnormal mucus secretion in the airways, leading to airway obstruction and mucus plugging, which in turn can lead to bacterial infection and further mucous production. Over time, this almost cyclical process contributes to severe airway damage and loss of respiratory function. Removal of airway secretions, termed airway clearance, is thus an integral component of the management of CF.
A variety of methods are available for airway clearance, some requiring mechanical devices, others physical manipulation of the body (e.g. physiotherapy). Conventional chest physiotherapy (CCPT), through the assistance of a caregiver, is the current standard of care for achieving airway clearance, particularly in young patients up to the ages of six or seven. CF patients are, however, living much longer now than in decades past. The median age of survival in Canada has risen to 37.0 years for the period of 1998-2002 (5-year window), up from 22.8 years for the 5-year window ending in 1977. The prevalence has also risen accordingly, last recorded as 3,453 in Canada in 2002, up from 1,630 in 1977. With individuals living longer, there is a greater need for independent methods of airway clearance.
Airway Clearance Devices
There are at least three classes of airway clearance devices: positive expiratory pressure devices (PEP), airway oscillating devices (AOD; either handheld or stationary) and high frequency chest compression (HFCC)/mechanical percussion (MP) devices. Within these classes are numerous different brands of devices from various manufacturers, each with subtle iterations. At least 10 devices are licensed by Health Canada (ranging from Class 1 to Class 3 devices).
Evidence-Based Analysis of Effectiveness
Research Questions
Does long-term use of ACDs improve outcomes of interest in comparison to CCPT in patients with CF?
Does long-term use of one class of ACD improve outcomes of interest in comparison to another class of ACD in CF patients?
Literature Search
A comprehensive literature search was performed on March 7, 2009 using OVID MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, EMBASE, the Cumulative Index to Nursing & Allied Health Literature (CINAHL), the Cochrane Library, and the International Agency for Health Technology Assessment (INAHTA) for studies published from January 1, 1950 to March 7, 2009.
Inclusion Criteria
All randomized controlled trials including those of parallel and crossover design,
Systematic reviews and/or meta-analyses. Randomized controlled trials (RCTs), systematic reviews and meta-analyses
Exclusion Criteria
Abstracts were generally excluded because their methods could not be examined; however, abstract data was included in several Cochrane meta-analyses presented in this paper;
Studies of less than seven days duration (including single treatment studies);
Studies that did not report primary outcomes;
Studies in which less than 10 patients completed the study.
Outcomes of Interest
Primary outcomes under review were percent-predicted forced expiratory volume (FEV-1), forced vital capacity (FVC), and forced expiratory flow between 25%-75% (FEF25-75). Secondary outcomes included number of hospitalizations, adherence, patient preference, quality of life and adverse events. All outcomes were decided a priori.
Summary of Findings
Literature searching and back-searching identified 13 RCTs meeting the inclusion criteria, along with three Cochrane systematic reviews. The Cochrane reviews were identified in preliminary searching and used as the basis for formulating this review. Results were subgrouped by comparison and according to the available literature. For example, results from Cochrane meta-analyses included abstract data and therefore, additional meta-analyses were also performed on trials reported as full publications only (MAS generally excludes abstracted data when full publications are available as the methodological quality of trials reported in abstract cannot be properly assessed).
Executive Summary Table 1 summarizes the results across all comparisons and subgroupings for primary outcomes of pulmonary function. Only two comparisons yielded evidence of moderate or high quality according to GRADE criteria–the comparisons of CCPT vs. PEP and handheld AOD vs. PEP–but only the comparison of CCPT vs. PEP noted a significant difference between treatment groups. In comparison to CCPT, there was a significant difference in favour of PEP for % predicted FEV-1 and FVC according to one long-term, parallel RCT. This trial was accepted as the best available evidence for the comparison. The body of evidence for the remaining comparisons was low to very low, according to GRADE criteria, being downgraded most often because of poor methodological quality and low generalizability. Specifically, trials were likely not adequately powered (low sample sizes), did not conduct intention-to-treat analyses, were conducted primarily in children and young adolescents, and outdated (conducted more than 10 years ago).
Secondary outcomes were poorly or inconsistently reported, and were generally not of value to decision-making. Of note, there were a significantly higher number of hospitalizations among participants undergoing AOD therapy in comparison to PEP therapy.
Summarization of results for primary outcomes by comparison and subgroupings
Bolding indicates significant difference
Positive summary statistics favour the former intervention
Abbreviations: AOD, airway oscillating device; CCPT, conventional chest physiotherapy; CI, confidence interval; HFCC, high frequency chest compression; MP, mechanical percussion; N/A: not applicable; PEP, positive expiratory pressure
Economic Analysis
Devices ranged in cost from around $60 for PEP and handheld AODs to upwards of $18,000 for a HFCC vest device. Although the majority of device costs are paid out-of-pocket by the patients themselves, their parents, or covered by third-party medical insurance, Ontario did provide funding assistance through the Assistive Devices Program (ADP) for postural drainage boards and MP devices. These technologies, however, are either obsolete or their clinical efficacy is not supported by evidence. ADP provided roughly $16,000 in funding for the 2008/09 fiscal year. Using device costs and prevalent and incident cases of CF in Ontario, budget impact projections were generated for Ontario. Prevalence of CF in Ontario for patients from ages 6 to 71 was cited as 1,047 cases in 2002 while incidence was estimated at 46 new cases of CF diagnosed per year in 2002. Budget impact projections indicated that PEP and handheld AODs were highly economically feasible costing around $90,000 for the entire prevalent population and less than $3,000 per year to cover new incident cases. HFCC vest devices were by far the most expensive, costing in excess of $19 million to cover the prevalent population alone.
Conclusions
There is currently a lack of sufficiently powered, long-term, parallel randomized controlled trials investigating the use of ACDs in comparison to other airway clearance techniques. While much of the current evidence suggests no significant difference between various ACDs and alternative therapies/technologies, at least according to outcomes of pulmonary function, there is a strong possibility that past trials were not sufficiently powered to identify a difference. Unfortunately, it is unlikely that there will be any future trials comparing ACDs to CCPT as withholding therapy using an ACD may be seen as unethical at present.
Conclusions of clinical effectiveness are as follows:
Moderate quality evidence suggests that PEP is at least as effective as or more effective than CCPT, according to primary outcomes of pulmonary function.
Moderate quality evidence suggests that there is no significant difference between PEP and handheld AODs, according to primary outcomes of pulmonary function; however, secondary outcomes may favour PEP.
Low quality evidence suggests that there is no significant difference between AODs or HFCC/MP and CCPT, according to both primary and secondary outcomes.
Very low quality evidence suggests that there is no significant difference between handheld AOD and CCPT, according to primary outcomes of pulmonary function.
Budget impact projections show PEP and handheld AODs to be highly economically feasible.
PMCID: PMC3377547  PMID: 23074531
9.  Guidelines for Exposure Assessment in Health Risk Studies Following a Nuclear Reactor Accident 
Background: Worldwide concerns regarding health effects after the Chernobyl and Fukushima nuclear power plant accidents indicate a clear need to identify short- and long-term health impacts that might result from accidents in the future. Fundamental to addressing this problem are reliable and accurate radiation dose estimates for the affected populations. The available guidance for activities following nuclear accidents is limited with regard to strategies for dose assessment in health risk studies.
Objectives: Here we propose a comprehensive systematic approach to estimating radiation doses for the evaluation of health risks resulting from a nuclear power plant accident, reflected in a set of seven guidelines.
Discussion: Four major nuclear reactor accidents have occurred during the history of nuclear power production. The circumstances leading to these accidents were varied, as were the magnitude of the releases of radioactive materials, the pathways by which persons were exposed, the data collected afterward, and the lifestyle factors and dietary consumption that played an important role in the associated radiation exposure of the affected populations. Accidents involving nuclear reactors may occur in the future under a variety of conditions. The guidelines we recommend here are intended to facilitate obtaining reliable dose estimations for a range of different exposure conditions. We recognize that full implementation of the proposed approach may not always be feasible because of other priorities during the nuclear accident emergency and because of limited resources in manpower and equipment.
Conclusions: The proposed approach can serve as a basis to optimize the value of radiation dose reconstruction following a nuclear reactor accident.
Citation: Bouville A, Linet MS, Hatch M, Mabuchi K, Simon SL. 2014. Guidelines for exposure assessment in health risk studies following a nuclear reactor accident. Environ Health Perspect 122:1–5; http://dx.doi.org/10.1289/ehp.1307120
doi:10.1289/ehp.1307120
PMCID: PMC3888574  PMID: 24184886
10.  G×G×E for Lifespan in Drosophila: Mitochondrial, Nuclear, and Dietary Interactions that Modify Longevity 
PLoS Genetics  2014;10(5):e1004354.
Dietary restriction (DR) is the most consistent means of extending longevity in a wide range of organisms. A growing body of literature indicates that mitochondria play an important role in longevity extension by DR, but the impact of mitochondrial genotypes on the DR process have received little attention. Mitochondrial function requires proper integration of gene products from their own genomes (mtDNA) and the nuclear genome as well as the metabolic state of the cell, which is heavily influenced by diet. These three-way mitochondrial-nuclear-dietary interactions influence cellular and organismal functions that affect fitness, aging, and disease in nature. To examine these interactions in the context of longevity, we generated 18 “mito-nuclear” genotypes by placing mtDNA from strains of Drosophila melanogaster and D. simulans onto controlled nuclear backgrounds of D. melanogaster (Oregon-R, w1118, SIR2 overexpression and control) and quantified the lifespan of each mitonuclear genotype on five different sugar:yeast diets spanning a range of caloric and dietary restriction (CR and DR). Using mixed effect models to quantify main and interaction effects, we uncovered strong mitochondrial-diet, mitochondrial-nuclear, and nuclear-diet interaction effects, in addition to three-way interactions. Survival analyses demonstrate that interaction effects can be more important than individual genetic or dietary effects on longevity. Overexpression of SIR2 reduces lifespan variation among different mitochondrial genotypes and further dampens the response of lifespan to CR but not to DR, suggesting that response to these two diets involve different underlying mechanisms. Overall the results reveal that mitochondrial-nuclear genetic interactions play important roles in modulating Drosophila lifespan and these epistatic interactions are further modified by diet. More generally, these findings illustrate that gene-by-gene and gene-by-environment interactions are not simply modifiers of key factors affecting longevity, but these interactions themselves are the very factors that underlie important variation in this trait.
Author Summary
It is widely recognized that mitochondrial function plays an important role in longevity and healthy aging. Considerable attention has been focused on the extension of longevity by caloric or dietary restriction and mutations that alter this process, and these interventions commonly are associated with shifts in mitochondrial function. While the genetic bases of these effects are the focus of much interest, relatively little effort has been directed at understanding the role that mitochondrial DNA (mtDNA) polymorphisms play in the diet restriction response. This work presents a comprehensive effort to quantify the effects of mtDNA variants, nuclear genetic variants and dietary manipulations on longevity in Drosophila, with a focus on testing for the importance of the interactions among these factors. We found that mitochondrial genotypes can have significant effects on longevity and the diet restriction response but these effects are highly dependent on nuclear genetic (G) background and the specific diet environment (E). For example, a mitochondrial haplotype that shortens lifespan in one nuclear background or diet regime shows no such effect when the genetic background or diet regime is changed. Our experiments indicate that identifying individual mitochondrial, nuclear or dietary effects on longevity is unlikely to provide general results without quantifying the prevalent mitochondrial × nuclear × diet (G×G×E) interactions.
doi:10.1371/journal.pgen.1004354
PMCID: PMC4022469  PMID: 24832080
11.  Glucose metabolism determines resistance of cancer cells to bioenergetic crisis after cytochrome-c release 
How can cancer cells survive the consequences of cyt-c release? Huber et al provide a quantitative analysis of the protective role of enhanced glucose utilization in cancer cells and investigate the impact of cell-to-cell heterogeneity in mitochondrial bioenergetics.
How can cancer cells survive the consequences of cyt-c release? Huber et al provide a quantitative analysis of the protective role of enhanced glucose utilization in cancer cells and investigate the impact of cell-to-cell heterogeneity in mitochondrial bioenergetics.
We combine ordinary differential equations based computational modelling, single-cell microscopy and in biochemistry assays to provide the first integrated system study to portray the bioenergetic crisis in cell populations subsequent to cytochrome-c (cyt-c) release; a hallmark during chemotherapeutically induced cell death.We experimentally identified a cell-to-cell heterogeneity in the dynamics of the ATP synthase subsequent to cyt-c release, which the model explained by variations in (i) accessible cytochrome-c after release and (ii) the cell's glycolytic capacity.Our model predicted, and single-cell imaging confirmed, that high (increasing) glucose in media was able to sustain (repolarise) ΔΨm in HeLa cervical cancer and MCF-7 breast cancer cells, suggesting that they might recover from bioenergetic crisis upon elevation of glucose. However, no significant repolarisation was found in non-transformed human epithelial CRL-1807 cells. Therefore, this mechanism may provide cancer cells with a competitive advantage to evade cell death induced by anticancer drugs or other stress conditions when compared with non-transformed cells.
How can cells cope with a bioenergetic crisis? In particular, how can cancer cells survive the bioenergetic consequences of cyt-c release that are often induced by chemotherapeutic agents, and that lead to depolarisation of the mitochondrial membrane potential ΔΨm, result in loss of ionic homeostasis and induce cell death? Is there an inherent population heterogeneity that can lead to a non-synchronous response to above cell death stimuli, thereby aggravating treatment and contributing to clinical relapse? Do cancer cells have a competitive advantage to non-transformed cells in averting such a bioenergetic crisis after cyt-c release. We have investigated these questions in our study, which we regard as the first rigorous system study of single-cell bioenergetics subsequent to cyt-c release and one that bridges single-cell microscopy, in vitro analysis with ordinary differential equations (ODE) based modelling of bioenergetics pathways in the mitochondria and the cytosol.
Several laboratories have so far investigated cyt-c release experimentally (Slee et al, 1999; Atlante et al, 2000; Goldstein et al, 2000; Luetjens et al, 2001; Plas et al, 2001; Waterhouse et al, 2001; Ricci et al, 2003; Colell et al, 2007; Dussmann et al, 2003a, 2003b) and isolated mitochondria (Chinopoulos and Adam-Vizi, 2009; Kushnareva et al, 2002; Kushnareva et al, 2001). However, the cause and mechanistic of several key findings remain elusive and need a system level understanding of post-cyt-c release bioenergetic and its potential cross-talk to apoptosis signalling.
