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1.  Interrupted or continuous slowly absorbable sutures – Design of a multi-centre randomised trial to evaluate abdominal closure techniques INSECT-Trial [ISRCTN24023541] 
BMC Surgery  2005;5:3.
Background
The closure of the abdomen after median laparotomy is still a matter of debate among surgeons. Further well designed and performed randomised controlled trials determining the optimal method of abdominal fascial closure are needed.
Design
This is a three armed, multi-centre, intra-operatively randomised, controlled, patient blinded trial. Over 20 surgical departments will enrol 600 patients who are planned for an elective primary abdominal operation. The objective of this study is to compare the frequency of abdominal incisional hernias between two continuous suture techniques with different, slowly absorbable monofilament materials and an interrupted suture using an absorbable braided suture material at one year postoperatively.
Conclusion
This trial will answer the question whether the continuous abdominal wall closure with a slowly absorbable material with longitudinal elasticity is superior to the continuous suture with a material lacking elasticity and to interrupted sutures with braided thread.
doi:10.1186/1471-2482-5-3
PMCID: PMC554977  PMID: 15755324
2.  Pralidoxime in Acute Organophosphorus Insecticide Poisoning—A Randomised Controlled Trial 
PLoS Medicine  2009;6(6):e1000104.
In a randomized controlled trial of individuals who had taken organophosphorus insecticides, Michael Eddleston and colleagues find that there is no evidence that the addition of the antidote pralidoxime offers benefit over atropine and supportive care.
Background
Poisoning with organophosphorus (OP) insecticides is a major global public health problem, causing an estimated 200,000 deaths each year. Although the World Health Organization recommends use of pralidoxime, this antidote's effectiveness remains unclear. We aimed to determine whether the addition of pralidoxime chloride to atropine and supportive care offers benefit.
Methods and Findings
We performed a double-blind randomised placebo-controlled trial of pralidoxime chloride (2 g loading dose over 20 min, followed by a constant infusion of 0.5 g/h for up to 7 d) versus saline in patients with organophosphorus insecticide self-poisoning. Mortality was the primary outcome; secondary outcomes included intubation, duration of intubation, and time to death. We measured baseline markers of exposure and pharmacodynamic markers of response to aid interpretation of clinical outcomes. Two hundred thirty-five patients were randomised to receive pralidoxime (121) or saline placebo (114). Pralidoxime produced substantial and moderate red cell acetylcholinesterase reactivation in patients poisoned by diethyl and dimethyl compounds, respectively. Mortality was nonsignificantly higher in patients receiving pralidoxime: 30/121 (24.8%) receiving pralidoxime died, compared with 18/114 (15.8%) receiving placebo (adjusted hazard ratio [HR] 1.69, 95% confidence interval [CI] 0.88–3.26, p = 0.12). Incorporating the baseline amount of acetylcholinesterase already aged and plasma OP concentration into the analysis increased the HR for patients receiving pralidoxime compared to placebo, further decreasing the likelihood that pralidoxime is beneficial. The need for intubation was similar in both groups (pralidoxime 26/121 [21.5%], placebo 24/114 [21.1%], adjusted HR 1.27 [95% CI 0.71–2.29]). To reduce confounding due to ingestion of different insecticides, we further analysed patients with confirmed chlorpyrifos or dimethoate poisoning alone, finding no evidence of benefit.
Conclusions
Despite clear reactivation of red cell acetylcholinesterase in diethyl organophosphorus pesticide poisoned patients, we found no evidence that this regimen improves survival or reduces need for intubation in patients with organophosphorus insecticide poisoning. The reason for this failure to benefit patients was not apparent. Further studies of different dose regimens or different oximes are required.
Trial Registration
Controlled-trials.com ISRCTN55264358
Please see later in the article for Editors' Summary
Editors' Summary
Background
Each year, about 200,000 people worldwide die from poisoning with organophosphorous insecticides, toxic chemicals that are widely used in agriculture, particularly in developing countries. Organophosphates disrupt communication between the brain and the body in both insects and people. The brain controls the body by sending electrical impulses along nerve cells (neurons) to the body's muscle cells. At the end of the neurons, these impulses are converted into chemical messages (neurotransmitters), which cross the gap between neurons and muscle cells (the neuromuscular junction) and bind to proteins (receptors) on the muscle cells that pass on the brain's message. One important neurotransmitter is acetylcholine. This is used at neuromuscular junctions, in the part of the nervous system that controls breathing and other automatic vital functions, and in parts of the central nervous system. Normally, the enzyme acetylcholinesterase quickly breaks down acetylcholine after it has delivered its message, but organophosphates inhibit acetylcholinesterase and, as a result, disrupt the transmission of nerve impulses at nerve endings. Symptoms of organophosphate poisoning include excessive sweating, diarrhea, muscle weakness, and breathing problems. Most deaths from organophosphate poisoning are caused by respiratory failure.
Why Was This Study Done?
Treatment for organophosphorous insecticide poisoning includes resuscitation and assistance with breathing (intubation) if necessary and the rapid administration of atropine. This antidote binds to “muscarinic” acetylcholine receptors and blocks the effects of acetylcholine at this type of receptor. Atropine can only reverse some of the effects of organophosphate poisoning, however, because it does not block the activity of acetylcholine at its other receptors. Consequently, the World Health Organization (WHO) recommends that a second type of antidote called an oxime acetylcholinesterase reactivator be given after atropine. But, although the beneficial effects of atropine are clear, controversy surrounds the role of oximes in treating organophosphate poisoning. There is even some evidence that the oxime pralidoxime can be harmful. In this study, the researchers try to resolve this controversy by studying the effects of pralidoxime treatment on patients poisoned by organophosphorous insecticides in Sri Lanka in a randomized controlled trial (a study in which groups of patients are randomly chosen to receive different treatments).
What Did the Researchers Do and Find?
The researchers enrolled 235 adults who had been admitted to two Sri Lankan district hospitals with organophosphorous insecticide self-poisoning (in Sri Lanka, more than 70% of fatal suicide attempts are the result of pesticide poisoning). The patients, all of whom had been given atropine, were randomized to receive either the WHO recommended regimen of pralidoxime or saline. The researchers determined how much and which pesticide each patient had been exposed to, measured the levels of pralidoxime and acetylcholinesterase activity in the patients' blood, and monitored the patients' progress during their hospital stay. Overall, 48 patients died—30 of the 121 patients who received pralidoxime and 18 of the 114 control patients. After adjusting for the baseline characteristics of the two treatment groups and for intubation at baseline, pralidoxime treatment increased the patients' risk of dying by two-thirds, although this increased risk of death was not statistically significant. In other words, this result does not prove that pralidoxime treatment was bad for the patients in this trial. However, in further analyses that adjusted for the ingestion of different insecticides, the baseline levels of insecticides in patients' blood, and other prespecified variables, pralidoxime treatment always increased the patients' risk of death.
What Do These Findings Mean?
These findings provide no evidence that the WHO recommended regimen of pralidoxime improves survival after organophosphorous pesticide poisoning even though other results from the trial show that the treatment reactivated acetylcholinesterase. Indeed, although limited by the small number of patients enrolled into this study (the trial recruited fewer patients than expected because results from another trial had a deleterious effect on recruitment), these findings actually suggest that pralidoxime treatment may be harmful at least in self-poisoned patients. This suspicion now needs be confirmed in trials that more fully assess the risks/benefits of oximes and that explore the effects of different dosing regimens and/or different oximes.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000104.
The US Environmental Protection Agency provides information about all aspects of insecticides (in English and Spanish)
Toxtown, an interactive site from the US National Library of Medicine provides information on exposure to pesticides and other environmental health concerns (in English and Spanish)
The US National Pesticide Information Center provides objective, science-based information about pesticides (in English and Spanish)
MedlinePlus also provides links to information on pesticides (in English and Spanish)
For more on Poisoning Prevention and Management see WHO's International Programme on Chemical Safety (IPCS)
WikiTox, a clinical toxicology teaching resource project, has detailed information on organophosphates
doi:10.1371/journal.pmed.1000104
PMCID: PMC2696321  PMID: 19564902
3.  A Multifaceted Intervention to Implement Guidelines and Improve Admission Paediatric Care in Kenyan District Hospitals: A Cluster Randomised Trial 
PLoS Medicine  2011;8(4):e1001018.