Ricci et al (2003) have identified that the cell death-inducing protease caspase-3, which get activated upon cyt-c release, can further impair mitochondrial function by cleaving and deactivating respiratory complexes I and II. We addressed the question of how such a mechanism could potentiate a bioenergetic crisis. To do so, we first assembled our ODE-based model by integrating approaches from metabolic modelling (Beard, 2005; Beard and Qian, 2007; Dash and Beard, 2008) and calibrated the model to literature data that describe bioenergetic state variables (mitochondrial membrane potential ΔΨm, mitochondrial transmembrane membrane ΔpH, respiration ratio between respiring and resting state mitochondria). By remodelling cyt-c release as observed experimentally and integrating it into our model as input, the single-cell model was able to correctly describe the kinetics of ΔΨm depolarisation and allowed its quantification. Moreover, it suggested that an additional complex I/II cleavage may further impair respiration and depolarise ΔΨm by approximately further 10%.
It was further reported that ATP synthase reversal, a change of direction in the ATP-producing enzyme that leads to pumping of protons from the mitochondrial matrix into the intramembrane space, can stabilise ΔΨm. By a remnant ΔΨm polarisation, cycling of Na+, Ca2+, K+, Cl− ions and protons across the mitochondrial and the plasma membranes is preserved, and ionic homeostasis can be maintained (Nicholls and Budd, 2000; Dussmann et al, 2003a; Chinopoulos and Adam-Vizi, 2009; Garedew et al, 2010). Our model confirmed that ATP synthase activity was reversed 10 min after onset of cyt-c release, predicted that ATP synthase reversal consumed ATP and that glycolysis was required and sufficient to provide the necessary ATP to sustain this reversal. Reverting back to our single-cell HeLa system, we confirmed the presence of ATP synthase reversal. However, reversal was only present in 20% of cells, 65% of cells showed no detectable reaction and even 15% maintained ATP synthase in forward direction.
To explain this cell-to-cell heterogeneity, we modelled that a cyt-c fraction remains accessible by respiratory complexes and for respiration subsequent to release, which we denoted as ‘respiration-accessible cyt-c'. Our model suggested that small variations in such levels can sufficiently explain the experimentally detected population heterogeneity in the direction and amount of ATP synthase proton flux (Figure 6AB). Variations in respiration-accessible cyt-c may arise from incomplete mitochondrial release. Such incomplete release has been associated with failure of cristae remodelling in the absence of the BH3-only family member BID or the intramitochondrial protein OPA1 (Frezza et al, 2006; Scorrano et al, 2002).
As the model identified glycolysis as necessary for sustaining ATP synthase reversal, we next investigated cells cultured in a medium that contained Na-pyruvate instead of glucose and which consequently were not able to perform glycolysis. We found that such cell populations had a significantly higher fraction of cells that maintained ATP synthase in forward mode consistent with our model predictions. The common influence of respiration-accessible cyt-c and the cell's ability to perform glycolysis is summarised in Figure 7A.
Because glycolysis was able to influence ATP synthase proton pumping, which can affect ΔΨm levels, we investigating the effect of higher glucose in single cells. Our model predicted that an increase in glucose utilisation that generates higher cytosolic ATP levels is able to stabilise and repolarise ΔΨm and after release. This mechanism is independent from ATP synthase direction. For cells that have ATP synthase in reverse mode, elevated ATP leads to increased proton efflux from the matrix, cell populations that maintain ATP synthase in forward mode achieve a similar result through a reduction of proton influx at increased ATP. In both cases, the proton gradient along the inner membrane, and therefore ΔΨm, is increased as a consequence of ATP elevation. The mechanism is depicted in Figure 7B.
We confirmed our model predictions that high glucose was able to stabilise (cells maintained in high-glucose media) and/or to repolarise (cells where glucose was added subsequent to release) ΔΨm (Figure 6). While a similar recovery was also present in MCF7 breast cancer cell lines, no significant effect of elevated glucose was found in non-transformed CRL-1807 cells. In conjunction with an impairment of caspase-dependent cell death observed in many human cancers, cancer cells may use this mechanism, and this mechanism may provide cancer cells with a competitive advantage to evade cell death induced by anticancer drugs or other stress conditions when compared with non-transformed cells.
Many anticancer drugs activate caspases via the mitochondrial apoptosis pathway. Activation of this pathway triggers a concomitant bioenergetic crisis caused by the release of cytochrome-c (cyt-c). Cancer cells are able to evade these processes by altering metabolic and caspase activation pathways. In this study, we provide the first integrated system study of mitochondrial bioenergetics and apoptosis signalling and examine the role of mitochondrial cyt-c release in these events. In accordance with single-cell experiments, our model showed that loss of cyt-c decreased mitochondrial respiration by 95% and depolarised mitochondrial membrane potential ΔΨm from −142 to −88 mV, with active caspase-3 potentiating this decrease. ATP synthase was reversed under such conditions, consuming ATP and stabilising ΔΨm. However, the direction and level of ATP synthase activity showed significant heterogeneity in individual cancer cells, which the model explained by variations in (i) accessible cyt-c after release and (ii) the cell's glycolytic capacity. Our results provide a quantitative and mechanistic explanation for the protective role of enhanced glucose utilisation for cancer cells to avert the otherwise lethal bioenergetic crisis associated with apoptosis initiation.
doi:10.1038/msb.2011.2
PMCID: PMC3094064  PMID: 21364572
apoptosis; bioenergetics; cancer; ODE; single-cell imaging
12.  Prevalence of Insomnia Among Residents of Tokyo and Osaka After the Great East Japan Earthquake: A Prospective Study 
Background
The Great East Japan Earthquake occurred on March 11, 2011. Tokyo and Osaka, which are located 375 km and 750 km, respectively, from the epicenter, experienced tremors of 5.0 lower and 3.0 seismic intensity on the Japan Meteorological Agency scale. The Great East Japan Earthquake was the fourth largest earthquake in the world and was accompanied by a radioactive leak at a nuclear power plant and a tsunami. In the aftermath of a disaster, some affected individuals presented to mental health facilities with acute stress disorder (ASD) and/or post-traumatic stress disorder (PTSD). However, few studies have addressed mental stress problems other than ASD or PTSD among the general public immediately after a disaster. Further, the effects of such a disaster on residents living at considerable distances from the most severely affected area have not been examined.
Objective
This study aimed to prospectively analyze the effect of a major earthquake on the prevalence of insomnia among residents of Tokyo and Osaka.
Methods
A prospective online questionnaire study was conducted in Tokyo and Osaka from January 20 to April 30, 2011. An Internet-based questionnaire, intended to be completed daily for a period of 101 days, was used to collect the data. All of the study participants lived in Tokyo or Osaka and were Consumers’ Co-operative Union (CO-OP) members who used an Internet-based food-ordering system. The presence or absence of insomnia was determined before and after the earthquake. These data were compared after stratification for the region and participants’ age. Multivariate analyses were conducted using logistic regression and a generalized estimating equation. This study was conducted with the assistance of the Japanese CO-OP.
Results
The prevalence of insomnia among adults and minors in Tokyo and adults in Osaka increased significantly after the earthquake. No such increase was observed among minors in Osaka. The overall adjusted odds ratios for the risk of insomnia post-earthquake versus pre-earthquake were 1.998 (95% CI 1.571–2.542) for Tokyo, 1.558 (95% CI 1.106–2.196) for Osaka, and 1.842 (95% CI,1.514–2.242) for both areas combined.
Conclusions
The prevalence of insomnia increased even in regions that were at a considerable distance from the epicenter. Both adults and minors in Tokyo, where the seismic intensity was greater, experienced stress after the earthquake. In Osaka, where the earthquake impact was milder, disturbing video images may have exacerbated insomnia among adults.
doi:10.2196/ijmr.2485
PMCID: PMC3628117  PMID: 23612152
insomnia; Web-based survey; population surveillance; disaster; nuclear accidents; earthquakes
13.  Metabolic Profiling of CSF: Evidence That Early Intervention May Impact on Disease Progression and Outcome in Schizophrenia 
PLoS Medicine  2006;3(8):e327.
Background
The identification of schizophrenia biomarkers is a crucial step towards improving current diagnosis, developing new presymptomatic treatments, identifying high-risk individuals and disease subgroups, and assessing the efficacy of preventative interventions at a rate that is not currently possible.
Methods and Findings
1H nuclear magnetic resonance spectroscopy in conjunction with computerized pattern recognition analysis were employed to investigate metabolic profiles of a total of 152 cerebrospinal fluid (CSF) samples from drug-naïve or minimally treated patients with first-onset paranoid schizophrenia (referred to as “schizophrenia” in the following text) and healthy controls. Partial least square discriminant analysis showed a highly significant separation of patients with first-onset schizophrenia away from healthy controls. Short-term treatment with antipsychotic medication resulted in a normalization of the disease signature in over half the patients, well before overt clinical improvement. No normalization was observed in patients in which treatment had not been initiated at first presentation, providing the first molecular evidence for the importance of early intervention for psychotic disorders. Furthermore, the alterations identified in drug-naïve patients could be validated in a test sample set achieving a sensitivity and specificity of 82% and 85%, respectively.
Conclusions
Our findings suggest brain-specific alterations in glucoregulatory processes in the CSF of drug-naïve patients with first-onset schizophrenia, implying that these abnormalities are intrinsic to the disease, rather than a side effect of antipsychotic medication. Short-term treatment with atypical antipsychotic medication resulted in a normalization of the CSF disease signature in half the patients well before a clinical improvement would be expected. Furthermore, our results suggest that the initiation of antipsychotic treatment during a first psychotic episode may influence treatment response and/or outcome.
Metabolic profiling of the cerebrospinal fluid shows differences between healthy controls and patients with first-onset schizophrenia. Early treatment appears to rapidly normalize the profiles in some of the patients.
Editors' Summary
Background.
Biological markers, or “biomarkers,” are combinations of molecules that are present in certain diseases. Scientists are interested in discovering new biomarkers because they could be useful for diagnosis of those diseases. The presence of such biomarkers might in some cases even precede the development of disease symptoms, which could help in early diagnosis, treatment, and maybe even prevention. Schizophrenia is a disease for which no “objective” biological test exists, and scientists are trying to find biomarkers that would help with diagnosis. The current diagnosis of schizophrenia is based on the symptoms experienced and reported by the patient, in combination with signs observed by a psychiatrist, clinical psychologist, or other clinician.
Why Was This Study Done?
This study was done to search for biomarkers for schizophrenia. The researchers studied the metabolic state of patients and healthy volunteers (controls). In other words, they focused on the small molecules present in cells, tissues, or body fluids. The metabolic state reflects what has been encoded by a person's genes and modified by environmental factors. Focusing on the metabolic state makes sense for a disease like schizophrenia, since many different genetic and environmental factors are thought to be responsible for causing it.
What Did the Researchers Do and Find?
The researchers studied the metabolic state of 82 patients with schizophrenia and 70 healthy controls by studying the levels of different molecules present in their cerebrospinal fluid (the clear body fluid that surrounds the brain and the spinal cord). Of the patients, 54 had just been diagnosed with schizophrenia (or a similar illness called brief psychotic disorder) and had not yet taken any medications to treat schizophrenia (so-called antipsychotic medication). The remaining patients were undergoing treatment with a range of antipsychotic drugs. The researchers found different levels of certain molecules in the spinal fluid of newly diagnosed patients who had never taken schizophrenia drugs compared with healthy individuals of the same ages. These molecules might therefore turn out to be useful biomarkers for schizophrenia. The differences between patients and controls suggested that the metabolism of several substances—including glucose and acetate—might be altered in the brains of patients with schizophrenia or brief psychotic disorder. The researchers also found that the levels of these molecules in some of the patients with newly diagnosed schizophrenia who were given medication became similar to the levels in the control individuals.
What Do These Findings Mean?
These results are encouraging because they suggest that studying “metabolic profiles” might lead to finding a set of biomarkers that could reliably help in early diagnosis of schizophrenia. Such biomarkers might possibly also help in monitoring patients' responses to drug treatment. However, as acknowledged by the study's authors and emphasized by Rima Kaddhurah Daouk in an accompanying Perspective, these early results need to be tested in larger studies and confirmed before their clinical relevance will be known. It will be important for such follow-up studies to involve patients with other psychiatric diseases (not just schizophrenia), to see whether the biomarkers are specific to schizophrenia or whether they indicate a broader range of psychiatric diseases.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0030327.
National Institutes of Mental Health pages on schizophrenia
The National Alliance for Research on Schizophrenia and Depression
The National Alliance for the Mentally Ill
The Schizophrenia Society of Canada
Wikipedia page on schizophrenia (note: Wikipedia is an online encyclopedia that anyone can edit)
doi:10.1371/journal.pmed.0030327
PMCID: PMC1551919  PMID: 16933966
14.  Selective Involvement of the Amygdala in Systemic Lupus Erythematosus 
PLoS Medicine  2006;3(12):e499.
Background
Antibodies specifically affect the amygdala in a mouse model of systemic lupus erythematosus (SLE). The aim of our study was to investigate whether there is also specific involvement of the amygdala in human SLE.
Methods and Findings
We analyzed a group of 37 patients with neuropsychiatric SLE (NP-SLE), 21 patients with SLE, and a group of 12 healthy control participants with diffusion weighted imaging (DWI). In addition, in a subset of eight patients, plasma was available to determine their anti-NMDAR antibody status. From the structural magnetic resonance imaging data, the amygdala and the hippocampus were segmented, as well as the white and gray matter, and the apparent diffusion coefficient (ADC) was retrieved. ADC values between controls, patients with SLE, and patients with NP-SLE were tested using analysis of variance with post-hoc Bonferroni correction. No differences were found in the gray or white matter segments. The average ADC in the amygdala of patients with NP-SLE and SLE (940 × 10−6 mm2/s; p = 0.006 and 949 × 10−6 mm2/s; p = 0.019, respectively) was lower than in healthy control participants (1152 × 10−6 mm2/s). Mann-Whitney analysis revealed that the average ADC in the amygdala of patients with anti-NMDAR antibodies (n = 4; 802 × 10−6 mm2/s) was lower (p = 0.029) than the average ADC of patients without anti-NMDAR antibodies (n = 4; 979 × 10−6 mm2/s) and also lower (p = 0.001) than in healthy control participants.
Conclusions
This is the first study to our knowledge to observe damage in the amygdala in patients with SLE. Patients with SLE with anti-NMDAR antibodies had more severe damage in the amygdala compared to SLE patients without anti-NMDAR antibodies.
Patients with SLE who also had antibodies against the NMDA receptor had more severe damage in the amygdala as compared with patients with SLE without these antibodies.
Editors' Summary
Background.
The human body is continually attacked by viruses, bacteria, fungi, and parasites, but the immune system usually prevents these pathogens from causing disease. To be effective, the immune system has to respond rapidly to foreign antigens (bits of proteins that are unique to the pathogen) but ignore self-antigens. In autoimmune diseases, this ability to discriminate between self and nonself fails for unknown reasons, and the immune system begins to destroy human tissues. In the chronic autoimmune disease systemic lupus erythematosus (SLE or lupus), the immune system attacks the skin, joints, nervous system, and many other organs. Patients with SLE make numerous “autoantibodies” (antibodies are molecules made by the immune system that recognize and attack antigens; autoantibodies attack self-antigens). These autoantibodies start the attack on the body; then other parts of the immune system join in, causing inflammation and forming deposits of immune cells, both of which damage tissues. Common symptoms of SLE include skin rashes and arthritis, but some patients develop NP-SLE, a form of SLE that includes neuropsychiatric symptoms such as amnesia, dementia, mood disorders, strokes, and seizures. There is no cure for SLE, but mild cases are controlled with ibuprofen and other non-steroidal anti-inflammatory drugs; severe cases are kept in check with corticosteroids and other powerful immunosuppressants.
Why Was This Study Done?
In most of the tissues affected by SLE, the damage done by autoantibodies and immune cells can be seen when the tissues are examined with a microscope. But there is little microscopic damage visible in the brains of patients with NP-SLE. More generally, it is unclear how or even whether the immune system affects mental functions and emotion. In this study, researchers used magnetic resonance imaging (MRI) to investigate whether there are any structural changes in the brains of patients with NP-SLE that could explain their neuropsychiatric symptoms. They have also examined whether any changes in the brain can be linked to the presence of autoantibodies that recognize a protein called the NMDA receptor (anti-NMDAR antibodies) that is present on brain cells.
What Did the Researchers Do and Find?
The researchers used an MRI technique called diffusion weighted imaging to examine the brains of several patients with NP-SLE or SLE and the brains of several healthy individuals. Using this technique, it is possible to quantify the amount of structural damage in different regions of the brain. The researchers found no differences in most areas of the brain between the two groups of patients and the healthy controls. However, there were clear signs of damage in the amygdala (the part of the brain that regulates emotions and triggers responses to danger) in the patients with SLE or NP-SLE when compared to the control individuals. The researchers also found that the damage was more severe in the patients who had anti-NMDAR autoantibodies than in those that did not have these autoantibodies.
What Do These Findings Mean?
These findings suggest that autoantibodies produced by patients with SLE specifically damage the amygdala, a discovery that helps to explain some of the neuropsychiatric symptoms of this condition. Previous work has shown that the treatment of mice with anti-NMDAR antibodies and epinephrine, a stress hormone that causes leaks in the blood-brain barrier (antibodies can't usually get into the brain because of this barrier), results in damage to the amygdala and a deficient response to dangerous stimuli. The researchers suggest that a similar series of events might happen in SLE—patients often mention that a period of major stress precedes the development of symptoms. To provide stronger evidence for such a scenario, a detailed study of how stress relates to neuropsychiatric symptoms is needed. The damage to the amygdala (and the lack of damage elsewhere in the brain) and the possible association between brain damage and anti-NMDAR antibodies seen in this small study also need to be confirmed in more patients. Nevertheless, these findings provide an intriguing glimpse into the interplay between the immune system and the brain and into how stress might lead to physical damage in the brain.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0030499.
MedlinePlus encyclopedia pages on autoimmunity and on systemic lupus erythematosus
US National Institute of Arthritis and Musculoskeletal and Skin Diseases booklet for patients with SLE
American College of Rheumatology information for patients on SLE
NHS Direct Online Health Encyclopedia pages on SLE
The Lupus Foundation of America information and support for patients with SLE
doi:10.1371/journal.pmed.0030499
PMCID: PMC1702559  PMID: 17177602
15.  Absorption of Radionuclides from the Fukushima Nuclear Accident by a Novel Algal Strain 
PLoS ONE  2012;7(9):e44200.
Large quantities of radionuclides have leaked from the Fukushima Daiichi Nuclear Power Plant into the surrounding environment. Effective prevention of health hazards resulting from radiation exposure will require the development of efficient and economical methods for decontaminating radioactive wastewater and aquatic ecosystems. Here we describe the accumulation of water-soluble radionuclides released by nuclear reactors by a novel strain of alga. The newly discovered green microalgae, Parachlorella sp. binos (Binos) has a thick alginate-containing extracellular matrix and abundant chloroplasts. When this strain was cultured with radioiodine, a light-dependent uptake of radioiodine was observed. In dark conditions, radioiodine uptake was induced by addition of hydrogen superoxide. High-resolution secondary ion mass spectrometry (SIMS) showed a localization of accumulated iodine in the cytosol. This alga also exhibited highly efficient incorporation of the radioactive isotopes strontium and cesium in a light-independent manner. SIMS analysis showed that strontium was distributed in the extracellular matrix of Binos. Finally we also showed the ability of this strain to accumulate radioactive nuclides from water and soil samples collected from a heavily contaminated area in Fukushima. Our results demonstrate that Binos could be applied to the decontamination of iodine, strontium and cesium radioisotopes, which are most commonly encountered after nuclear reactor accidents.
doi:10.1371/journal.pone.0044200
PMCID: PMC3440386  PMID: 22984475
16.  Vulnerability of populations and the urban health care systems to nuclear weapon attack – examples from four American cities 
Background
The threat posed by the use of weapons of mass destruction (WMD) within the United States has grown significantly in recent years, focusing attention on the medical and public health disaster capabilities of the nation in a large scale crisis. While the hundreds of thousands or millions of casualties resulting from a nuclear weapon would, in and of itself, overwhelm our current medical response capabilities, the response dilemma is further exacerbated in that these resources themselves would be significantly at risk. There are many limitations on the resources needed for mass casualty management, such as access to sufficient hospital beds including specialized beds for burn victims, respiration and supportive therapy, pharmaceutical intervention, and mass decontamination.
Results
The effects of 20 kiloton and 550 kiloton nuclear detonations on high priority target cities are presented for New York City, Chicago, Washington D.C. and Atlanta. Thermal, blast and radiation effects are described, and affected populations are calculated using 2000 block level census data. Weapons of 100 Kts and up are primarily incendiary or radiation weapons, able to cause burns and start fires at distances greater than they can significantly damage buildings, and to poison populations through radiation injuries well downwind in the case of surface detonations. With weapons below 100 Kts, blast effects tend to be stronger than primary thermal effects from surface bursts. From the point of view of medical casualty treatment and administrative response, there is an ominous pattern where these fatalities and casualties geographically fall in relation to the location of hospital and administrative facilities. It is demonstrated that a staggering number of the main hospitals, trauma centers, and other medical assets are likely to be in the fatality plume, rendering them essentially inoperable in a crisis.
Conclusion
Among the consequences of this outcome would be the probable loss of command-and-control, mass casualties that will have to be treated in an unorganized response by hospitals on the periphery, as well as other expected chaotic outcomes from inadequate administration in a crisis. Vigorous, creative, and accelerated training and coordination among the federal agencies tasked for WMD response, military resources, academic institutions, and local responders will be critical for large-scale WMD events involving mass casualties.
doi:10.1186/1476-072X-6-5
PMCID: PMC1828719  PMID: 17328796
17.  ON THE FORMATION OF PRECIPITATES AFTER THE INTRAVENOUS INJECTION OF SALVARSAN 
The results of these experiments are definite. There is, in the first place, a very striking difference with regard to precipitate formation between the acid and alkaline solutions of salvarsan when injected intravenously. Intravenous injections of alkaline solutions of salvarsan produce no precipitate in the blood, while injections of the acid solution nearly always give a precipitate. Furthermore, after injections of the acid solution, there is a striking difference between the blood from the right side of the heart and that from the left side. At the end of injections of an acid solution of salvarsan, a precipitate was seldom present in the arterial blood. Blood taken from the left ventricle at this time (at autopsy) also showed no precipitate in a large majority of cases; in eight experiments there was no precipitate, in three a doubtful trace of precipitate, and in one a definite small amount. On the other hand, blood obtained from the right ventricle and the lungs showed a very different condition. In ten out of twelve animals (rabbits and dogs), blood from the right ventricle contained a definite precipitate, and in a number of these cases the amount of precipitate was large. Blood squeezed from the lungs showed in eight out of ten cases at least as much precipitate as was found in the blood from the right ventricle. The results of injections of alkaline solutions of salvarsan, as pointed out before, are quite different from those produced by the acid solutions. In thirteen experiments upon dogs and rabbits, no trace of a precipitate was found in the arterial blood, the blood from the left ventricle, the right ventricle, or the lungs. There is no apparent difference in the process of precipitate formation whether salvarsan solutions and the blood are mixed in vivo or in vitro. In both mixtures the acid solutions produce a precipitate, while the alkaline solutions of salvarsan do not. These experiments have demonstrated the fact that a precipitate is present in the blood after an injection of an acid solution of salvarsan. One would expect that such a precipitate, consisting as it usually does of rather coarse particles, would, if brought to the medulla, cause immediate death by producing emboli. However, the freedom from such occurrences may be explained by the fact that the precipitate, which is abundantly present in the right ventricle, is only rarely seen in blood taken from the carotid or femoral arteries or even from the left ventricle itself. The fact itself, however, is quite difficult to interpret. It might perhaps be assumed that the precipitate is filtered out during its passage through the lung capillaries. If this is the case, we might expect intravenous injections of salvarsan to produce embolism in the pulmonary vessels with consequent fatal results. As a matter of fact, we have in the recent literature an instance which seems to point to such a result. Miessner (6) tried the effects of salvarsan in cattle which had foot and mouth disease. He used at first the acid solution, and though the dose was small, seven milligrams per kilo of body weight, all the animals (four) died in from ten hours to two days after the injection. They all showed labored respiration during or soon after the injection of salvarsan. He then decreased the dose to five milligrams per kilo of body weight, and repeated the experiments. He used also normal animals as controls upon those which had the foot and mouth disease. Both the sick and normal (control) animals showed labored respiration. One died after four days. At autopsy all organs except the lungs appeared to be normal. The lungs presented the following appearance: There were grayish yellow spots scattered irregularly over the surface. On the cut surface these were seen as grayish yellow spots the size of a pea, which appeared in groups and which sometimes filled a lobule completely. Other spots were surrounded by a small area of dark red lung parenchyma. The affected portion contained no air and felt solid. In adjacent parts the tissue seemed normal. A microscopic examination showed that the larger and smaller pulmonary arteries were filled with uniform, homogeneous, yellow masses. About the vessels there was a serous exudate. In brief, the changes seen indicated, he believed, that there was a thrombosis of the blood-vessels with inflammatory exudative changes of the lung parenchyma. Miessner states that a similar pathological condition was found in a normal control animal that died. He suggests that the acid solution of salvarsan might lead in man to a thrombosis of the pulmonary arteries. In support of this suggestion, he mentions a case reported to him by Ehrlich of a man who died following the injection of an acid solution. The lung picture in this case was somewhat similar to that which he had found in cattle. It may be mentioned in passing that Miessner found that alkaline solutions of salvarsan were far less toxic than the acid solutions. Animals (cattle) which received in an alkaline solution 400 milligrams of salvarsan per kilo of body weight did not show the least symptom of disturbance. In contrast to Miessner's results seem to stand my observations and those of Auer described in the introduction of this paper. Auer (5) found (in 8 rabbits) that no evident harmful effects followed the injections of very large doses of the acid solution, if they were given in a highly diluted form (one tenth per cent.). In my own experiments, it was found that a one fifth per cent. acid solution (3 rabbits) and even a one half per cent. solution (1 rabbit) produced no ill effects. The experiments described in this paper make it certain that the doses of the acid solution given to these last mentioned four animals must have produced a precipitate in the right ventricle and in the lungs, and yet the animals survived and showed no symptoms whatever of disturbance following the injection. This difference between our observations and those of Miessner might perhaps be explained by the assumption that the action of salvarsan in acid solution is more deleterious to cattle than to rabbits. Furthermore, Miessner seems to have injected the salvarsan in high concentrations. In one instance, in which figures are given, the drug was administered in a five per cent. solution. As mentioned before, Auer has shown the importance of the concentration. While in a one tenth per cent. solution twenty and thirty milligrams per kilo of body weight of the acid solution may be injected with impunity, even six or seven milligrams per kilo may prove rapidly fatal when injected in a one half per cent. solution. Our own results, however, leave us with two puzzling questions : First, if the acid solution of salvarsan causes such a coarse precipitate in the right ventricle and in the lungs, how does it happen that this precipitate does not bring about the death of the animal? Second, what is the real cause of the remarkable fact that this precipitate does not pass over into the arterial side of the circulation? Does the precipitate undergo a profound chemical or mechanical change while it passes through the lung capillaries? In future investigations we may try to answer these interesting questions. For the present, it is necessary to be content with the establishment of the bare facts as they are presented in the conclusions.
PMCID: PMC2124903  PMID: 19867454
18.  Collagen Cross-Linking Using Riboflavin and Ultraviolet-A for Corneal Thinning Disorders 
Executive Summary
Objective
The main objectives for this evidence-based analysis were to determine the safety and effectiveness of photochemical corneal collagen cross-linking with riboflavin (vitamin B2) and ultraviolet-A radiation, referred to as CXL, for the management of corneal thinning disease conditions. The comparative safety and effectiveness of corneal cross-linking with other minimally invasive treatments such as intrastromal corneal rings was also reviewed. The Medical Advisory Secretariat (MAS) evidence-based analysis was performed to support public financing decisions.
Subject of the Evidence-Based Analysis
The primary treatment objective for corneal cross-linking is to increase the strength of the corneal stroma, thereby stabilizing the underlying disease process. At the present time, it is the only procedure that treats the underlying disease condition. The proposed advantages for corneal cross-linking are that the procedure is minimally invasive, safe and effective, and it can potentially delay or defer the need for a corneal transplant. In addition, corneal cross-linking does not adversely affect subsequent surgical approaches, if they are necessary, or interfere with corneal transplants. The evidence for these claims for corneal cross-linking in the management of corneal thinning disorders such as keratoconus will be the focus of this review.
The specific research questions for the evidence review were as follows:
Technical: How technically demanding is corneal cross-linking and what are the operative risks?
Safety: What is known about the broader safety profile of corneal cross-linking?
Effectiveness - Corneal Surface Topographic Affects:
What are the corneal surface remodeling effects of corneal cross-linking?
Do these changes interfere with subsequent interventions, particularly corneal transplant known as penetrating keratoplasty (PKP)?
Effectiveness -Visual Acuity:
What impacts does the remodeling have on visual acuity?
Are these impacts predictable, stable, adjustable and durable?
Effectiveness - Refractive Outcomes: What impact does remodeling have on refractive outcomes?
Effectiveness - Visual Quality (Symptoms): What impact does corneal cross-linking have on vision quality such as contrast vision, and decreased visual symptoms (halos, fluctuating vision)?