Philip Ayieko and colleagues report the outcomes of a cluster-randomized trial carried out in eight Kenyan district hospitals evaluating the effects of a complex intervention involving improved training and supervision for clinicians. They found a higher performance of hospitals assigned to the complex intervention on a variety of process of care measures, as compared to those receiving the control intervention.
Background
In developing countries referral of severely ill children from primary care to district hospitals is common, but hospital care is often of poor quality. However, strategies to change multiple paediatric care practices in rural hospitals have rarely been evaluated.
Methods and Findings
This cluster randomized trial was conducted in eight rural Kenyan district hospitals, four of which were randomly assigned to a full intervention aimed at improving quality of clinical care (evidence-based guidelines, training, job aides, local facilitation, supervision, and face-to-face feedback; n = 4) and the remaining four to control intervention (guidelines, didactic training, job aides, and written feedback; n = 4). Prespecified structure, process, and outcome indicators were measured at baseline and during three and five 6-monthly surveys in control and intervention hospitals, respectively. Primary outcomes were process of care measures, assessed at 18 months postbaseline.
In both groups performance improved from baseline. Completion of admission assessment tasks was higher in intervention sites at 18 months (mean = 0.94 versus 0.65, adjusted difference 0.54 [95% confidence interval 0.05–0.29]). Uptake of guideline recommended therapeutic practices was also higher within intervention hospitals: adoption of once daily gentamicin (89.2% versus 74.4%; 17.1% [8.04%–26.1%]); loading dose quinine (91.9% versus 66.7%, 26.3% [−3.66% to 56.3%]); and adequate prescriptions of intravenous fluids for severe dehydration (67.2% versus 40.6%; 29.9% [10.9%–48.9%]). The proportion of children receiving inappropriate doses of drugs in intervention hospitals was lower (quinine dose >40 mg/kg/day; 1.0% versus 7.5%; −6.5% [−12.9% to 0.20%]), and inadequate gentamicin dose (2.2% versus 9.0%; −6.8% [−11.9% to −1.6%]).
Conclusions
Specific efforts are needed to improve hospital care in developing countries. A full, multifaceted intervention was associated with greater changes in practice spanning multiple, high mortality conditions in rural Kenyan hospitals than a partial intervention, providing one model for bridging the evidence to practice gap and improving admission care in similar settings.
Trial registration
Current Controlled Trials ISRCTN42996612
Please see later in the article for the Editors' Summary
Editors' Summary
Background
In 2008, nearly 10 million children died in early childhood. Nearly all these deaths were in low- and middle-income countries—half were in Africa. In Kenya, for example, 74 out every 1,000 children born died before they reached their fifth birthday. About half of all childhood (pediatric) deaths in developing countries are caused by pneumonia, diarrhea, and malaria. Deaths from these common diseases could be prevented if all sick children had access to quality health care in the community (“primary” health care provided by health centers, pharmacists, family doctors, and traditional healers) and in district hospitals (“secondary” health care). Unfortunately, primary health care facilities in developing countries often lack essential diagnostic capabilities and drugs, and pediatric hospital care is frequently inadequate with many deaths occurring soon after admission. Consequently, in 1996, as part of global efforts to reduce childhood illnesses and deaths, the World Health Organization (WHO) and the United Nations Children's Fund (UNICEF) introduced the Integrated Management of Childhood Illnesses (IMCI) strategy. This approach to child health focuses on the well-being of the whole child and aims to improve the case management skills of health care staff at all levels, health systems, and family and community health practices.
Why Was This Study Done?
The implementation of IMCI has been evaluated at the primary health care level, but its implementation in district hospitals has not been evaluated. So, for example, interventions designed to encourage the routine use of WHO disease-specific guidelines in rural pediatric hospitals have not been tested. In this cluster randomized trial, the researchers develop and test a multifaceted intervention designed to improve the implementation of treatment guidelines and admission pediatric care in district hospitals in Kenya. In a cluster randomized trial, groups of patients rather than individual patients are randomly assigned to receive alternative interventions and the outcomes in different “clusters” of patients are compared. In this trial, each cluster is a district hospital.
What Did the Researchers Do and Find?
The researchers randomly assigned eight Kenyan district hospitals to the “full” or “control” intervention, interventions that differed in intensity but that both included more strategies to promote implementation of best practice than are usually applied in Kenyan rural hospitals. The full intervention included provision of clinical practice guidelines and training in their use, six-monthly survey-based hospital assessments followed by face-to-face feedback of survey findings, 5.5 days training for health care workers, provision of job aids such as structured pediatric admission records, external supervision, and the identification of a local facilitator to promote guideline use and to provide on-site problem solving. The control intervention included the provision of clinical practice guidelines (without training in their use) and job aids, six-monthly surveys with written feedback, and a 1.5-day lecture-based seminar to explain the guidelines. The researchers compared the implementation of various processes of care (activities of patients and doctors undertaken to ensure delivery of care) in the intervention and control hospitals at baseline and 18 months later. The performance of both groups of hospitals improved during the trial but more markedly in the intervention hospitals than in the control hospitals. At 18 months, the completion of admission assessment tasks and the uptake of guideline-recommended clinical practices were both higher in the intervention hospitals than in the control hospitals. Moreover, a lower proportion of children received inappropriate doses of drugs such as quinine for malaria in the intervention hospitals than in the control hospitals.
What Do These Findings Mean?
These findings show that specific efforts are needed to improve pediatric care in rural Kenya and suggest that interventions that include more approaches to changing clinical practice may be more effective than interventions that include fewer approaches. These findings are limited by certain aspects of the trial design, such as the small number of participating hospitals, and may not be generalizable to other hospitals in Kenya or to hospitals in other developing countries. Thus, although these findings seem to suggest that efforts to implement and scale up improved secondary pediatric health care will need to include more than the production and dissemination of printed materials, further research including trials or evaluation of test programs are necessary before widespread adoption of any multifaceted approach (which will need to be tailored to local conditions and available resources) can be contemplated.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001018.
WHO provides information on efforts to reduce global child mortality and on Integrated Management of Childhood Illness (IMCI); the WHO pocket book “Hospital care for children contains guidelines for the management of common illnesses with limited resources (available in several languages)
UNICEF also provides information on efforts to reduce child mortality and detailed statistics on child mortality
The iDOC Africa Web site, which is dedicated to improving the delivery of hospital care for children and newborns in Africa, provides links to the clinical guidelines and other resources used in this study
doi:10.1371/journal.pmed.1001018
PMCID: PMC3071366  PMID: 21483712
4.  The Prostate Cancer Intervention Versus Observation Trial:VA/NCI/AHRQ Cooperative Studies Program #407 (PIVOT): Design and Baseline Results of a Randomized Controlled Trial Comparing Radical Prostatectomy With Watchful Waiting for Men With Clinically Localized Prostate Cancer 
Prostate cancer is the most common noncutaneous malignancy and the second leading cause of cancer death in men. In the United States, 90% of men with prostate cancer are more than age 60 years, diagnosed by early detection with the prostate-specific antigen (PSA) blood test, and have disease believed confined to the prostate gland (clinically localized). Common treatments for clinically localized prostate cancer include watchful waiting (WW), surgery to remove the prostate gland (radical prostatectomy), external-beam radiation therapy and interstitial radiation therapy (brachytherapy), and androgen deprivation. Little is known about the relative effectiveness and harms of treatments because of the paucity of randomized controlled trials. The Department of Veterans Affairs/National Cancer Institute/Agency for Healthcare Research and Quality Cooperative Studies Program Study #407:Prostate Cancer Intervention Versus Observation Trial (PIVOT), initiated in 1994, is a multicenter randomized controlled trial comparing radical prostatectomy with WW in men with clinically localized prostate cancer. We describe the study rationale, design, recruitment methods, and baseline characteristics of PIVOT enrollees. We provide comparisons with eligible men declining enrollment and men participating in another recently reported randomized trial of radical prostatectomy vs WW conducted in Scandinavia. We screened 13 022 men with prostate cancer at 52 US medical centers for potential enrollment. From these, 5023 met initial age, comorbidity, and disease eligibility criteria, and a total of 731 men agreed to participate and were randomized. The mean age of enrollees was 67 years. Nearly one-third were African American. Approximately 85% reported that they were fully active. The median PSA was 7.8ng/mL (mean 10.2ng/mL). In three-fourths of men, the primary reason for biopsy leading to a diagnosis of prostate cancer was a PSA elevation or rise. Using previously developed tumor risk categorizations incorporating PSA levels, Gleason histologic grade, and tumor stage, it was found that approximately 40% had low-risk, 34% had medium-risk, and 21% had high-risk prostate cancer based on local histopathology. Comparison to our national sample of eligible men declining PIVOT participation as well as to men enrolled in the Scandinavian trial indicated that PIVOT enrollees are representative of men being diagnosed and treated in the United States and quite different from men in the Scandinavian trial. PIVOT enrolled an ethnically diverse population representative of men diagnosed with prostate cancer in the United States. Results will yield important information regarding the relative effectiveness and harms of surgery compared with WW for men with predominately PSA-detected clinically localized prostate cancer.