Effectiveness - Contact lens tolerance: To what extent does contact lens intolerance improve after corneal cross-linking?
Vision-Related QOL: What is the impact of corneal cross-linking on functional visual rehabilitation and quality of life?
Patient satisfaction: Are patients satisfied with their vision following the procedure?
Disease Process:
What impact does corneal cross-linking have on the underling corneal thinning disease process?
Does corneal cross-linking delay or defer the need for a corneal transplant?
What is the comparative safety and effectiveness of corneal cross-linking compared with other minimally invasive treatments for corneal ectasia such as intrastromal corneal rings?
Clinical Need: Target Population and Condition
Corneal ectasia (thinning) disorders represent a range of disorders involving either primary disease conditions, such as keratoconus (KC) and pellucid marginal corneal degeneration, or secondary iatrogenic conditions, such as corneal thinning occurring after laser in situ keratomileusis (LASIK) refractive surgery.
Corneal thinning is a disease that occurs when the normally round dome-shaped cornea progressively thins causing a cone-like bulge or forward protrusion in response to the normal pressure of the eye. The thinning occurs primarily in the stroma layers and is believed to be a breakdown in the collagen process. This bulging can lead to irregular astigmatism or shape of the cornea. Because the anterior part of the cornea is responsible for most of the focusing of the light on the retina, this can then result in loss of visual acuity. The reduced visual acuity can make even simple daily tasks, such as driving, watching television or reading, difficult to perform.
Keratoconus is the most common form of corneal thinning disorder and involves a noninflammatory chronic disease process of progressive corneal thinning. Although the specific cause for the biomechanical alterations in the corneal stroma is unknown, there is a growing body of evidence suggesting that genetic factors may play an important role. Keratoconus is a rare disease (< 0.05% of the population) and is unique among chronic eye diseases because it has an early onset, with a median age of 25 years. Disease management for this condition follows a step-wise approach depending on disease severity. Contact lenses are the primary treatment of choice when there is irregular astigmatism associated with the disease. Patients are referred for corneal transplants as a last option when they can no longer tolerate contact lenses or when lenses no longer provide adequate vision.
Keratoconus is one of the leading indications for corneal transplants and has been so for the last 3 decades. Despite the high success rate of corneal transplants (up to 20 years) there are reasons to defer it as long as possible. Patients with keratoconus are generally young and a longer-term graft survival of at least 30 or 40 years may be necessary. The surgery itself involves lengthy time off work and postsurgery, while potential complications include long-term steroid use, secondary cataracts, and glaucoma. After a corneal transplant, keratoconus may recur resulting in a need for subsequent interventions. Residual refractive errors and astigmatism can remain challenges after transplantation, and high refractive surgery and regraft rates in KC patients have been reported. Visual rehabilitation or recovery of visual acuity after transplant may be slow and/or unsatisfactory to patients.
Description of Technology/Therapy
Corneal cross-linking involves the use of riboflavin (vitamin B2) and ultraviolet-A (UVA) radiation. A UVA irradiation device known as the CXL® device (license number 77989) by ACCUTECH Medical Technologies Inc. has been licensed by Health Canada as a Class II device since September 19, 2008. An illumination device that emits homogeneous UVA, in combination with any generic form of riboflavin, is licensed by Health Canada for the indication to slow or stop the progression of corneal thinning caused by progressive keratectasia, iatrogenic keratectasia after laser-assisted in situ keratomileusis (LASIK) and pellucid marginal degeneration. The same device is named the UV-X® device by IROCMedical, with approvals in Argentina, the European Union and Australia.
UVA devices all use light emitting diodes to generate UVA at a wavelength of 360-380 microns but vary in the number of diodes (5 to 25), focusing systems, working distance, beam diameter, beam uniformity and extent to which the operator can vary the parameters. In Ontario, CXL is currently offered at over 15 private eye clinics by refractive surgeons and ophthalmologists.
The treatment is an outpatient procedure generally performed with topical anesthesia. The treatment consists of several well defined procedures. The epithelial cell layer is first removed, often using a blunt spatula in a 9.0 mm diameter under sterile conditions. This step is followed by the application of topical 0.1% riboflavin (vitamin B2) solution every 3 to 5 minutes for 25 minutes to ensure that the corneal stroma is fully penetrated. A solid-state UVA light source with a wavelength of 370 nm (maximum absorption of riboflavin) and an irradiance of 3 mW/cm2 is used to irradiate the central cornea. Following treatment, a soft bandage lens is applied and prescriptions are given for oral pain medications, preservative-free tears, anti-inflammatory drops (preferably not nonsteroidal anti-inflammatory drugs, or NSAIDs) and antibiotic eye drops. Patients are recalled 1 week following the procedure to evaluate re-epithelialization and they are followed-up subsequently.
Evidence-Based Analysis Methods
A literature search was conducted on photochemical corneal collagen cross-linking with riboflavin (vitamin B2) and ultraviolet-A for the management of corneal thinning disorders using a search strategy with appropriate keywords and subject headings for CXL for literature published up until April 17, 2011. The literature search for this Health Technology Assessment (HTA) review was performed using the Cochrane Library, the Emergency Care Research Institute (ECRI) and the Centre for Reviews and Dissemination. The websites of several other health technology agencies were also reviewed, including the Canadian Agency for Drugs and Technologies in Health (CADTH) and the United Kingdom’s National Institute for Clinical Excellence (NICE). The databases searched included OVID MEDLINE, MEDLINE IN-Process and other Non-Indexed Citations such as EMBASE.
As the evidence review included an intervention for a rare condition, case series and case reports, particularly for complications and adverse events, were reviewed. A total of 316 citations were identified and all abstracts were reviewed by a single reviewer for eligibility. For those studies meeting the eligibility criteria, full-text articles were obtained. Reference lists were also examined for any additional relevant studies not identified through the search.
Inclusion Criteria
English-language reports and human studies
patients with any corneal thinning disorder
reports with CXL procedures used alone or in conjunction with other interventions
original reports with defined study methodology
reports including standardized measurements on outcome events such as technical success, safety effectiveness, durability, vision quality of life or patient satisfaction
systematic reviews, meta-analyses, randomized controlled trials, observational studies, retrospective analyses, case series, or case reports for complications and adverse events
Exclusion Criteria
nonsystematic reviews, letters, comments and editorials
reports not involving outcome events such as safety, effectiveness, durability, vision quality or patient satisfaction following an intervention with corneal implants
reports not involving corneal thinning disorders and an intervention involving CXL
Summary of Evidence Findings
In the Medical Advisory Secretariat evidence review on corneal cross-linking, 65 reports (16 case reports) involving 1403 patients were identified on the use of CXL for managing corneal thinning disorders. The reports were summarized according to their primary clinical indication, whether or not secondary interventions were used in conjunction with CXL (referred to as CXL-Plus) and whether or not it was a safety-related report.
The safety review was based on information from the cohort studies evaluating effectiveness, clinical studies evaluating safety, treatment response or recovery, and published case reports of complications. Complications, such as infection and noninfectious keratitis (inflammatory response), reported in case reports, generally occurred in the first week and were successfully treated with topical antibiotics and steroids. Other complications, such as the cytotoxic effects on the targeted corneal stroma, occurred as side effects of the photo-oxidative process generated by riboflavin and ultraviolet-A and were usually reversible.
The reports on treatment effectiveness involved 15 pre-post longitudinal cohort follow-up studies ranging from follow-up of patients’ treated eye only, follow-up in both the treated and untreated fellow-eye; and follow-up in the treated eye only and a control group not receiving treatment. One study was a 3-arm randomized control study (RCT) involving 2 comparators: one comparator was a sham treatment in which one eye was treated with riboflavin only; and the other comparator was the untreated fellow-eye. The outcomes reported across the studies involved statistically significant and clinically relevant improvements in corneal topography and refraction after CXL. In addition, improvements in treated eyes were accompanied by worsening outcomes in the untreated fellow-eyes. Improvements in corneal topography reported at 6 months were maintained at 1- and 2-year follow-up. Visual acuity, although not always improved, was infrequently reported as vision loss. Additional procedures such as the use of intrastromal corneal ring segments, intraocular lenses and refractive surgical practices were reported to result in additional improvements in topography and visual acuity after CXL.
Considerations for Ontario Health System
The total costs of providing CXL therapy to keratoconus patients in Ontario was calculated based on estimated physician, clinic, and medication costs. The total cost per patient was approximately $1,036 for the treatment of one eye, and $1,751 for the treatment of both eyes. The prevalence of keratoconus was estimated at 4,047 patients in FY2011, with an anticipated annual incidence (new cases) of about 148 cases. After distributing the costs of CXL therapy for the FY2011 prevalent keratoconus population over the next 3 years, the estimated average annual cost was approximately $2.1 million, of which about $1.3 million would be physician costs specifically.
Conclusion
Corneal cross-linking effectively stabilizes the underlying disease, and in some cases reverses disease progression as measured by key corneal topographic measures. The affects of CXL on visual acuity are less predictable and the use of adjunct interventions with CXL, such as intrastromal corneal ring segments, refractive surgery, and intraocular lens implants are increasingly employed to both stabilize disease and restore visual acuity. Although the use of adjunct interventions have been shown to result in additional clinical benefit, the order, timing, and risks of performing adjunctive interventions have not been well established.
Although there is potential for serious adverse events with corneal UVA irradiation and photochemical reactions, there have been few reported complications. Those that have occurred tended to be related to side effects of the induced photochemical reactions and were generally reversible. However, to ensure that there are minimal complications with the use of CXL and irradiation, strict adherence to defined CXL procedural protocols is essential.
Keywords
Keratoconus, corneal cross-linking, corneal topography, corneal transplant, visual acuity, refractive error.
PMCID: PMC3377552  PMID: 23074417
19.  Cross-National Analysis of the Associations among Mental Disorders and Suicidal Behavior: Findings from the WHO World Mental Health Surveys 
PLoS Medicine  2009;6(8):e1000123.
Using data from over 100,000 individuals in 21 countries participating in the WHO World Mental Health Surveys, Matthew Nock and colleagues investigate which mental health disorders increase the odds of experiencing suicidal thoughts and actual suicide attempts, and how these relationships differ across developed and developing countries.
Background
Suicide is a leading cause of death worldwide. Mental disorders are among the strongest predictors of suicide; however, little is known about which disorders are uniquely predictive of suicidal behavior, the extent to which disorders predict suicide attempts beyond their association with suicidal thoughts, and whether these associations are similar across developed and developing countries. This study was designed to test each of these questions with a focus on nonfatal suicide attempts.
Methods and Findings
Data on the lifetime presence and age-of-onset of Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) mental disorders and nonfatal suicidal behaviors were collected via structured face-to-face interviews with 108,664 respondents from 21 countries participating in the WHO World Mental Health Surveys. The results show that each lifetime disorder examined significantly predicts the subsequent first onset of suicide attempt (odds ratios [ORs] = 2.9–8.9). After controlling for comorbidity, these associations decreased substantially (ORs = 1.5–5.6) but remained significant in most cases. Overall, mental disorders were equally predictive in developed and developing countries, with a key difference being that the strongest predictors of suicide attempts in developed countries were mood disorders, whereas in developing countries impulse-control, substance use, and post-traumatic stress disorders were most predictive. Disaggregation of the associations between mental disorders and nonfatal suicide attempts showed that these associations are largely due to disorders predicting the onset of suicidal thoughts rather than predicting progression from thoughts to attempts. In the few instances where mental disorders predicted the transition from suicidal thoughts to attempts, the significant disorders are characterized by anxiety and poor impulse-control. The limitations of this study include the use of retrospective self-reports of lifetime occurrence and age-of-onset of mental disorders and suicidal behaviors, as well as the narrow focus on mental disorders as predictors of nonfatal suicidal behaviors, each of which must be addressed in future studies.
Conclusions
This study found that a wide range of mental disorders increased the odds of experiencing suicide ideation. However, after controlling for psychiatric comorbidity, only disorders characterized by anxiety and poor impulse-control predict which people with suicide ideation act on such thoughts. These findings provide a more fine-grained understanding of the associations between mental disorders and subsequent suicidal behavior than previously available and indicate that mental disorders predict suicidal behaviors similarly in both developed and developing countries. Future research is needed to delineate the mechanisms through which people come to think about suicide and subsequently progress from ideation to attempts.
Please see later in the article for Editors' Summary
Editors' Summary
Background
Suicide is a leading cause of death worldwide. Every 40 seconds, someone somewhere commits suicide. Over a year, this adds up to about 1 million self-inflicted deaths. In the USA, for example, where suicide is the 11th leading cause of death, more than 30,000 people commit suicide every year. The figures for nonfatal suicidal behavior (suicidal thoughts or ideation, suicide planning, and suicide attempts) are even more shocking. Globally, suicide attempts, for example, are estimated to be 20 times as frequent as completed suicides. Risk factors for nonfatal suicidal behaviors and for suicide include depression and other mental disorders, alcohol or drug abuse, stressful life events, a family history of suicide, and having a friend or relative commit suicide. Importantly, nonfatal suicidal behaviors are powerful predictors of subsequent suicide deaths so individuals who talk about killing themselves must always be taken seriously and given as much help as possible by friends, relatives, and mental-health professionals.
Why Was This Study Done?
Experts believe that it might be possible to find ways to decrease suicide rates by answering three questions. First, which individual mental disorders are predictive of nonfatal suicidal behaviors? Although previous studies have reported that virtually all mental disorders are associated with an increased risk of suicidal behaviors, people often have two or more mental disorders (“comorbidity”), so many of these associations may reflect the effects of only a few disorders. Second, do some mental disorders predict suicidal ideation whereas others predict who will act on these thoughts? Finally, are the associations between mental disorders and suicidal behavior similar in developed countries (where most studies have been done) and in developing countries? By answering these questions, it should be possible to improve the screening, clinical risk assessment, and treatment of suicide around the world. Thus, in this study, the researchers undertake a cross-national analysis of the associations among mental disorders (as defined by the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition [DSM-IV]) and nonfatal suicidal behaviors.
What Did the Researchers Do and Find?
The researchers collected and analyzed data on the lifetime presence and age-of-onset of mental disorders and of nonfatal suicidal behaviors in structured interviews with nearly 110,000 participants from 21 countries (part of the World Health Organization's World Mental Health Survey Initiative). The lifetime presence of each of the 16 disorders considered (mood disorders such as depression; anxiety disorders such as post-traumatic stress disorder [PTSD]; impulse-control disorders such as attention deficit/hyperactivity disorder; and substance misuse) predicted first suicide attempts in both developed and developing countries. However, the increased risk of a suicide attempt associated with each disorder varied. So, for example, in developed countries, after controlling for comorbid mental disorders, major depression increased the risk of a suicide attempt 3-fold but drug abuse/dependency increased the risk only 2-fold. Similarly, although the strongest predictors of suicide attempts in developed countries were mood disorders, in developing countries the strongest predictors were impulse-control disorders, substance misuse disorders, and PTSD. Other analyses indicate that mental disorders were generally more predictive of the onset of suicidal thoughts than of suicide plans and attempts, but that anxiety and poor impulse-control disorders were the strongest predictors of suicide attempts in both developed and developing countries.
What Do These Findings Mean?
Although this study has several limitations—for example, it relies on retrospective self-reports by study participants—its findings nevertheless provide a more detailed understanding of the associations between mental disorders and subsequent suicidal behaviors than previously available. In particular, its findings reveal that a wide range of individual mental disorders increase the chances of an individual thinking about suicide in both developed and developing countries and provide new information about the mental disorders that predict which people with suicidal ideas will act on such thoughts. However, the findings also show that only half of people who have seriously considered killing themselves have a mental disorder. Thus although future suicide prevention efforts should include a focus on screening and treating mental disorders, ways must also be found to identify the many people without mental disorders who are at risk of suicidal behaviors.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000123.
The US National Institute of Mental Health provides information about suicide in the US: statistics and prevention
The UK National Health Service provides information about suicide, including statistics about suicide in the UK and links to other resources
The World Health Organization provides global statistics about suicide and information on suicide prevention
MedlinePlus provides links to further information and advice about suicide and about mental health (in English and Spanish)
Further details about the World Mental Health Survey Initiative and about DSM-IV are available
doi:10.1371/journal.pmed.1000123
PMCID: PMC2717212  PMID: 19668361
20.  Noninvasive Positive Pressure Ventilation for Acute Respiratory Failure Patients With Chronic Obstructive Pulmonary Disease (COPD) 
Executive Summary
In July 2010, the Medical Advisory Secretariat (MAS) began work on a Chronic Obstructive Pulmonary Disease (COPD) evidentiary framework, an evidence-based review of the literature surrounding treatment strategies for patients with COPD. This project emerged from a request by the Health System Strategy Division of the Ministry of Health and Long-Term Care that MAS provide them with an evidentiary platform on the effectiveness and cost-effectiveness of COPD interventions.
After an initial review of health technology assessments and systematic reviews of COPD literature, and consultation with experts, MAS identified the following topics for analysis: vaccinations (influenza and pneumococcal), smoking cessation, multidisciplinary care, pulmonary rehabilitation, long-term oxygen therapy, noninvasive positive pressure ventilation for acute and chronic respiratory failure, hospital-at-home for acute exacerbations of COPD, and telehealth (including telemonitoring and telephone support). Evidence-based analyses were prepared for each of these topics. For each technology, an economic analysis was also completed where appropriate. In addition, a review of the qualitative literature on patient, caregiver, and provider perspectives on living and dying with COPD was conducted, as were reviews of the qualitative literature on each of the technologies included in these analyses.
The Chronic Obstructive Pulmonary Disease Mega-Analysis series is made up of the following reports, which can be publicly accessed at the MAS website at: http://www.hqontario.ca/en/mas/mas_ohtas_mn.html.
Chronic Obstructive Pulmonary Disease (COPD) Evidentiary Framework
Influenza and Pneumococcal Vaccinations for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Smoking Cessation for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Community-Based Multidisciplinary Care for Patients With Stable Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Pulmonary Rehabilitation for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Long-term Oxygen Therapy for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Noninvasive Positive Pressure Ventilation for Acute Respiratory Failure Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Noninvasive Positive Pressure Ventilation for Chronic Respiratory Failure Patients With Stable Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Hospital-at-Home Programs for Patients With Acute Exacerbations of Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Home Telehealth for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Cost-Effectiveness of Interventions for Chronic Obstructive Pulmonary Disease Using an Ontario Policy Model
Experiences of Living and Dying With COPD: A Systematic Review and Synthesis of the Qualitative Empirical Literature
For more information on the qualitative review, please contact Mita Giacomini at: http://fhs.mcmaster.ca/ceb/faculty_member_giacomini.htm.
For more information on the economic analysis, please visit the PATH website: http://www.path-hta.ca/About-Us/Contact-Us.aspx.
The Toronto Health Economics and Technology Assessment (THETA) collaborative has produced an associated report on patient preference for mechanical ventilation. For more information, please visit the THETA website: http://theta.utoronto.ca/static/contact.
Objective
The objective of this evidence-based analysis was to examine the effectiveness, safety, and cost-effectiveness of noninvasive positive pressure ventilation (NPPV) in the following patient populations: patients with acute respiratory failure (ARF) due to acute exacerbations of chronic obstructive pulmonary disease (COPD); weaning of COPD patients from invasive mechanical ventilation (IMV); and prevention of or treatment of recurrent respiratory failure in COPD patients after extubation from IMV.
Clinical Need and Target Population
Acute Hypercapnic Respiratory Failure
Respiratory failure occurs when the respiratory system cannot oxygenate the blood and/or remove carbon dioxide from the blood. It can be either acute or chronic and is classified as either hypoxemic (type I) or hypercapnic (type II) respiratory failure. Acute hypercapnic respiratory failure frequently occurs in COPD patients experiencing acute exacerbations of COPD, so this is the focus of this evidence-based analysis. Hypercapnic respiratory failure occurs due to a decrease in the drive to breathe, typically due to increased work to breathe in COPD patients.
Technology
There are several treatment options for ARF. Usual medical care (UMC) attempts to facilitate adequate oxygenation and treat the cause of the exacerbation, and typically consists of supplemental oxygen, and a variety of medications such as bronchodilators, corticosteroids, and antibiotics. The failure rate of UMC is high and has been estimated to occur in 10% to 50% of cases.
The alternative is mechanical ventilation, either invasive or noninvasive. Invasive mechanical ventilation involves sedating the patient, creating an artificial airway through endotracheal intubation, and attaching the patient to a ventilator. While this provides airway protection and direct access to drain sputum, it can lead to substantial morbidity, including tracheal injuries and ventilator-associated pneumonia (VAP).
While both positive and negative pressure noninvasive ventilation exists, noninvasive negative pressure ventilation such as the iron lung is no longer in use in Ontario. Noninvasive positive pressure ventilation provides ventilatory support through a facial or nasal mask and reduces inspiratory work. Noninvasive positive pressure ventilation can often be used intermittently for short periods of time to treat respiratory failure, which allows patients to continue to eat, drink, talk, and participate in their own treatment decisions. In addition, patients do not require sedation, airway defence mechanisms and swallowing functions are maintained, trauma to the trachea and larynx are avoided, and the risk for VAP is reduced. Common complications are damage to facial and nasal skin, higher incidence of gastric distension with aspiration risk, sleeping disorders, and conjunctivitis. In addition, NPPV does not allow direct access to the airway to drain secretions and requires patients to cooperate, and due to potential discomfort, compliance and tolerance may be low.
In addition to treating ARF, NPPV can be used to wean patients from IMV through the gradual removal of ventilation support until the patient can breathe spontaneously. Five to 30% of patients have difficultly weaning. Tapering levels of ventilatory support to wean patients from IMV can be achieved using IMV or NPPV. The use of NPPV helps to reduce the risk of VAP by shortening the time the patient is intubated.
Following extubation from IMV, ARF may recur, leading to extubation failure and the need for reintubation, which has been associated with increased risk of nosocomial pneumonia and mortality. To avoid these complications, NPPV has been proposed to help prevent ARF recurrence and/or to treat respiratory failure when it recurs, thereby preventing the need for reintubation.
Research Questions
What is the effectiveness, cost-effectiveness, and safety of NPPV for the treatment of acute hypercapnic respiratory failure due to acute exacerbations of COPD compared with
usual medical care, and
invasive mechanical ventilation?
What is the effectiveness, cost-effectiveness, and safety of NPPV compared with IMV in COPD patients after IMV for the following purposes:
weaning COPD patients from IMV,
preventing ARF in COPD patients after extubation from IMV, and
treating ARF in COPD patients after extubation from IMV?
Research Methods
Literature Search
A literature search was performed on December 3, 2010 using OVID MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, OVID EMBASE, the Cumulative Index to Nursing & Allied Health Literature (CINAHL), Wiley Cochrane, and the Centre for Reviews and Dissemination/International Agency for Health Technology Assessment (INAHTA) for studies published from January 1, 2004 until December 3, 2010. Abstracts were reviewed by a single reviewer and, for those studies meeting the eligibility criteria, full-text articles were obtained. Reference lists were also examined for any additional relevant studies not identified through the search.
Since there were numerous studies that examined the effectiveness of NPPV for the treatment of ARF due to exacerbations of COPD published before 2004, pre-2004 trials which met the inclusion/exclusion criteria for this evidence-based review were identified by hand-searching reference lists of included studies and systematic reviews.
Inclusion Criteria
English language full-reports;
health technology assessments, systematic reviews, meta-analyses, and randomized controlled trials (RCTs);
studies performed exclusively in patients with a diagnosis of COPD or studies performed with patients with a mix of conditions if results are reported for COPD patients separately;
patient population: (Question 1) patients with acute hypercapnic respiratory failure due to an exacerbation of COPD; (Question 2a) COPD patients being weaned from IMV; (Questions 2b and 2c) COPD patients who have been extubated from IMV.
Exclusion Criteria
< 18 years of age
animal studies
duplicate publications
grey literature
studies examining noninvasive negative pressure ventilation
studies comparing modes of ventilation
studies comparing patient-ventilation interfaces
studies examining outcomes not listed below, such as physiologic effects including heart rate, arterial blood gases, and blood pressure
Outcomes of Interest
mortality
intubation rates
length of stay (intensive care unit [ICU] and hospital)
health-related quality of life
breathlessness
duration of mechanical ventilation
weaning failure
complications
NPPV tolerance and compliance
Statistical Methods
When possible, results were pooled using Review Manager 5 Version 5.1, otherwise, the results were summarized descriptively. Dichotomous data were pooled into relative risks using random effects models and continuous data were pooled using weighted mean differences with a random effects model. Analyses using data from RCTs were done using intention-to-treat protocols; P values < 0.05 were considered significant. A priori subgroup analyses were planned for severity of respiratory failure, location of treatment (ICU or hospital ward), and mode of ventilation with additional subgroups as needed based on the literature. Post hoc sample size calculations were performed using STATA 10.1.
Quality of Evidence
The quality of each included study was assessed taking into consideration allocation concealment, randomization, blinding, power/sample size, withdrawals/dropouts, and intention-to-treat analyses.
The quality of the body of evidence was assessed as high, moderate, low, or very low according to the GRADE Working Group criteria. The following definitions of quality were used in grading the quality of the evidence:
Summary of Findings
NPPV for the Treatment of ARF due to Acute Exacerbations of COPD
NPPV Plus Usual Medical Care Versus Usual Medical Care Alone for First Line Treatment
A total of 1,000 participants were included in 11 RCTs1; the sample size ranged from 23 to 342. The mean age of the participants ranged from approximately 60 to 72 years of age. Based on either the Global Initiative for Chronic Obstructive Lung Disease (GOLD) COPD stage criteria or the mean percent predicted forced expiratory volume in 1 second (FEV1), 4 of the studies included people with severe COPD, and there was inadequate information to classify the remaining 7 studies by COPD severity. The severity of the respiratory failure was classified into 4 categories using the study population mean pH level as follows: mild (pH ≥ 7.35), moderate (7.30 ≤ pH < 7.35), severe (7.25 ≤ pH < 7.30), and very severe (pH < 7.25). Based on these categories, 3 studies included patients with a mild respiratory failure, 3 with moderate respiratory failure, 4 with severe respiratory failure, and 1 with very severe respiratory failure.
The studies were conducted either in the ICU (3 of 11 studies) or general or respiratory wards (8 of 11 studies) in hospitals, with patients in the NPPV group receiving bilevel positive airway pressure (BiPAP) ventilatory support, except in 2 studies, which used pressure support ventilation and volume cycled ventilation, respectively. Patients received ventilation through nasal, facial, or oronasal masks. All studies specified a protocol or schedule for NPPV delivery, but this varied substantially across the studies. For example, some studies restricted the amount of ventilation per day (e.g., 6 hours per day) and the number of days it was offered (e.g., maximum of 3 days); whereas, other studies provided patients with ventilation for as long as they could tolerate it and recommended it for much longer periods of time (e.g., 7 to 10 days). These differences are an important source of clinical heterogeneity between the studies. In addition to NPPV, all patients in the NPPV group also received UMC. Usual medical care varied between the studies, but common medications included supplemental oxygen, bronchodilators, corticosteroids, antibiotics, diuretics, and respiratory stimulators.
The individual quality of the studies ranged. Common methodological issues included lack of blinding and allocation concealment, and small sample sizes.
Need for Endotracheal Intubation
Eleven studies reported the need for endotracheal intubation as an outcome. The pooled results showed a significant reduction in the need for endotracheal intubation in the NPPV plus UMC group compared with the UMC alone group (relative risk [RR], 0.38; 95% confidence interval [CI], 0.28−0.50). When subgrouped by severity of respiratory failure, the results remained significant for the mild, severe, and very severe respiratory failure groups.
GRADE: moderate
Inhospital Mortality
Nine studies reported inhospital mortality as an outcome. The pooled results showed a significant reduction in inhospital mortality in the NPPV plus UMC group compared with the UMC group (RR, 0.53; 95% CI, 0.35−0.81). When subgrouped by severity of respiratory failure, the results remained significant for the moderate and severe respiratory failure groups.
GRADE: moderate
Hospital Length of Stay
Eleven studies reported hospital length of stay (LOS) as an outcome. The pooled results showed a significant decrease in the mean length of stay for the NPPV plus UMC group compared with the UMC alone group (weighted mean difference [WMD], −2.68 days; 95% CI, −4.41 to −0.94 days). When subgrouped by severity of respiratory failure, the results remained significant for the mild, severe, and very severe respiratory failure groups.
GRADE: moderate
Complications
Five studies reported complications. Common complications in the NPPV plus UMC group included pneumonia, gastrointestinal disorders or bleeds, skin abrasions, eye irritation, gastric insufflation, and sepsis. Similar complications were observed in the UMC group including pneumonia, sepsis, gastrointestinal disorders or bleeds, pneumothorax, and complicated endotracheal intubations. Many of the more serious complications in both groups occurred in those patients who required endotracheal intubation. Three of the studies compared complications in the NPPV plus UMC and UMC groups. While the data could not be pooled, overall, the NPPV plus UMC group experienced fewer complications than the UMC group.