doi:10.1093/jncimonographs/lgs041
PMCID: PMC3540866  PMID: 23271771
5.  Predicting Outcome after Traumatic Brain Injury: Development and International Validation of Prognostic Scores Based on Admission Characteristics 
PLoS Medicine  2008;5(8):e165.
Background
Traumatic brain injury (TBI) is a leading cause of death and disability. A reliable prediction of outcome on admission is of great clinical relevance. We aimed to develop prognostic models with readily available traditional and novel predictors.
Methods and Findings
Prospectively collected individual patient data were analyzed from 11 studies. We considered predictors available at admission in logistic regression models to predict mortality and unfavorable outcome according to the Glasgow Outcome Scale at 6 mo after injury. Prognostic models were developed in 8,509 patients with severe or moderate TBI, with cross-validation by omission of each of the 11 studies in turn. External validation was on 6,681 patients from the recent Medical Research Council Corticosteroid Randomisation after Significant Head Injury (MRC CRASH) trial. We found that the strongest predictors of outcome were age, motor score, pupillary reactivity, and CT characteristics, including the presence of traumatic subarachnoid hemorrhage. A prognostic model that combined age, motor score, and pupillary reactivity had an area under the receiver operating characteristic curve (AUC) between 0.66 and 0.84 at cross-validation. This performance could be improved (AUC increased by approximately 0.05) by considering CT characteristics, secondary insults (hypotension and hypoxia), and laboratory parameters (glucose and hemoglobin). External validation confirmed that the discriminative ability of the model was adequate (AUC 0.80). Outcomes were systematically worse than predicted, but less so in 1,588 patients who were from high-income countries in the CRASH trial.
Conclusions
Prognostic models using baseline characteristics provide adequate discrimination between patients with good and poor 6 mo outcomes after TBI, especially if CT and laboratory findings are considered in addition to traditional predictors. The model predictions may support clinical practice and research, including the design and analysis of randomized controlled trials.
Ewout Steyerberg and colleagues describe a prognostic model for the prediction of outcome of traumatic brain injury using data available on admission.
Editors' Summary
Background.
Traumatic brain injury (TBI) causes a large amount of morbidity and mortality worldwide. According to the Centers for Disease Control, for example, about 1.4 million Americans will sustain a TBI—a head injury—each year. Of these, 1.1 million will be treated and released from an emergency department, 235,000 will be hospitalized, and 50,000 will die. The burden of disease is much higher in the developing world, where the causes of TBI such as traffic accidents occur at higher rates and treatment may be less available.
Why Was This Study Done?
Given the resources required to treat TBI, a very useful research tool would be the ability to accurately predict on admission to hospital what the outcome of a given injury might be. Currently, scores such as the Glasgow Coma Scale are useful to predict outcome 24 h after the injury but not before.
Prognostic models are useful for several reasons. Clinically, they help doctors and patients make decisions about treatment. They are also useful in research studies that compare outcomes in different groups of patients and when planning randomized controlled trials. The study presented here is one of a number of analyses done by the IMPACT research group over the past several years using a large database that includes data from eight randomized controlled trials and three observational studies conducted between 1984 and 1997. There are other ongoing studies that also seek to develop new prognostic models; one such recent study was published in BMJ by a group involving the lead author of the PLoS Medicine paper described here.
What Did the Researchers Do and Find?
The authors analyzed data that had been collected prospectively on individual patients from the 11 studies included in the database and derived models to predict mortality and unfavorable outcome at 6 mo after injury for the 8,509 patients with severe or moderate TBI. They found that the strongest predictors of outcome were age, motor score, pupillary reactivity, and characteristics on the CT scan, including the presence of traumatic subarachnoid hemorrhage. A core prognostic model could be derived from the combination of age, motor score, and pupillary reactivity. A better score could be obtained by adding CT characteristics, secondary problems (hypotension and hypoxia), and laboratory measurements of glucose and hemoglobin. The scores were then tested to see how well they predicted outcome in a different group of patients—6,681 patients from the recent Medical Research Council Corticosteroid Randomisation after Significant Head Injury (MRC CRASH) trial.
What Do These Findings Mean?
In this paper the authors show that it is possible to produce prognostic models using characteristics collected on admission as part of routine care that can discriminate between patients with good and poor outcomes 6 mo after TBI, especially if the results from CT scans and laboratory findings are added to basic models. This paper has to be considered together with other studies, especially the paper mentioned above, which was recently published in the BMJ (MRC CRASH Trial Collaborators [2008] Predicting outcome after traumatic brain injury: practical prognostic models based on large cohort of international patients. BMJ 336: 425–429.). The BMJ study presented a set of similar, but subtly different models, with specific focus on patients in developing countries; in that case, the patients in the CRASH trial were used to produce the models, and the patients in the IMPACT database were used to verify one variant of the models. Unfortunately this related paper was not disclosed to us during the initial review process; however, during PLoS Medicine's subsequent consideration of this manuscript we learned of it. After discussion with the reviewers, we took the decision that the models described in the PLoS Medicine paper are sufficiently different from those reported in the other paper and as such proceeded with publication of the paper. Ideally, however, these two sets of models would have been reviewed and published side by side, so that readers could easily evaluate the respective merits and value of the two different sets of models in the light of each other. The two sets of models are, however, discussed in a Perspective article also published in PLoS Medicine (see below).
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050165.
This paper and the BMJ paper mentioned above are discussed further in a PLoS Medicine Perspective article by Andrews and Young
The TBI Impact site provides a tool to calculate the scores described in this paper
The CRASH trial, which is used to validate the scores mentioned here, has a Web site explaining the trial and its results
The R software, which was used for the prognostic analyses, is freely available
The MedlinePlus encyclopedia has information on head injury
The WHO site on neurotrauma discusses head injury from a global perspective
The CDC's National Center for Injury Prevention and Control gives statistics on head injury in the US and advice on prevention
doi:10.1371/journal.pmed.0050165
PMCID: PMC2494563  PMID: 18684008
6.  Effect of a Community-Based Nursing Intervention on Mortality in Chronically Ill Older Adults: A Randomized Controlled Trial 
PLoS Medicine  2012;9(7):e1001265.
Kenneth Coburn and colleagues report findings from a randomized trial evaluating the effects of a complex nursing intervention on mortality risk among older individuals diagnosed with chronic health conditions.
Background
Improving the health of chronically ill older adults is a major challenge facing modern health care systems. A community-based nursing intervention developed by Health Quality Partners (HQP) was one of 15 different models of care coordination tested in randomized controlled trials within the Medicare Coordinated Care Demonstration (MCCD), a national US study. Evaluation of the HQP program began in 2002. The study reported here was designed to evaluate the survival impact of the HQP program versus usual care up to five years post-enrollment.