GRADE: low
Tolerance/Compliance
Eight studies reported patient tolerance or compliance with NPPV as an outcome. NPPV intolerance ranged from 5% to 29%. NPPV tolerance was generally higher for patients with more severe respiratory failure. Compliance with the NPPV protocol was reported by 2 studies, which showed compliance decreases over time, even over short periods such as 3 days.
NPPV Versus IMV for the Treatment of Patients Who Failed Usual Medical Care
A total of 205 participants were included in 2 studies; the sample sizes of these studies were 49 and 156. The mean age of the patients was 71 to 73 years of age in 1 study, and the median age was 54 to 58 years of age in the second study. Based on either the GOLD COPD stage criteria or the mean percent predicted FEV1, patients in 1 study had very severe COPD. The COPD severity could not be classified in the second study. Both studies had study populations with a mean pH less than 7.23, which was classified as very severe respiratory failure in this analysis. One study enrolled patients with ARF due to acute exacerbations of COPD who had failed medical therapy. The patient population was not clearly defined in the second study, and it was not clear whether they had to have failed medical therapy before entry into the study.
Both studies were conducted in the ICU. Patients in the NPPV group received BiPAP ventilatory support through nasal or full facial masks. Patients in the IMV group received pressure support ventilation.
Common methodological issues included small sample size, lack of blinding, and unclear methods of randomization and allocation concealment. Due to the uncertainty about whether both studies included the same patient population and substantial differences in the direction and significance of the results, the results of the studies were not pooled.
Mortality
Both studies reported ICU mortality. Neither study showed a significant difference in ICU mortality between the NPPV and IMV groups, but 1 study showed a higher mortality rate in the NPPV group (21.7% vs. 11.5%) while the other study showed a lower mortality rate in the NPPV group (5.1% vs. 6.4%). One study reported 1-year mortality and showed a nonsignificant reduction in mortality in the NPPV group compared with the IMV group (26.1% vs. 46.1%).
GRADE: low to very low
Intensive Care Unit Length of Stay
Both studies reported LOS in the ICU. The results were inconsistent. One study showed a statistically significant shorter LOS in the NPPV group compared with the IMV group (5 ± 1.35 days vs. 9.29 ± 3 days; P < 0.001); whereas, the other study showed a nonsignificantly longer LOS in the NPPV group compared with the IMV group (22 ± 19 days vs. 21 ± 20 days; P = 0.86).
GRADE: very low
Duration of Mechanical Ventilation
Both studies reported the duration of mechanical ventilation (including both invasive and noninvasive ventilation). The results were inconsistent. One study showed a statistically significant shorter duration of mechanical ventilation in the NPPV group compared with the IMV group (3.92 ± 1.08 days vs. 7.17 ± 2.22 days; P < 0.001); whereas, the other study showed a nonsignificantly longer duration of mechanical ventilation in the NPPV group compared with the IMV group (16 ± 19 days vs. 15 ± 21 days; P = 0.86). GRADE: very low
Complications
Both studies reported ventilator-associated pneumonia and tracheotomies. Both showed a reduction in ventilator-associated pneumonia in the NPPV group compared with the IMV group, but the results were only significant in 1 study (13% vs. 34.6%, P = 0.07; and 6.4% vs. 37.2%, P < 0.001, respectively). Similarly, both studies showed a reduction in tracheotomies in the NPPV group compared with the IMV group, but the results were only significant in 1 study (13% vs. 23.1%, P = 0.29; and 6.4% vs. 34.6%; P < 0.001).
GRADE: very low
Other Outcomes
One of the studies followed patients for 12 months. At the end of follow-up, patients in the NPPV group had a significantly lower rate of needing de novo oxygen supplementation at home. In addition, the IMV group experienced significant increases in functional limitations due to COPD, while no increase was seen in the NPPV group. Finally, no significant differences were observed for hospital readmissions, ICU readmissions, and patients with an open tracheotomy, between the NPPV and IMV groups.
NPPV for Weaning COPD Patients From IMV
A total of 80 participants were included in the 2 RCTs; the sample sizes of the studies were 30 and 50 patients. The mean age of the participants ranged from 58 to 69 years of age. Based on either the GOLD COPD stage criteria or the mean percent predicted FEV1, both studies included patients with very severe COPD. Both studies also included patients with very severe respiratory failure (mean pH of the study populations was less than 7.23). Chronic obstructive pulmonary disease patients receiving IMV were enrolled in the study if they failed a T-piece weaning trial (spontaneous breathing test), so they could not be directly extubated from IMV.
Both studies were conducted in the ICU. Patients in the NPPV group received weaning using either BiPAP or pressure support ventilation NPPV through a face mask, and patients in the IMV weaning group received pressure support ventilation. In both cases, weaning was achieved by tapering the ventilation level.
The individual quality of the studies ranged. Common methodological problems included unclear randomization methods and allocation concealment, lack of blinding, and small sample size.
Mortality
Both studies reported mortality as an outcome. The pooled results showed a significant reduction in ICU mortality in the NPPV group compared with the IMV group (RR, 0.47; 95% CI, 0.23−0.97; P = 0.04).
GRADE: moderate
Intensive Care Unit Length of Stay
Both studies reported ICU LOS as an outcome. The pooled results showed a nonsignificant reduction in ICU LOS in the NPPV group compared with the IMV group (WMD, −5.21 days; 95% CI, −11.60 to 1.18 days).
GRADE: low
Duration of Mechanical Ventilation
Both studies reported duration of mechanical ventilation (including both invasive and noninvasive ventilation) as an outcome. The pooled results showed a nonsignificant reduction in duration of mechanical ventilation (WMD, −3.55 days; 95% CI, −8.55 to 1.44 days).
GRADE: low
Nosocomial Pneumonia
Both studies reported nosocominal pneumonia as an outcome. The pooled results showed a significant reduction in nosocomial pneumonia in the NPPV group compared with the IMV group (RR, 0.14; 95% CI, 0.03−0.71; P = 0.02).
GRADE: moderate
Weaning Failure
One study reported a significant reduction in weaning failure in the NPPV group compared with the IMV group, but the results were not reported in the publication. In this study, 1 of 25 patients in the NPPV group and 2 of 25 patients in the IMV group could not be weaned after 60 days in the ICU.
NPPV After Extubation of COPD Patients From IMV
The literature was reviewed to identify studies examining the effectiveness of NPPV compared with UMC in preventing recurrence of ARF after extubation from IMV or treating acute ARF which has recurred after extubation from IMV. No studies that included only COPD patients or reported results for COPD patients separately were identified for the prevention of ARF postextubation.
One study was identified for the treatment of ARF in COPD patients that recurred within 48 hours of extubation from IMV. This study included 221 patients, of whom 23 had COPD. A post hoc subgroup analysis was conducted examining the rate of reintubation in the COPD patients only. A nonsignificant reduction in the rate of reintubation was observed in the NPPV group compared with the UMC group (7 of 14 patients vs. 6 of 9 patients, P = 0.67). GRADE: low
Conclusions
NPPV Plus UMC Versus UMC Alone for First Line Treatment of ARF due to Acute Exacerbations of COPD
Moderate quality of evidence showed that compared with UMC, NPPV plus UMC significantly reduced the need for endotracheal intubation, inhospital mortality, and the mean length of hospital stay.
Low quality of evidence showed a lower rate of complications in the NPPV plus UMC group compared with the UMC group.
NPPV Versus IMV for the Treatment of ARF in Patients Who Have Failed UMC
Due to inconsistent and low to very low quality of evidence, there was insufficient evidence to draw conclusions on the comparison of NPPV versus IMV for patients who failed UMC.
NPPV for Weaning COPD Patients From IMV
Moderate quality of evidence showed that weaning COPD patients from IMV using NPPV results in significant reductions in mortality, nosocomial pneumonia, and weaning failure compared with weaning with IMV.
Low quality of evidence showed a nonsignificant reduction in the mean LOS and mean duration of mechanical ventilation in the NPPV group compared with the IMV group.
NPPV for the Treatment of ARF in COPD Patients After Extubation From IMV
Low quality of evidence showed a nonsignificant reduction in the rate of reintubation in the NPPV group compared with the UMC group; however, there was inadequate evidence to draw conclusions on the effectiveness of NPPV for the treatment of ARF in COPD patients after extubation from IMV
PMCID: PMC3384377  PMID: 23074436
21.  Neuroimaging for the Evaluation of Chronic Headaches 
Executive Summary
Objective
The objectives of this evidence based review are:
i) To determine the effectiveness of computed tomography (CT) and magnetic resonance imaging (MRI) scans in the evaluation of persons with a chronic headache and a normal neurological examination.
ii) To determine the comparative effectiveness of CT and MRI scans for detecting significant intracranial abnormalities in persons with chronic headache and a normal neurological exam.
iii) To determine the budget impact of CT and MRI scans for persons with a chronic headache and a normal neurological exam.
Clinical Need: Condition and Target Population
Headaches disorders are generally classified as either primary or secondary with further sub-classifications into specific headache types. Primary headaches are those not caused by a disease or medical condition and include i) tension-type headache, ii) migraine, iii) cluster headache and, iv) other primary headaches, such as hemicrania continua and new daily persistent headache. Secondary headaches include those headaches caused by an underlying medical condition. While primary headaches disorders are far more frequent than secondary headache disorders, there is an urge to carry out neuroimaging studies (CT and/or MRI scans) out of fear of missing uncommon secondary causes and often to relieve patient anxiety.
Tension type headaches are the most common primary headache disorder and migraines are the most common severe primary headache disorder. Cluster headaches are a type of trigeminal autonomic cephalalgia and are less common than migraines and tension type headaches. Chronic headaches are defined as headaches present for at least 3 months and lasting greater than or equal to 15 days per month. The International Classification of Headache Disorders states that for most secondary headaches the characteristics of the headache are poorly described in the literature and for those headache disorders where it is well described there are few diagnostically important features.
The global prevalence of headache in general in the adult population is estimated at 46%, for tension-type headache it is 42% and 11% for migraine headache. The estimated prevalence of cluster headaches is 0.1% or 1 in 1000 persons. The prevalence of chronic daily headache is estimated at 3%.
Neuroimaging
Computed Tomography
Computed tomography (CT) is a medical imaging technique used to aid diagnosis and to guide interventional and therapeutic procedures. It allows rapid acquisition of high-resolution three-dimensional images, providing radiologists and other physicians with cross-sectional views of a person’s anatomy. CT scanning poses risk of radiation exposure. The radiation exposure from a conventional CT scanner may emit effective doses of 2-4mSv for a typical head CT.
Magnetic Resonance Imaging
Magnetic resonance imaging (MRI) is a medical imaging technique used to aid diagnosis but unlike CT it does not use ionizing radiation. Instead, it uses a strong magnetic field to image a person’s anatomy. Compared to CT, MRI can provide increased contrast between the soft tissues of the body. Because of the persistent magnetic field, extra care is required in the magnetic resonance environment to ensure that injury or harm does not come to any personnel while in the environment.
Research Questions
What is the effectiveness of CT and MRI scanning in the evaluation of persons with a chronic headache and a normal neurological examination?
What is the comparative effectiveness of CT and MRI scanning for detecting significant intracranial abnormality in persons with chronic headache and a normal neurological exam?
What is the budget impact of CT and MRI scans for persons with a chronic headache and a normal neurological exam.
Research Methods
Literature Search
Search Strategy
A literature search was performed on February 18, 2010 using OVID MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, EMBASE, the Cumulative Index to Nursing & Allied Health Literature (CINAHL), the Cochrane Library, and the International Agency for Health Technology Assessment (INAHTA) for studies published from January, 2005 to February, 2010. Abstracts were reviewed by a single reviewer and, for those studies meeting the eligibility criteria full-text articles were obtained. Reference lists were also examined for any additional relevant studies not identified through the search. Articles with an unknown eligibility were reviewed with a second clinical epidemiologist and then a group of epidemiologists until consensus was established.
Inclusion Criteria
Systematic reviews, randomized controlled trials, observational studies
Outpatient adult population with chronic headache and normal neurological exam
Studies reporting likelihood ratio of clinical variables for a significant intracranial abnormality
English language studies
2005-present
Exclusion Criteria
Studies which report outcomes for persons with seizures, focal symptoms, recent/new onset headache, change in presentation, thunderclap headache, and headache due to trauma
Persons with abnormal neurological examination
Case reports
Outcomes of Interest
Primary Outcome
Probability for intracranial abnormality
Secondary Outcome
Patient relief from anxiety
System service use
System costs
Detection rates for significant abnormalities in MRI and CT scans
Summary of Findings
Effectiveness
One systematic review, 1 small RCT, and 1 observational study met the inclusion and exclusion criteria. The systematic review completed by Detsky, et al. reported the likelihood ratios of specific clinical variables to predict significant intracranial abnormalities. The RCT completed by Howard et al., evaluated whether neuroimaging persons with chronic headache increased or reduced patient anxiety. The prospective observational study by Sempere et al., provided evidence for the pre-test probability of intracranial abnormalities in persons with chronic headache as well as minimal data on the comparative effectiveness of CT and MRI to detect intracranial abnormalities.
Outcome 1: Pre-test Probability.
The pre-test probability is usually related to the prevalence of the disease and can be adjusted depending on the characteristics of the population. The study by Sempere et al. determined the pre-test probability (prevalence) of significant intracranial abnormalities in persons with chronic headaches defined as headache experienced for at least a 4 week duration with a normal neurological exam. There is a pre-test probability of 0.9% (95% CI 0.5, 1.4) in persons with chronic headache and normal neurological exam. The highest pre-test probability of 5 found in persons with cluster headaches. The second highest, that of 3.7, was reported in persons with indeterminate type headache. There was a 0.75% rate of incidental findings.
Likelihood ratios for detecting a significant abnormality
Clinical findings from the history and physical may be used as screening test to predict abnormalities on neuroimaging. The extent to which the clinical variable may be a good predictive variable can be captured by reporting its likelihood ratio. The likelihood ratio provides an estimate of how much a test result will change the odds of having a disease or condition. The positive likelihood ratio (LR+) tells you how much the odds of having the disease increases when a test is positive. The negative likelihood ratio (LR-) tells you how much the odds of having the disease decreases when the test is negative.
Detsky et al., determined the likelihood ratio for specific clinical variable from 11 studies. There were 4 clinical variables with both statistically significant positive and negative likelihood ratios. These included: abnormal neurological exam (LR+ 5.3, LR- 0.72), undefined headache (LR+ 3.8, LR- 0.66), headache aggravated by exertion or valsalva (LR+ 2.3, LR- 0.70), and headache with vomiting (LR+ 1.8, and LR- 0.47). There were two clinical variables with a statistically significant positive likelihood ratio and non significant negative likelihood ratio. These included: cluster-type headache (LR+ 11, LR- 0.95), and headache with aura (LR+ 12.9, LR- 0.52). Finally, there were 8 clinical variables with both statistically non significant positive and negative likelihood ratios. These included: headache with focal symptoms, new onset headache, quick onset headache, worsening headache, male gender, headache with nausea, increased headache severity, and migraine type headache.
Outcome 2: Relief from Anxiety
Howard et al. completed an RCT of 150 persons to determine if neuroimaging for headaches was anxiolytic or anxiogenic. Persons were randomized to receiving either an MRI scan or no scan for investigation of their headache. The study population was stratified into those persons with a Hospital Anxiety and Depression scale (HADS) > 11 (the high anxiety and depression group) and those < 11 (the low anxiety and depression) so that there were 4 groups:
Group 1: High anxiety and depression, no scan group
Group 2: High anxiety and depression, scan group
Group 3: Low anxiety and depression, no scan group
Group 4: Low anxiety and depression, scan group
Anxiety
There was no evidence for any overall reduction in anxiety at 1 year as measured by a visual analogue scale of ‘level of worry’ when analysed by whether the person received a scan or not. Similarly, there was no interaction between anxiety and depression status and whether a scan was offered or not on patient anxiety. Anxiety did not decrease at 1 year to any statistically significant degree in the high anxiety and depression group (HADS positive) compared with the low anxiety and depression group (HADS negative).
There are serious methodological limitations in this study design which may have contributed to these negative results. First, when considering the comparison of ‘scan’ vs. ‘no scan’ groups, 12 people (16%) in the ‘no scan group’ actually received a scan within the follow up year. If indeed scanning does reduce anxiety then this contamination of the ‘no scan’ group may have reduced the effect between the groups results resulting in a non significant difference in anxiety scores between the ‘scanned’ and the ‘no scan’ group. Second, there was an inadequate sample size at 1 year follow up in each of the 4 groups which may have contributed to a Type II statistical error (missing a difference when one may exist) when comparing scan vs. no scan by anxiety and depression status. Therefore, based on the results and study limitations it is inconclusive as to whether scanning reduces anxiety.
Outcome 3: System Services
Howard et al., considered services used and system costs a secondary outcome. These were determined by examining primary care case notes at 1 year for consultation rates, symptoms, further investigations, and contact with secondary and tertiary care.
System Services
The authors report that the use of neurologist and psychiatrist services was significantly higher for those persons not offered as scan, regardless of their anxiety and depression status (P<0.001 for neurologist, and P=0.033 for psychiatrist)
Outcome 4: System Costs
System Costs
There was evidence of statistically significantly lower system costs if persons with high levels of anxiety and depression (Hospital Anxiety and Depression Scale score >11) were provided with a scan (P=0.03 including inpatient costs, and 0.047 excluding inpatient costs).
Comparative Effectiveness of CT and MRI Scans
One study reported the detection rate for significant intracranial abnormalities using CT and MRI. In a cohort of 1876 persons with a non acute headache defined as any type of headache that had begun at least 4 weeks before enrolment Sempere et al. reported that the detection rate was 19/1432 (1.3%) using CT and 4/444 (0.9%) using MRI. Of 119 normal CT scans 2 (1.7%) had significant intracranial abnormality on MRI. The 2 cases were a small meningioma, and an acoustic neurinoma.
Summary
The evidence presented can be summarized as follows:
Pre-test Probability
Based on the results by Sempere et al., there is a low pre-test probability for intracranial abnormalities in persons with chronic headaches and a normal neurological exam (defined as headaches experiences for a minimum of 4 weeks). The Grade quality of evidence supporting this outcome is very low.
Likelihood Ratios
Based on the systematic review by Detsky et al., there is a statistically significant positive and negative likelihood ratio for the following clinical variables: abnormal neurological exam, undefined headache, headache aggravated by exertion or valsalva, headache with vomiting. Grade quality of evidence supporting this outcome is very low.
Based on the systematic review by Detsky et al. there is a statistically significant positive likelihood ratio but non statistically significant negative likelihood ratio for the following clinical variables: cluster headache and headache with aura. The Grade quality of evidence supporting this outcome is very low.
Based on the systematic review by Detsky et al., there is a non significant positive and negative likelihood ratio for the following clinical variables: headache with focal symptoms, new onset headache, quick onset headache, worsening headache, male gender, headache with nausea, increased headache severity, migraine type headache. The Grade quality of evidence supporting this outcome is very low.
Relief from Anxiety
Based on the RCT by Howard et al., it is inconclusive whether neuroimaging scans in persons with a chronic headache are anxiolytic. The Grade quality of evidence supporting this outcome is low.
System Services
Based on the RCT by Howard et al. scanning persons with chronic headache regardless of their anxiety and/or depression level reduces service use. The Grade quality of evidence is low.
System Costs
Based on the RCT by Howard et al., scanning persons with a score greater than 11 on the High Anxiety and Depression Scale reduces system costs. The Grade quality of evidence is moderate.
Comparative Effectiveness of CT and MRI Scans
There is sparse evidence to determine the relative effectiveness of CT compared with MRI scanning for the detection of intracranial abnormalities. The Grade quality of evidence supporting this is very low.
Economic Analysis
Ontario Perspective
Volumes for neuroimaging of the head i.e. CT and MRI scans, from the Ontario Health Insurance Plan (OHIP) data set were used to investigate trends in the province for Fiscal Years (FY) 2004-2009.
Assumptions were made in order to investigate neuroimaging of the head for the indication of headache. From the literature, 27% of all CT and 13% of all MRI scans for the head were assumed to include an indication of headache. From that same retrospective chart review and personal communication with the author 16% of CT scans and 4% of MRI scans for the head were for the sole indication of headache. From the Ministry of Health and Long-Term Care (MOHLTC) wait times data, 73% of all CT and 93% of all MRI scans in the province, irrespective of indication were outpatient procedures.
The expenditure for each FY reflects the volume for that year and since volumes have increased in the past 6 FYs, the expenditure has also increased with a pay-out reaching 3.0M and 2.8M for CT and MRI services of the head respectively for the indication of headache and a pay-out reaching 1.8M and 0.9M for CT and MRI services of the head respectively for the indication of headache only in FY 08/09.
Cost per Abnormal Finding
The yield of abnormal finding for a CT and MRI scan of the head for the indication of headache only is 2% and 5% respectively. Based on these yield a high-level estimate of the cost per abnormal finding with neuroimaging of the head for headache only can be calculated for each FY. In FY 08/09 there were 37,434 CT and 16,197 MRI scans of the head for headache only. These volumes would generate a yield of abnormal finding of 749 and 910 with a CT scan and MRI scan respectively. The expenditure for FY 08/09 was 1.8M and 0.9M for CT and MRI services respectively. Therefore the cost per abnormal finding would be $2,409 for CT and $957 for MRI. These cost per abnormal finding estimates were limited because they did not factor in comparators or the consequences associated with an abnormal reading or FNs. The estimates only consider the cost of the neuroimaging procedure and the yield of abnormal finding with the respective procedure.
PMCID: PMC3377587  PMID: 23074404
22.  Noninvasive Positive Pressure Ventilation for Chronic Respiratory Failure Patients With Stable Chronic Obstructive Pulmonary Disease (COPD) 
Executive Summary
In July 2010, the Medical Advisory Secretariat (MAS) began work on a Chronic Obstructive Pulmonary Disease (COPD) evidentiary framework, an evidence-based review of the literature surrounding treatment strategies for patients with COPD. This project emerged from a request by the Health System Strategy Division of the Ministry of Health and Long-Term Care that MAS provide them with an evidentiary platform on the effectiveness and cost-effectiveness of COPD interventions.
After an initial review of health technology assessments and systematic reviews of COPD literature, and consultation with experts, MAS identified the following topics for analysis: vaccinations (influenza and pneumococcal), smoking cessation, multidisciplinary care, pulmonary rehabilitation, long-term oxygen therapy, noninvasive positive pressure ventilation for acute and chronic respiratory failure, hospital-at-home for acute exacerbations of COPD, and telehealth (including telemonitoring and telephone support). Evidence-based analyses were prepared for each of these topics. For each technology, an economic analysis was also completed where appropriate. In addition, a review of the qualitative literature on patient, caregiver, and provider perspectives on living and dying with COPD was conducted, as were reviews of the qualitative literature on each of the technologies included in these analyses.
The Chronic Obstructive Pulmonary Disease Mega-Analysis series is made up of the following reports, which can be publicly accessed at the MAS website at: http://www.hqontario.ca/en/mas/mas_ohtas_mn.html.
Chronic Obstructive Pulmonary Disease (COPD) Evidentiary Framework
Influenza and Pneumococcal Vaccinations for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Smoking Cessation for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Community-Based Multidisciplinary Care for Patients With Stable Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Pulmonary Rehabilitation for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Long-term Oxygen Therapy for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Noninvasive Positive Pressure Ventilation for Acute Respiratory Failure Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Noninvasive Positive Pressure Ventilation for Chronic Respiratory Failure Patients With Stable Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Hospital-at-Home Programs for Patients With Acute Exacerbations of Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Home Telehealth for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Cost-Effectiveness of Interventions for Chronic Obstructive Pulmonary Disease Using an Ontario Policy Model
Experiences of Living and Dying With COPD: A Systematic Review and Synthesis of the Qualitative Empirical Literature
For more information on the qualitative review, please contact Mita Giacomini at: http://fhs.mcmaster.ca/ceb/faculty_member_giacomini.htm.
For more information on the economic analysis, please visit the PATH website: http://www.path-hta.ca/About-Us/Contact-Us.aspx.
The Toronto Health Economics and Technology Assessment (THETA) collaborative has produced an associated report on patient preference for mechanical ventilation. For more information, please visit the THETA website: http://theta.utoronto.ca/static/contact.
Objective
The objective of this health technology assessment was to determine the effectiveness and cost-effectiveness of noninvasive ventilation for stable chronic obstructive pulmonary disease (COPD).
Clinical Need: Condition and Target Population
Noninvasive ventilation is used for COPD patients with chronic respiratory failure. Chronic respiratory failure in COPD patients may be due to the inability of the pulmonary system to coordinate ventilation, leading to adverse arterial levels of oxygen and carbon dioxide. Noninvasive ventilation in stable COPD patients has the potential to improve quality of life, prolong survival, and improve gas exchange and sleep quality in patients who are symptomatic after optimal therapy, have hypercapnia or nocturnal hypoventilation and mild hypercapnia, and are frequently hospitalized.
Technology
Noninvasive positive pressure ventilation (NPPV) is any form of positive ventilatory support without the use of an endotracheal tube. For stable COPD, the standard of care when using noninvasive ventilation is bilevel positive airway pressure (BiPAP). Bilevel positive airway pressure involves both inspiratory and expiratory pressure, high during inspiration and lower during expiration. It acts as a pressure support to accentuate a patient’s inspiratory efforts. The gradient between pressures maintains alveolar ventilation and helps to reduce carbon dioxide levels. Outpatients typically use BiPAP at night. Additional advantages of using BiPAP include resting of respiratory muscles, decreased work of breathing, and control of obstructive hypopnea.
Research Question
What is the effectiveness and cost-effectiveness of noninvasive ventilation, compared with no ventilation while receiving usual care, for stable COPD patients?
Research Methods
Literature Search
Search Strategy
A literature search was performed on December 3, 2010, using OVID MEDLINE, OVID MEDLINE In-Process and Other Non-Indexed Citations, OVID EMBASE, EBSCO Cumulative Index to Nursing & Allied Health Literature (CINAHL), the Wiley Cochrane Library, and the Centre for Reviews and Dissemination database for studies published from January 1, 2004 to December 3, 2010. Abstracts were reviewed by a single reviewer and, for those studies meeting the eligibility criteria, full-text articles were obtained. Reference lists were also examined for any additional relevant studies not identified through the search. When the reviewer was unsure of the eligibility of articles, a second clinical epidemiologist and then a group of epidemiologists reviewed these until consensus was reached.
Inclusion Criteria
full-text English language articles,
studies published between January 1, 2004 and December 3, 2010,
journal articles that report on the effectiveness or cost-effectiveness of noninvasive ventilation,
clearly described study design and methods, and
health technology assessments, systematic reviews, meta-analyses, randomized controlled trials (RCTs).
Exclusion Criteria
non-English papers
animal or in vitro studies
case reports, case series, or case-case studies
cross-over RCTs
studies on noninvasive negative pressure ventilation (e.g., iron lung)
studies that combine ventilation therapy with other regimens (e.g., daytime NPPV plus exercise or pulmonary rehabilitation)
studies on heliox with NPPV
studies on pulmonary rehabilitation with NPPV
Outcomes of Interest
mortality/survival
hospitalizations/readmissions
length of stay in hospital
forced expiratory volume
arterial partial pressure of oxygen
arterial partial pressure of carbon dioxide
dyspnea
exercise tolerance
health-related quality of life
Note: arterial pressure of oxygen and carbon dioxide are surrogate outcomes.
Statistical Methods
A meta-analysis and an analysis of individual studies were performed using Review Manager Version 5. For continuous data, a mean difference was calculated, and for dichotomous data, a relative risk ratio was calculated for RCTs. For continuous variables with mean baseline and mean follow-up data, a change value was calculated as the difference between the 2 mean values.
Quality of Evidence
The quality of each included study was assessed taking into consideration allocation concealment, randomization, blinding, power/sample size, withdrawals/dropouts, and intention-to-treat analyses.
The quality of the body of evidence was assessed as high, moderate, low, or very low according to the GRADE Working Group criteria. The following definitions of quality were used in grading the quality of the evidence:
Summary of Findings
Conclusions
The following conclusions refer to stable, severe COPD patients receiving usual care.
Short-Term Studies
Based on low quality of evidence, there is a beneficial effect of NPPV compared with no ventilation on oxygen gas exchange, carbon dioxide gas exchange, and exercise tolerance measured using the 6 Minute Walking Test.
Based on very low quality of evidence, there is no effect of NPPV therapy on lung function measured as forced expiratory volume in 1 second (Type II error not excluded).
Long-Term Studies
Based on moderate quality of evidence, there is no effect of NPPV therapy for the outcomes of mortality, lung function measured as forced expiratory volume in 1 second, and exercise tolerance measured using the 6 Minute Walking Test.
Based on low quality of evidence, there is no effect of NPPV therapy for the outcomes of oxygen gas exchange and carbon dioxide gas exchange (Type II error not excluded).
Qualitative Assessment
Based on low quality of evidence, there is a beneficial effect of NPPV compared with no ventilation for dyspnea based on reduced Borg score or Medical Research Council dyspnea score.
Based on moderate quality of evidence, there is no effect of NPPV therapy for hospitalizations.
Health-related quality of life could not be evaluated.