Methods and Findings
HQP enrolled 1,736 adults aged 65 and over, with one or more eligible chronic conditions (coronary artery disease, heart failure, diabetes, asthma, hypertension, or hyperlipidemia) during the first six years of the study. The intervention group (n = 873) was offered a comprehensive, integrated, and tightly managed system of care coordination, disease management, and preventive services provided by community-based nurse care managers working collaboratively with primary care providers. The control group (n = 863) received usual care. Overall, a 25% lower relative risk of death (hazard ratio [HR] 0.75 [95% CI 0.57–1.00], p = 0.047) was observed among intervention participants with 86 (9.9%) deaths in the intervention group and 111 (12.9%) deaths in the control group during a mean follow-up of 4.2 years. When covariates for sex, age group, primary diagnosis, perceived health, number of medications taken, hospital stays in the past 6 months, and tobacco use were included, the adjusted HR was 0.73 (95% CI 0.55–0.98, p = 0.033). Subgroup analyses did not demonstrate statistically significant interaction effects for any subgroup. No suspected program-related adverse events were identified.
Conclusions
The HQP model of community-based nurse care management appeared to reduce all-cause mortality in chronically ill older adults. Limitations of the study are that few low-income and non-white individuals were enrolled and implementation was in a single geographic region of the US. Additional research to confirm these findings and determine the model's scalability and generalizability is warranted.
Trial Registration
ClinicalTrials.gov NCT01071967
Please see later in the article for the Editors' Summary
Editors' Summary
Background
In almost every country in the world, the proportion of people aged over 60 years is growing faster than any other age group because of increased life expectancy. This demographic change has several implications for public health, especially as older age is a risk factor for many chronic diseases—diseases of long duration and generally slow progression. Chronic diseases, such as heart disease, stroke, cancer, chronic respiratory diseases, and diabetes, are by far the leading cause of death in the world, representing almost two-thirds of all deaths. Therefore in most countries, the challenge of managing increasingly ageing populations who have chronic illnesses demands an urgent response and countries such as the United States are actively researching possible solutions.
Why Was This Study Done?
Some studies suggest that innovations in chronic disease management that are led by nurses may help address the epidemic of chronic diseases by increasing the quality and reducing the cost of care. However, to date, reports of the evaluation of such interventions lack rigor and do not provide evidence of improved long-term health outcomes or reduced health care costs. So in this study, the researchers used the gold standard of research, a randomized controlled trial, to examine the impact of a community-based nurse care management model for older adults with chronic illnesses in the United States as part of a series of studies supported by the Centers for Medicare and Medicaid Services.
What Did the Researchers Do and Find?
The researchers recruited eligible patients aged 65 years and over with heart failure, coronary heart disease, asthma, diabetes, hypertension, and/or hyperlipidemia who received traditional Medicare—a fee for service insurance scheme in which beneficiaries can choose to receive their care from any Medicare provider—from participating primary care practices in Pennsylvania. The researchers then categorized patients according to their risk on the basis of several factors including the number of chronic diseases each individual had before randomizing patients to receive usual care or the nurse-led intervention. The intervention included an individualized plan comprising education, symptom monitoring, medication, counseling for adherence, help identifying, arranging, and monitoring community health and social service referrals in addition to group interventions such as weight loss maintenance and exercise classes. The researchers checked whether any participating patients had died by using the online Social Security Death Master File. Then the researchers used a statistical model to calculate the risk of death in both groups.
Of the 1,736 patients the researchers recruited into the trial, 873 were randomized to receive the intervention and 863 were in the control group (usual care). The researchers found that 86 (9.9%) participants in the intervention group and 111 (12.9%) participants in the control group died during the study period, representing a 25% lower relative risk of death among the intervention group. However, when the researchers considered other factors, such as sex, age group, primary diagnosis, perceived health, number of medications taken, hospital stays in the past 6 months, and tobacco use in their statistical model, this risk was slightly altered—0.73 risk of death in the intervention group.
What Do These Findings Mean?
These findings suggest that that community-based nurse care management is associated with a reduction in all-cause mortality among older adults with chronic illnesses who are beneficiaries of the fee for service Medicare scheme in the United States. These findings also support the important role of nurses in improving health outcomes in this group of patients and show the feasibility of implementing this program in collaboration with primary care practices. Future research is needed to test the adaptability, scalability, and generalizability of this model of care.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001265.
This study is further discussed in a PLoS Medicine Perspective by Arlene Bierman
Information about the Centers for Medicare and Medicaid Services is available
The World Health Organization provides statistics on the prevalence of both chronic illness and ageing
Heath Quality Partners provide information about the study
doi:10.1371/journal.pmed.1001265
PMCID: PMC3398966  PMID: 22815653
7.  The Tinnitus Retraining Therapy Trial (TRTT): study protocol for a randomized controlled trial 
Trials  2014;15(1):396.
Background
Subjective tinnitus is the perception of sound in the absence of a corresponding external sound for which there is no known medical etiology. For a minority of individuals with tinnitus, the condition impacts their ability to lead a normal lifestyle and is severely debilitating. There is no known cure for tinnitus, so current therapy focuses on reducing the effect of tinnitus on the patient’s quality of life. Tinnitus retraining therapy (TRT) uses nonpsychiatric tinnitus-specific educational counseling and sound therapy in a habituation-based protocol to reduce the patient’s tinnitus-evoked negative reaction to, and awareness of, the tinnitus, with the ultimate goal of reducing the tinnitus impact on the patient’s quality of life. Some studies support the efficacy of TRT, but no trial to date has compared TRT with the current standard of care or evaluated the separate contributions of TRT counseling and sound therapy. The Tinnitus Retraining Therapy Trial (TRTT) is a randomized, double-blind, placebo-controlled, multicenter trial for individuals with intolerable tinnitus.
Methods/design
The TRTT is enrolling active-duty and retired military personnel and their dependents with functionally adequate hearing sensitivity and severe tinnitus at US Air Force, Navy, and Army medical centers. Eligible study participants are randomized to TRT, partial TRT, or standard care to determine the efficacy of TRT and its components (TRT counseling and sound therapy). The primary outcome is change in score on the Tinnitus Questionnaire assessed longitudinally between baseline and follow-up (3, 6, 12, and 18 months following treatment). Secondary outcomes include subscale score changes in the Tinnitus Questionnaire, overall and subscale score changes in the Tinnitus Functional Index and Tinnitus Handicap Inventory, and change in the visual analog scale of the TRT Interview Form. Audiological outcomes include tinnitus pitch and loudness match and measures of loudness discomfort levels. The incidence of depression as a safety measure is assessed at each visit using the Beck Depression Inventory Fast Screen.
Trial registration
Clinicaltrials.gov NCT01177137.
doi:10.1186/1745-6215-15-396
PMCID: PMC4210573  PMID: 25319676
Randomized clinical trial; Tinnitus; Tinnitus retraining therapy
8.  Non-pharmacological, multicomponent group therapy in patients with degenerative dementia: a 12-month randomzied, controlled trial 
BMC Medicine  2011;9:129.
Background
Currently available pharmacological and non-pharmacological treatments have shown only modest effects in slowing the progression of dementia. Our objective was to assess the impact of a long-term non-pharmacological group intervention on cognitive function in dementia patients and on their ability to carry out activities of daily living compared to a control group receiving the usual care.
Methods
A randomized, controlled, single-blind longitudinal trial was conducted with 98 patients (follow-up: n = 61) with primary degenerative dementia in five nursing homes in Bavaria, Germany. The highly standardized intervention consisted of motor stimulation, practice in activities of daily living, and cognitive stimulation (acronym MAKS). It was conducted in groups of ten patients led by two therapists for 2 hours, 6 days a week for 12 months. Control patients received treatment as usual. Cognitive function was assessed using the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-Cog), and the ability to carry out activities of daily living using the Erlangen Test of Activities of Daily Living (E-ADL test) at baseline and after 12 months.
Results
Of the 553 individuals screened, 119 (21.5%) were eligible and 98 (17.7%) were ultimately included in the study. At 12 months, the results of the per protocol analysis (n = 61) showed that cognitive function and the ability to carry out activities of daily living had remained stable in the intervention group but had decreased in the control patients (ADAS-Cog: adjusted mean difference: -7.7, 95% CI -14.0 to -1.4, P = 0.018, Cohen's d = 0.45; E-ADL test: adjusted mean difference: 3.6, 95% CI 0.7 to 6.4, P = 0.015, Cohen's d = 0.50). The effect sizes for the intervention were greater in the subgroup of patients (n = 50) with mild to moderate disease (ADAS-Cog: Cohen's d = 0.67; E-ADL test: Cohen's d = 0.69).