PMCID: PMC3384378  PMID: 23074437
23.  Assessing Potential Radiological Harm to Fukushima Recovery Workers 
Dose-Response  2011;9(3):301-312.
A radiological emergency exists at the Fukushima Daiichi (Fukushima I) nuclear power plant in Japan as a result of the March 11, 2011 magnitude 9.0 earthquake and the massive tsunami that arrived later. News media misinformation related to the emergency triggered enormous social fear worldwide of the radioactivity that is being released from damaged fuel rods. The heroic recovery workers are a major concern because they are being exposed to mostly gamma radiation during their work shifts and life-threatening damage to the radiosensitive bone marrow could occur over time. This paper presents a way in which the bone marrow equivalent dose (in millisieverts), as estimated per work shift, could be used along with the hazard function model previously developed for radiological risk assessment to repeatedly check for potential life-threatening harm (hematopoietic system damage) to workers. Three categories of radiation hazard indication are proposed: 1, life-threatening damage unlikely; 2, life-threatening damage possible; 3, life-threatening damage likely. Categories 2 and 3 would be avoided if the whole body effective dose did not exceed the annual effective dose limit of 250 mSv. For down-wind populations, hormetic effects (activated natural protective processes) are much more likely than are deleterious effects.
doi:10.2203/dose-response.11-004.Scott
PMCID: PMC3186926  PMID: 22013394
radiological emergency; risk assessment; hormesis
24.  Mortality from Parkinson's disease and other causes among a workforce manufacturing paraquat: a retrospective cohort study 
BMJ Open  2011;1(2):e000283.
Objective
To assess the risk of Parkinson's disease (PD) and update information on mortality from major causes of death among a UK workforce who manufactured paraquat (PQ) between 1961 and 1995. There have been no previous studies of the incidence of PD among PQ production workers, although much epidemiological literature exists concerning the relationship between pesticides and PD, and interest has focused on PQ and its users.
Methods
The cohort included all employees who had ever worked on any of the four plants at Widnes where PQ was manufactured between 1961 and 1995, and 926 male and 42 female workers were followed through 30 June 2009. Mortalities for males were compared with national and local rates, including rates for PD as a mentioned cause of death.
Results
Overall, 307 workers had died by 30 June 2009. One male death was due to PD, and no other death certificate mentioned PD. At least 3.3 death certificates of male employees would have been expected to have mentioned PD (standardised mortality ratio=31; 95% CI 1 to 171). Personal monitoring results were indicative that the exposure of a PQ production worker on a daily basis was at least comparable with that of a PQ sprayer or mixer/loader. Reduced mortalities compared with local rates were found for major causes of death.
Conclusions
The study provided no evidence of an increased risk of PD, or increased mortalities from other causes.
Article summary
Article focus
Many epidemiological studies have been conducted to investigate the relationship between exposure to pesticides and Parkinson's disease (PD) since a report that the toxicant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) caused acute parkinsonism in a small group of drug addicts, and several have focused on paraquat (PQ) in part because of its structural similarity to a toxic metabolite of MPTP.
Case–control studies provide much of the information about a possible association between PD and exposure to PQ, but most have small numbers of subjects exposed to PQ and/or limited exposure information.
This study is the first investigation of mortality from PD among a cohort of PQ manufacturing workers.
Key messages
The study provided no evidence of increased mortalities from major causes of death. There was no evidence of increased mortality (underlying and mentioned cause) from PD.
Personal monitoring results indicated that workers engaged in PQ production were likely to have had a higher exposure to PQ than many of the subjects in case–control studies classified as exposed to PQ.
Strengths and limitations of this study
A major strength of the study is that it is a cohort study. Exposure of workers to PQ is confirmed by comprehensive job histories and the availability of personal monitoring information.
Limitations of the study include its size and power, although the upper confidence limit of the standardised mortality ratio for mentions of PD is relatively low (171). In addition, only information from death certificates of deceased workers was available, and it was not possible to study the morbidity of the entire group.
doi:10.1136/bmjopen-2011-000283
PMCID: PMC3211049  PMID: 22080539
25.  Hospital-at-Home Programs for Patients With Acute Exacerbations of Chronic Obstructive Pulmonary Disease (COPD) 
Executive Summary
In July 2010, the Medical Advisory Secretariat (MAS) began work on a Chronic Obstructive Pulmonary Disease (COPD) evidentiary framework, an evidence-based review of the literature surrounding treatment strategies for patients with COPD. This project emerged from a request by the Health System Strategy Division of the Ministry of Health and Long-Term Care that MAS provide them with an evidentiary platform on the effectiveness and cost-effectiveness of COPD interventions.
After an initial review of health technology assessments and systematic reviews of COPD literature, and consultation with experts, MAS identified the following topics for analysis: vaccinations (influenza and pneumococcal), smoking cessation, multidisciplinary care, pulmonary rehabilitation, long-term oxygen therapy, noninvasive positive pressure ventilation for acute and chronic respiratory failure, hospital-at-home for acute exacerbations of COPD, and telehealth (including telemonitoring and telephone support). Evidence-based analyses were prepared for each of these topics. For each technology, an economic analysis was also completed where appropriate. In addition, a review of the qualitative literature on patient, caregiver, and provider perspectives on living and dying with COPD was conducted, as were reviews of the qualitative literature on each of the technologies included in these analyses.
The Chronic Obstructive Pulmonary Disease Mega-Analysis series is made up of the following reports, which can be publicly accessed at the MAS website at: http://www.hqontario.ca/en/mas/mas_ohtas_mn.html.
Chronic Obstructive Pulmonary Disease (COPD) Evidentiary Framework
Influenza and Pneumococcal Vaccinations for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Smoking Cessation for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Community-Based Multidisciplinary Care for Patients With Stable Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Pulmonary Rehabilitation for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Long-term Oxygen Therapy for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Noninvasive Positive Pressure Ventilation for Acute Respiratory Failure Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Noninvasive Positive Pressure Ventilation for Chronic Respiratory Failure Patients With Stable Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Hospital-at-Home Programs for Patients With Acute Exacerbations of Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Home Telehealth for Patients with Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Cost-Effectiveness of Interventions for Chronic Obstructive Pulmonary Disease Using an Ontario Policy Model
Experiences of Living and Dying With COPD: A Systematic Review and Synthesis of the Qualitative Empirical Literature
For more information on the qualitative review, please contact Mita Giacomini at: http://fhs.mcmaster.ca/ceb/faculty_member_giacomini.htm.
For more information on the economic analysis, please visit the PATH website: http://www.path-hta.ca/About-Us/Contact-Us.aspx.
The Toronto Health Economics and Technology Assessment (THETA) collaborative has produced an associated report on patient preference for mechanical ventilation. For more information, please visit the THETA website: http://theta.utoronto.ca/static/contact.
Objective
The objective of this analysis was to compare hospital-at-home care with inpatient hospital care for patients with acute exacerbations of chronic obstructive pulmonary disease (COPD) who present to the emergency department (ED).
Clinical Need: Condition and Target Population
Acute Exacerbations of Chronic Obstructive Pulmonary Disease
Chronic obstructive pulmonary disease is a disease state characterized by airflow limitation that is not fully reversible. This airflow limitation is usually both progressive and associated with an abnormal inflammatory response of the lungs to noxious particles or gases. The natural history of COPD involves periods of acute-onset worsening of symptoms, particularly increased breathlessness, cough, and/or sputum, that go beyond normal day-to-day variations; these are known as acute exacerbations.
Two-thirds of COPD exacerbations are caused by an infection of the tracheobronchial tree or by air pollution; the cause in the remaining cases is unknown. On average, patients with moderate to severe COPD experience 2 or 3 exacerbations each year.
Exacerbations have an important impact on patients and on the health care system. For the patient, exacerbations result in decreased quality of life, potentially permanent losses of lung function, and an increased risk of mortality. For the health care system, exacerbations of COPD are a leading cause of ED visits and hospitalizations, particularly in winter.
Technology
Hospital-at-home programs offer an alternative for patients who present to the ED with an exacerbation of COPD and require hospital admission for their treatment. Hospital-at-home programs provide patients with visits in their home by medical professionals (typically specialist nurses) who monitor the patients, alter patients’ treatment plans if needed, and in some programs, provide additional care such as pulmonary rehabilitation, patient and caregiver education, and smoking cessation counselling.
There are 2 types of hospital-at-home programs: admission avoidance and early discharge hospital-at-home. In the former, admission avoidance hospital-at-home, after patients are assessed in the ED, they are prescribed the necessary medications and additional care needed (e.g., oxygen therapy) and then sent home where they receive regular visits from a medical professional. In early discharge hospital-at-home, after being assessed in the ED, patients are admitted to the hospital where they receive the initial phase of their treatment. These patients are discharged into a hospital-at-home program before the exacerbation has resolved. In both cases, once the exacerbation has resolved, the patient is discharged from the hospital-at-home program and no longer receives visits in his/her home.
In the models that exist to date, hospital-at-home programs differ from other home care programs because they deal with higher acuity patients who require higher acuity care, and because hospitals retain the medical and legal responsibility for patients. Furthermore, patients requiring home care services may require such services for long periods of time or indefinitely, whereas patients in hospital-at-home programs require and receive the services for a short period of time only.
Hospital-at-home care is not appropriate for all patients with acute exacerbations of COPD. Ineligible patients include: those with mild exacerbations that can be managed without admission to hospital; those who require admission to hospital; and those who cannot be safely treated in a hospital-at-home program either for medical reasons and/or because of a lack of, or poor, social support at home.
The proposed possible benefits of hospital-at-home for treatment of exacerbations of COPD include: decreased utilization of health care resources by avoiding hospital admission and/or reducing length of stay in hospital; decreased costs; increased health-related quality of life for patients and caregivers when treated at home; and reduced risk of hospital-acquired infections in this susceptible patient population.
Ontario Context
No hospital-at-home programs for the treatment of acute exacerbations of COPD were identified in Ontario. Patients requiring acute care for their exacerbations are treated in hospitals.
Research Question
What is the effectiveness, cost-effectiveness, and safety of hospital-at-home care compared with inpatient hospital care of acute exacerbations of COPD?
Research Methods
Literature Search
Search Strategy
A literature search was performed on August 5, 2010, using OVID MEDLINE, OVID MEDLINE In-Process and Other Non-Indexed Citations, OVID EMBASE, EBSCO Cumulative Index to Nursing & Allied Health Literature (CINAHL), the Wiley Cochrane Library, and the Centre for Reviews and Dissemination database for studies published from January 1, 1990, to August 5, 2010. Abstracts were reviewed by a single reviewer and, for those studies meeting the eligibility criteria, full-text articles were obtained. Reference lists and health technology assessment websites were also examined for any additional relevant studies not identified through the systematic search.
Inclusion Criteria
English language full-text reports;
health technology assessments, systematic reviews, meta-analyses, and randomized controlled trials (RCTs);
studies performed exclusively in patients with a diagnosis of COPD or studies including patients with COPD as well as patients with other conditions, if results are reported for COPD patients separately;
studies performed in patients with acute exacerbations of COPD who present to the ED;
studies published between January 1, 1990, and August 5, 2010;
studies comparing hospital-at-home and inpatient hospital care for patients with acute exacerbations of COPD;
studies that include at least 1 of the outcomes of interest (listed below).
Cochrane Collaboration reviews have defined hospital-at-home programs as those that provide patients with active treatment for their acute exacerbation in their home by medical professionals for a limited period of time (in this case, until the resolution of the exacerbation). If a hospital-at-home program had not been available, these patients would have been admitted to hospital for their treatment.
Exclusion Criteria
< 18 years of age
animal studies
duplicate publications
grey literature
Outcomes of Interest
Patient/clinical outcomes
mortality
lung function (forced expiratory volume in 1 second)
health-related quality of life
patient or caregiver preference
patient or caregiver satisfaction with care
complications
Health system outcomes
hospital readmissions
length of stay in hospital and hospital-at-home
ED visits
transfer to long-term care
days to readmission
eligibility for hospital-at-home
Statistical Methods
When possible, results were pooled using Review Manager 5 Version 5.1; otherwise, results were summarized descriptively. Data from RCTs were analyzed using intention-to-treat protocols. In addition, a sensitivity analysis was done assigning all missing data/withdrawals to the event. P values less than 0.05 were considered significant. A priori subgroup analyses were planned for the acuity of hospital-at-home program, type of hospital-at-home program (early discharge or admission avoidance), and severity of the patients’ COPD. Additional subgroup analyses were conducted as needed based on the identified literature. Post hoc sample size calculations were performed using STATA 10.1.
Quality of Evidence
The quality of each included study was assessed, taking into consideration allocation concealment, randomization, blinding, power/sample size, withdrawals/dropouts, and intention-to-treat analyses.
The quality of the body of evidence was assessed as high, moderate, low, or very low according to the GRADE Working Group criteria. The following definitions of quality were used in grading the quality of the evidence:
Summary of Findings
Fourteen studies met the inclusion criteria and were included in this review: 1 health technology assessment, 5 systematic reviews, and 7 RCTs.
The following conclusions are based on low to very low quality of evidence. The reviewed evidence was based on RCTs that were inadequately powered to observe differences between hospital-at-home and inpatient hospital care for most outcomes, so there is a strong possibility of type II error. Given the low to very low quality of evidence, these conclusions must be considered with caution.
Approximately 21% to 37% of patients with acute exacerbations of COPD who present to the ED may be eligible for hospital-at-home care.
Of the patients who are eligible for care, some may refuse to participate in hospital-at-home care.
Eligibility for hospital-at-home care may be increased depending on the design of the hospital-at-home program, such as the size of the geographical service area for hospital-at-home and the hours of operation for patient assessment and entry into hospital-at-home.
Hospital-at-home care for acute exacerbations of COPD was associated with a nonsignificant reduction in the risk of mortality and hospital readmissions compared with inpatient hospital care during 2- to 6-month follow-up.
Limited, very low quality evidence suggests that hospital readmissions are delayed in patients who received hospital-at-home care compared with those who received inpatient hospital care (mean additional days before readmission comparing hospital-at-home to inpatient hospital care ranged from 4 to 38 days).
There is insufficient evidence to determine whether hospital-at-home care, compared with inpatient hospital care, is associated with improved lung function.
The majority of studies did not find significant differences between hospital-at-home and inpatient hospital care for a variety of health-related quality of life measures at follow-up. However, follow-up may have been too late to observe an impact of hospital-at-home care on quality of life.
A conclusion about the impact of hospital-at-home care on length of stay for the initial exacerbation (defined as days in hospital or days in hospital plus hospital-at-home care for inpatient hospital and hospital-at-home, respectively) could not be determined because of limited and inconsistent evidence.
Patient and caregiver satisfaction with care is high for both hospital-at-home and inpatient hospital care.
PMCID: PMC3384361  PMID: 23074420

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