Conclusions
A highly standardized, non-pharmacological, multicomponent group intervention conducted in a nursing-home setting was able to postpone a decline in cognitive function in dementia patients and in their ability to carry out activities of daily living for at least 12 months.
Trial Registration
http://www.isrctn.com Identifier: ISRCTN87391496
doi:10.1186/1741-7015-9-129
PMCID: PMC3254071  PMID: 22133165
dementia; non-pharmacological intervention; group therapy; RCT; nursing home
9.  Effect of a Nutrition Supplement and Physical Activity Program on Pneumonia and Walking Capacity in Chilean Older People: A Factorial Cluster Randomized Trial 
PLoS Medicine  2011;8(4):e1001023.
Alan Dangour and colleagues report results from the CENEX (Cost-effectiveness Evaluation of a Nutritional supplement and EXercise program for older people) trial, which evaluates a nutritional and exercise program aiming to prevent pneumonia and physical decline in Chilean people.
Background
Ageing is associated with increased risk of poor health and functional decline. Uncertainties about the health-related benefits of nutrition and physical activity for older people have precluded their widespread implementation. We investigated the effectiveness and cost-effectiveness of a national nutritional supplementation program and/or a physical activity intervention among older people in Chile.
Methods and Findings
We conducted a cluster randomized factorial trial among low to middle socioeconomic status adults aged 65–67.9 years living in Santiago, Chile. We randomized 28 clusters (health centers) into the study and recruited 2,799 individuals in 2005 (∼100 per cluster). The interventions were a daily micronutrient-rich nutritional supplement, or two 1-hour physical activity classes per week, or both interventions, or neither, for 24 months. The primary outcomes, assessed blind to allocation, were incidence of pneumonia over 24 months, and physical function assessed by walking capacity 24 months after enrolment. Adherence was good for the nutritional supplement (∼75%), and moderate for the physical activity intervention (∼43%). Over 24 months the incidence rate of pneumonia did not differ between intervention and control clusters (32.5 versus 32.6 per 1,000 person years respectively; risk ratio = 1.00; 95% confidence interval 0.61–1.63; p = 0.99). In intention-to-treat analysis, after 24 months there was a significant difference in walking capacity between the intervention and control clusters (mean difference 33.8 meters; 95% confidence interval 13.9–53.8; p = 0.001). The overall cost of the physical activity intervention over 24 months was US$164/participant; equivalent to US$4.84/extra meter walked. The number of falls and fractures was balanced across physical activity intervention arms and no serious adverse events were reported for either intervention.
Conclusions
Chile's nutritional supplementation program for older people is not effective in reducing the incidence of pneumonia. This trial suggests that the provision of locally accessible physical activity classes in a transition economy population can be a cost-effective means of enhancing physical function in later life.
Trial registration
Current Controlled Trials ISRCTN 48153354
Please see later in the article for the Editors' Summary
Editors' Summary
Background
By 2050, about a quarter of the world's population will be aged 60 years or over, with Asia and Latin America experiencing the most dramatic increases in the proportion of older people. For example, in Chile, which has recently undergone rapid demographic transition, the proportion of the population aged 60 years or over has increased from 8% to 12% over the past 25 years.
Current global policy initiatives that promote healthy ageing include an emphasis on adequate nutrient intakes, as longitudinal studies (conducted in high-income countries) suggest that achieving nutritional sufficiency and maintaining moderate levels of physical activity both decrease risk of mortality by preserving immune function and lean body mass and so reduce the numerous risk factors for disability and chronic disease in later life. Such interventions may also decrease the risk of infection, particularly pneumonia, a common cause of death in older people. However, older people in low- and middle-income countries frequently have diets with insufficient calories (energy) and/or micronutrients.
Why Was This Study Done?
Currently, there is no high-quality evidence to support the benefits of improved nutrition and increased physical activity levels from low-income or transition economies, where the ongoing demographic trends suggest that the needs are greatest. National policies aimed at preserving health and function in older people with interventions such as cash-transfers and provision of “food baskets” are often used in Latin American countries, such as Chile, but are rarely formally evaluated. Therefore, the purpose of this study (the Cost-effectiveness Evaluation of a Nutritional supplement and EXercise program for older people—CENEX) was to evaluate Chile's national nutritional supplementation program and/or physical exercise, to investigate whether this program prevented pneumonia and physical functional decline in older people in Santiago, and also to investigate whether these interventions were cost-effective.
What Did the Researchers Do and Find?
The researchers randomly allocated 28 participating health centers in Santiago, Chile, into one of four arms: (1) nutritional supplementation; (2) nutritional supplementation+physical activity; (3) physical activity alone; (4) control. From May to December 2005, 2,799 eligible adults aged 65–67.9 years and living in low to middle socioeconomic circumstances, who attended each health center, were recruited into the study and received the allocated intervention—daily micronutrient-rich nutritional supplement, or two 1-hour physical activity classes per week, or both interventions or neither—for 24 months. The researchers did not know the allocation arm of each patient and over the course of the study assessed the incidence of pneumonia (viral and bacterial as based on diagnosis at the health center or hospital) and physical function was measured by walking capacity (meters walked in 6 minutes). The researchers used administrative records and interviews with staff and patients to estimate the cost-effectiveness of the interventions.
Participant retention in the study was 84%, although only three-quarters of patients receiving the nutritional intervention and less than half (43%) of patients in the physical activity intervention arm adhered to their respective programs. Over 24 months, the incidence rate of pneumonia did not differ between intervention and control groups (32.5 versus 32.6 per 1,000 person years, respectively), but at the end of the study period, there was a significant difference in walking capacity between the intervention and control clusters (mean difference 33.8 meters). The number of falls and fractures in the study arms were similar. The overall costs over 24 months were US$91.00 and US$163.70 per participant for the nutritional supplement and physical activity interventions, respectively. The cost of the physical activity intervention per extra meter walked at 24 months was US$4.84.
What Do These Findings Mean?
The results of this trial suggest that there is little evidence to support the effectiveness of Chile's national nutritional supplementation program in reducing the incidence of pneumonia for 65.0–67.9 year olds. Therefore, given Chile's high burden of infectious and nutrition-related chronic diseases and the associated high health costs, this program should not be considered as a priority preventive public health intervention. However, the provision of locally available physical activity classes to older people could be of clinical benefit, especially in urban settings such as Santiago, although future challenges include increasing the uptake of, and retention to, such programs.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001023.
The World Health Organization provides information about the state of health in Chile
Wikipedia also provides information about health and health care in Chile (please note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
doi:10.1371/journal.pmed.1001023
PMCID: PMC3079648  PMID: 21526229
10.  The randomized shortened dental arch study (RaSDA): design and protocol 
Trials  2010;11:15.
Background
Various treatment options for the prosthetic treatment of jaws where all molars are lost are under discussion. Besides the placement of implants, two main treatment types can be distinguished: replacement of the missing molars with removable dental prostheses and non-replacement of the molars, i.e. preservation of the shortened dental arch. Evidence is lacking regarding the long-term outcome and the clinical performance of these approaches. High treatment costs and the long time required for the treatment impede respective clinical trials.
Methods/design
This 14-center randomized controlled investigator-initiated trial is ongoing. Last patient out will be in 2010. Patients over 35 years of age with all molars missing in one jaw and with at least both canines and one premolar left on each side were eligible. One group received a treatment with removable dental prostheses for molar replacement (treatment A). The other group received a treatment limited to the replacement of all missing anterior and premolar teeth using fixed bridges (treatment B). A pilot trial with 32 patients was carried out. Two hundred and fifteen patients were enrolled in the main trial where 109 patients were randomized for treatment A and 106 for treatment B. The primary outcome measure is further tooth loss during the 5-year follow-up. The secondary outcome measures encompassed clinical, technical and subjective variables. The study is funded by the Deutsche Forschungsgemeinschaft (German Research Foundation, DFG WA 831/2-1, 2-2, 2-3, 2-4, 2-5).
Discussion
The particular value of this trial is the adaptation of common design components to the very specific features of complex dental prosthetic treatments. The pilot trial proved to be indispensable because it led to a number of adjustments in the study protocol that considerably improved the practicability. The expected results are of high clinical relevance and will show the efficacy of two common treatment approaches in terms of oral health. An array of secondary outcome measures will deliver valuable supplementary information. If the results can be implemented in the clinical practice, the daily dental care should strongly profit thereof.
Trial registration
The trial is registered at ClinicalTrials.gov under ISRCTN68590603 (pilot trial) and ISRCTN97265367 (main trial).
doi:10.1186/1745-6215-11-15
PMCID: PMC2843681  PMID: 20170481
11.  A randomized controlled trial to investigate the influence of low dose radiotherapy on immune stimulatory effects in liver metastases of colorectal cancer 
BMC Cancer  2011;11:419.
Background
Insufficient migration and activation of tumor specific effector T cells in the tumor is one of the main reasons for inadequate host anti-tumor immune response. External radiation seems to induce inflammation and activate the immune response. This phase I/II clinical trial aims to evaluate whether low dose single fraction radiotherapy can improve T cell associated antitumor immune response in patients with colorectal liver metastases.
Methods/Design
This is an investigator-initiated, prospective randomised, 4-armed, controlled Phase I/II trial. Patients undergoing elective hepatic resection due to colorectal cancer liver metastasis will be enrolled in the study. Patients will receive 0 Gy, 0.5 Gy, 2 Gy or 5 Gy radiation targeted to their liver metastasis. Radiation will be applied by external beam radiotherapy using a 6 MV linear accelerator (Linac) with intensity modulated radiotherapy (IMRT) technique two days prior to surgical resection. All patients admitted to the Department of General-, Visceral-, and Transplantion Surgery, University of Heidelberg for elective hepatic resection are consecutively screened for eligibility into this trial, and written informed consent is obtained before inclusion. The primary objective is to assess the effect of active local external beam radiation dose on, tumor infiltrating T cells as a surrogate parameter for antitumor activity. Secondary objectives include radiogenic treatment toxicity, postoperative morbidity and mortality, local tumor control and recurrence patterns, survival and quality of life. Furthermore, frequencies of systemic tumor reactive T cells in blood and bone marrow will be correlated with clinical outcome.
Discussion
This is a randomized controlled patient blinded trial to assess the safety and efficiency of low dose radiotherapy on metastasis infiltrating T cells and thus potentially enhance the antitumor immune response.
Trial registration
ClinicalTrials.gov: NCT01191632
doi:10.1186/1471-2407-11-419
PMCID: PMC3195202  PMID: 21961577
colorectal liver metastasis; low dose radiation; tumor specific T cells
12.  Timing and Completeness of Trial Results Posted at ClinicalTrials.gov and Published in Journals 
PLoS Medicine  2013;10(12):e1001566.
Agnes Dechartres and colleagues searched ClinicalTrials.gov for completed drug RCTs with results reported and then searched for corresponding studies in PubMed to evaluate timeliness and completeness of reporting.
Please see later in the article for the Editors' Summary
Background
The US Food and Drug Administration Amendments Act requires results from clinical trials of Food and Drug Administration–approved drugs to be posted at ClinicalTrials.gov within 1 y after trial completion. We compared the timing and completeness of results of drug trials posted at ClinicalTrials.gov and published in journals.
Methods and Findings
We searched ClinicalTrials.gov on March 27, 2012, for randomized controlled trials of drugs with posted results. For a random sample of these trials, we searched PubMed for corresponding publications. Data were extracted independently from ClinicalTrials.gov and from the published articles for trials with results both posted and published. We assessed the time to first public posting or publishing of results and compared the completeness of results posted at ClinicalTrials.gov versus published in journal articles. Completeness was defined as the reporting of all key elements, according to three experts, for the flow of participants, efficacy results, adverse events, and serious adverse events (e.g., for adverse events, reporting of the number of adverse events per arm, without restriction to statistically significant differences between arms for all randomized patients or for those who received at least one treatment dose).
From the 600 trials with results posted at ClinicalTrials.gov, we randomly sampled 50% (n = 297) had no corresponding published article. For trials with both posted and published results (n = 202), the median time between primary completion date and first results publicly posted was 19 mo (first quartile = 14, third quartile = 30 mo), and the median time between primary completion date and journal publication was 21 mo (first quartile = 14, third quartile = 28 mo). Reporting was significantly more complete at ClinicalTrials.gov than in the published article for the flow of participants (64% versus 48% of trials, p<0.001), efficacy results (79% versus 69%, p = 0.02), adverse events (73% versus 45%, p<0.001), and serious adverse events (99% versus 63%, p<0.001).
The main study limitation was that we considered only the publication describing the results for the primary outcomes.
Conclusions
Our results highlight the need to search ClinicalTrials.gov for both unpublished and published trials. Trial results, especially serious adverse events, are more completely reported at ClinicalTrials.gov than in the published article.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
When patients consult a doctor, they expect to be recommended what their doctor believes is the most effective treatment with the fewest adverse effects. To determine which treatment to recommend, clinicians rely on sources that include research studies. Among studies, the best evidence is generally agreed to come from systematic reviews and randomized controlled clinical trials (RCTs), studies that test the efficacy and safety of medical interventions by comparing clinical outcomes in groups of patients randomly chosen to receive different interventions. Decision-making based on the best available evidence is called evidence-based medicine. However, evidence-based medicine can only guide clinicians if trial results are published in a timely and complete manner. Unfortunately, underreporting of trials is common. For example, an RCT in which a new drug performs better than existing drugs is more likely to be published than one in which the new drug performs badly or has unwanted adverse effects (publication bias). There can also be a delay in publishing the results of negative trials (time-lag bias) or a failure to publish complete results for all the prespecified outcomes of a trial (reporting bias). All three types of bias threaten informed medical decision-making and the health of patients.
Why Was This Study Done?
One initiative that aims to prevent these biases was included in the 2007 US Food and Drug Administration Amendments Act (FDAAA). The Food and Drug Administration (FDA) is responsible for approving drugs and devices that are marketed in the US. The FDAAA requires that results from clinical trials of FDA-approved drugs and devices conducted in the United States be made publicly available at ClinicalTrials.gov within one year of trial completion. ClinicalTrials.gov—a web-based registry that includes US and international clinical trials—was established in 2000 in response to the 1997 FDA Modernization Act, which required mandatory registration of trial titles and designs and of the conditions and interventions under study. The FDAAA expanded these mandatory requirements by requiring researchers studying FDA-approved drugs and devices to report additional information such as the baseline characteristics of the participants in each arm of the trial and the results of primary and secondary outcome measures (the effects of the intervention on predefined clinical measurements) and their statistical significance (an indication of whether differences in outcomes might have happened by chance). Researchers of other trials registered in ClinicalTrials.gov are welcome to post trial results as well. Here, the researchers compare the timing and completeness (i.e., whether all relevant information was fully reported) of results of drug trials posted at ClinicalTrials.gov with those published in medical journals.
What Did the Researchers Do and Find?
The researchers searched ClinicalTrials.gov for reports of completed phase III and IV (late-stage) RCTs of drugs with posted results. For a random sample of 600 eligible trials, they searched PubMed (a database of biomedical publications) for corresponding publications. Only 50% of trials with results posted at ClinicalTrials.gov had a matching published article. For 202 trials with both posted and published results, the researchers compared the timing and completeness of the results posted at ClinicalTrials.gov and of results reported in the corresponding journal publication. The median time between the study completion date and the first results being publicly posted at ClinicalTrials.gov was 19 months, whereas the time between completion and publication in a journal was 21 months. The flow of participants through trials was completely reported in 64% of the ClinicalTrials.gov postings but in only 48% of the corresponding publications. Results for the primary outcome measure were completely reported in 79% and 69% of the ClinicalTrials.gov postings and corresponding publications, respectively. Finally, adverse events were completely reported in 73% of the ClinicalTrials.gov postings but in only 45% of the corresponding publications, and serious adverse events were reported in 99% and 63% of the ClinicalTrials.gov postings and corresponding publications, respectively.
What Do These Findings Mean?
These findings suggest that the reporting of trial results is significantly more complete at ClinicalTrials.gov than in published journal articles reporting the main trial results. Certain aspects of this study may affect the accuracy of this conclusion. For example, the researchers compared the results posted at ClinicalTrials.gov only with the results in the publication that described the primary outcome of each trial, even though some trials had multiple publications. Importantly, these findings suggest that, to enable patients and physicians to make informed treatment decisions, experts undertaking assessments of drugs should consider seeking efficacy and safety data posted at ClinicalTrials.gov, both for trials whose results are not published yet and for trials whose results are published. Moreover, they suggest that the use of templates to guide standardized reporting of trial results in journals and broader mandatory posting of results may help to improve the reporting and transparency of clinical trials and, consequently, the evidence available to inform treatment of patients.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001566.
Wikipedia has pages on evidence-based medicine and on publication bias (note: Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
The US Food and Drug Administration provides information about drug approval in the US for consumers and health-care professionals, plus detailed information on the 2007 Food and Drug Administration Amendments Act
ClinicalTrials.gov provides information about the US National Institutes of Health clinical trial registry, including background information about clinical trials, and a fact sheet detailing the requirements of the 2007 Food and Drug Administration Amendments Act
PLOS Medicine recently launched a Reporting Guidelines Collection, an open access collection of reporting guidelines, commentary, and related research on guidelines from across PLOS journals that aims to help advance the efficiency, effectiveness, and equitability of the dissemination of biomedical information; a 2008 PLOS Medicine editorial discusses the 2007 Food and Drug Administration Amendments Act
doi:10.1371/journal.pmed.1001566
PMCID: PMC3849189  PMID: 24311990
13.  Effect of an Educational Toolkit on Quality of Care: A Pragmatic Cluster Randomized Trial 
PLoS Medicine  2014;11(2):e1001588.
In a pragmatic cluster-randomized trial, Baiju Shah and colleagues evaluated the effectiveness of printed educational materials for clinician education focusing on cardiovascular disease screening and risk reduction in people with diabetes.
Please see later in the article for the Editors' Summary
Background
Printed educational materials for clinician education are one of the most commonly used approaches for quality improvement. The objective of this pragmatic cluster randomized trial was to evaluate the effectiveness of an educational toolkit focusing on cardiovascular disease screening and risk reduction in people with diabetes.
Methods and Findings
All 933,789 people aged ≥40 years with diagnosed diabetes in Ontario, Canada were studied using population-level administrative databases, with additional clinical outcome data collected from a random sample of 1,592 high risk patients. Family practices were randomly assigned to receive the educational toolkit in June 2009 (intervention group) or May 2010 (control group). The primary outcome in the administrative data study, death or non-fatal myocardial infarction, occurred in 11,736 (2.5%) patients in the intervention group and 11,536 (2.5%) in the control group (p = 0.77). The primary outcome in the clinical data study, use of a statin, occurred in 700 (88.1%) patients in the intervention group and 725 (90.1%) in the control group (p = 0.26). Pre-specified secondary outcomes, including other clinical events, processes of care, and measures of risk factor control, were also not improved by the intervention. A limitation is the high baseline rate of statin prescribing in this population.
Conclusions
The educational toolkit did not improve quality of care or cardiovascular outcomes in a population with diabetes. Despite being relatively easy and inexpensive to implement, printed educational materials were not effective. The study highlights the need for a rigorous and scientifically based approach to the development, dissemination, and evaluation of quality improvement interventions.
Trial Registration
http://www.ClinicalTrials.gov NCT01411865 and NCT01026688
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Clinical practice guidelines help health care providers deliver the best care to patients by combining all the evidence on disease management into specific recommendations for care. However, the implementation of evidence-based guidelines is often far from perfect. Take the example of diabetes. This common chronic disease, which is characterized by high levels of sugar (glucose) in the blood, impairs the quality of life of patients and shortens life expectancy by increasing the risk of cardiovascular diseases (conditions that affect the heart and circulation) and other life-threatening conditions. Patients need complex care to manage the multiple risk factors (high blood sugar, high blood pressure, high levels of fat in the blood) that are associated with the long-term complications of diabetes, and they need to be regularly screened and treated for these complications. Clinical practice guidelines for diabetes provide recommendations on screening and diagnosis, drug treatment, and cardiovascular disease risk reduction, and on helping patients self-manage their disease. Unfortunately, the care delivered to patients with diabetes frequently fails to meet the standards laid down in these guidelines.
Why Was This Study Done?
How can guideline adherence and the quality of care provided to patients be improved? A common approach is to send printed educational materials to clinicians. For example, when the Canadian Diabetes Association (CDA) updated its clinical practice guidelines in 2008, it mailed educational toolkits that contained brochures and other printed materials targeting key themes from the guidelines to family physicians. In this pragmatic cluster randomized trial, the researchers investigate the effect of the CDA educational toolkit that targeted cardiovascular disease screening and treatment on the quality of care of people with diabetes. A pragmatic trial asks whether an intervention works under real-life conditions and whether it works in terms that matter to the patient; a cluster randomized trial randomly assigns groups of people to receive alternative interventions and compares outcomes in the differently treated “clusters.”
What Did the Researchers Do and Find?
The researchers randomly assigned family practices in Ontario, Canada to receive the educational toolkit in June 2009 (intervention group) or in May 2010 (control group). They examined outcomes between July 2009 and April 2010 in all patients with diabetes in Ontario aged over 40 years (933,789 people) using population-level administrative data. In Canada, administrative databases record the personal details of people registered with provincial health plans, information on hospital visits and prescriptions, and physician service claims for consultations, assessments, and diagnostic and therapeutic procedures. They also examined clinical outcome data from a random sample of 1,592 patients at high risk of cardiovascular complications. In the administrative data study, death or non-fatal heart attack (the primary outcome) occurred in about 11,500 patients in both the intervention and control group. In the clinical data study, the primary outcome―use of a statin to lower blood fat levels―occurred in about 700 patients in both study groups. Secondary outcomes, including other clinical events, processes of care, and measures of risk factor control were also not improved by the intervention. Indeed, in the administrative data study, some processes of care outcomes related to screening for heart disease were statistically significantly worse in the intervention group than in the control group, and in the clinical data study, fewer patients in the intervention group reached blood pressure targets than in the control group.
What Do These Findings Mean?
These findings suggest that the CDA cardiovascular diseases educational toolkit did not improve quality of care or cardiovascular outcomes in a population with diabetes. Indeed, the toolkit may have led to worsening in some secondary outcomes although, because numerous secondary outcomes were examined, this may be a chance finding. Limitations of the study include its length, which may have been too short to see an effect of the intervention on clinical outcomes, and the possibility of a ceiling effect—the control group in the clinical data study generally had good care, which left little room for improvement of the quality of care in the intervention group. Overall, however, these findings suggest that printed educational materials may not be an effective way to improve the quality of care for patients with diabetes and other complex conditions and highlight the need for a rigorous, scientific approach to the development, dissemination, and evaluation of quality improvement interventions.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001588.
The US National Diabetes Information Clearinghouse provides information about diabetes for patients, health care professionals, and the general public (in English and Spanish)
The UK National Health Service Choices website provides information (including some personal stories) for patients and carers about type 2 diabetes, the commonest form of diabetes
The Canadian Diabetes Association also provides information about diabetes for patients (including some personal stories about living with diabetes) and health care professionals; its latest clinical practice guidelines are available on its website
The UK National Institute for Health and Care Excellence provides general information about clinical guidelines and about health care quality standards in the UK
The US Agency for Healthcare Research and Quality aims to improve the quality, safety, efficiency, and effectiveness of health care for all Americans (information in English and Spanish); the US National Guideline Clearinghouse is a searchable database of clinical practice guidelines
The International Diabetes Federation provides information about diabetes for patients and health care professionals, along with international statistics on the burden of diabetes
doi:10.1371/journal.pmed.1001588
PMCID: PMC3913553  PMID: 24505216
14.  Emergency department-initiated palliative care for advanced cancer patients: protocol for a pilot randomized controlled trial 
Trials  2014;15:251.
Background
For patients with advanced cancer, visits to the emergency department (ED) are common. Such patients present to the ED with a specific profile of palliative care needs, including burdensome symptoms such as pain, dyspnea, or vomiting that cannot be controlled in other settings and a lack of well-defined goals of care. The goals of this study are: i) to test the feasibility of recruiting, enrolling, and randomizing patients with serious illness in the ED; and ii) to evaluate the impact of ED-initiated palliative care on health care utilization, quality of life, and survival.
Methods/Design
This is a protocol for a single center parallel, two-arm randomized controlled trial in ED patients with metastatic solid tumors comparing ED-initiated palliative care referral to a control group receiving usual care. We plan to enroll 125 to 150 ED-advanced cancer patients at Mount Sinai Hospital in New York, USA, who meet the following criteria: i) pass a brief cognitive screen; ii) speak fluent English or Spanish; and iii) have never been seen by palliative care. We will use balanced block randomization in groups of 50 to assign patients to the intervention or control group after completion of a baseline questionnaire. All research staff performing assessment or analysis will be blinded to patient assignment. We will measure the impact of the palliative care intervention on the following outcomes: i) timing and rate of palliative care consultation; ii) quality of life and depression at 12 weeks, measured using the FACT-G and PHQ-9; iii) health care utilization; and iv) length of survival. The primary analysis will be based on intention-to-treat.
Discussion
This pilot randomized controlled trial will test the feasibility of recruiting, enrolling, and randomizing patients with advanced cancer in the ED, and provide a preliminary estimate of the impact of palliative care referral on health care utilization, quality of life, and survival.
Trial registration
Clinical Trials.gov identifier: NCT01358110 (Entered 5/19/2011).
doi:10.1186/1745-6215-15-251
PMCID: PMC4090632  PMID: 24962353
Cancer; Emergency medicine; Palliative care
15.  The external validity of published randomized controlled trials in primary care 
BMC Family Practice  2009;10:5.
Background
A criticism of Randomized Controlled Trials (RCTs) in primary care is that they lack external validity, participants being unrepresentative of the wider population. Our aim was to determine whether published primary care-based RCTs report information about how the study sample is assembled, and whether this is associated with RCT characteristics.
Methods
We reviewed RCTs published in four primary care journals in the years 2001–2004. Main outcomes were: (1) eligibility fraction (proportion eligible of those screened), (2) enrolment fraction (proportion randomised of those eligible), (3) recruitment fraction (proportion of potential participants actually randomised), and (4) number of patients needed to be screened (NNS) in order to randomize one participant.
Results
A total of 148 RCTs were reviewed. One hundred and three trials (70%) reported the number of individuals assessed by investigators for eligibility, 119 (80%) reported the number eligible for participation, and all reported the actual number recruited. The median eligibility fraction was 83% (IQR 40% to 100%), and the median enrolment fraction was 74% (IQR 49% to 92%). The median NNS was 2.43, with some trials reportedly recruiting every patient or practice screened for eligibility, and one trial screening 484 for each patient recruited. We found no association between NNS and journal, trial size, multi- or single-centre, funding source or type of intervention. There may be associations between provision of sufficient recruitment data for the calculation of NNS and funding source and type of intervention.
Conclusion
RCTs reporting recruitment data in primary care suggest that once screened for eligibility and found to match inclusion criteria patients are likely to be randomized. This finding needs to be treated with caution as it may represent inadequate identification or reporting of the eligible population. A substantial minority of RCTs did not provide sufficient information about the patient recruitment process.
doi:10.1186/1471-2296-10-5
PMCID: PMC2632986  PMID: 19152681
16.  The Multicenter Uveitis Steroid Treatment (MUST) Trial: Rationale, Design and Baseline Characteristics 
American journal of ophthalmology  2010;149(4):550-561.e10.
Purpose
To describe the design and methods of the Multicenter Uveitis Steroid Treatment (MUST) Trial, and the baseline characteristics of enrolled patients.
Design
Baseline data from a 1:1 randomized, parallel treatment design clinical trial at 23 clinical centers comparing systemic corticosteroid therapy (and immunosuppression when indicated) to fluocinolone acetonide implant placement.
Methods
Eligible patients have active or recently active non-infectious intermediate, posterior, or panuveitis. The study design had 90% power (two-sided type I error rate=0.05) to detect a 7.5 letter (1.5 line) difference between groups in the mean visual acuity change between baseline and two years. Secondary outcomes include ocular and systemic complications of therapy and quality of life. Baseline characteristics include demographic and clinical characteristics, quality of life, and reading center gradings of lens and fundus photos, optical coherence tomography images, and fluorescein angiograms.
Results
Over three years, 255 patients were enrolled (481 eyes with uveitis). At baseline, 50% of eyes with uveitis had best-corrected visual acuity worse than 20/40 (16% worse than 20/200), with a similar distribution of reduced visual acuity for intermediate uveitis and posterior or panuveitis cases. Structural complications, including macular edema (36%) and epiretinal membrane (48%), were common.
Conclusions
The MUST Trial will compare fluocinolone acetonide implant versus systemic therapy for management of intermediate, posterior and panuveitis. Patients with intermediate, posterior, or panuveitis enrolled in the trial had a high burden of reduced visual acuity, cataract, macular edema and epiretinal membrane; overall quality of life was lower than expected based on visual acuity.
doi:10.1016/j.ajo.2009.11.019
PMCID: PMC2975449  PMID: 20097325
Uveitis; fluocinolone acetonide implant; corticosteroid; immunosuppressive drug therapy; clinical trial
17.  Open reduction and internal fixation versus casting for highly comminuted and intra-articular fractures of the distal radius (ORCHID): protocol for a randomized clinical multi-center trial 
Trials  2011;12:84.
Background
Fractures of the distal radius represent the most common fracture in elderly patients, and often indicate the onset of symptomatic osteoporosis. A variety of treatment options is available, including closed reduction and plaster casting, K-wire-stabilization, external fixation and open reduction and internal fixation (ORIF) with volar locked plating. The latter is widely promoted by clinicians and hardware manufacturers. Closed reduction and cast stabilization for six weeks is a simple, convenient, and ubiquitously available intervention. In contrast, ORIF requires hospitalization, but allows for functional rehabilitation.
Given the lack of randomized controlled trials, it remains unclear whether ORIF leads to better functional outcomes one year after injury than closed reduction and casting.
Methods/Design
ORCHID (Open reduction and internal fixation versus casting for highly comminuted intra-articular fractures of the distal radius) is a pragmatic, randomized, multi-center, clinical trial with two parallel treatment arms. It is planned to include 504 patients in 15 participating centers throughout Germany over a three-year period. Patients are allocated by a central web-based randomization tool.
The primary objective is to determine differences in the Short Form 36 (SF-36) Physical Component Score (PCS) between volar locked plating and closed reduction and casting of intraarticular, comminuted distal radius fractures in patients > 65 years of age one year after the fracture. Secondary outcomes include differences in other SF-36 dimensions, the EuroQol-5D questionnaire, the Disability of the Arm, Shoulder, and Hand (DASH) instrument. Also, the range of motion in the affected wrist, activities of daily living, complications (including secondary ORIF and revision surgery), as well as serious adverse events will be assessed. Data obtained during the trial will be used for later health-economic evaluations. The trial architecture involves a central statistical unit, an independent monitoring institute, and a data safety monitoring board. Following approval by the institutional review boards of all participating centers, conduct and reporting will strictly adhere to national and international rules, regulations, and recommendations (e.g., Good Clinical Practice, data safety laws, and EQUATOR/CONSORT proposals)
Discussion
To our knowledge, ORCHID is the first multicenter RCT designed to assess quality of life and functional outcomes following operative treatment compared to conservative treatment of complex, intra-articular fractures of the distal radius in elderly patients. The results are expected to influence future treatment recommendations and policies on an international level.
Trial registration
ISRCTN: ISRCTN76120052
Registration date: 31.07.2008; Randomization of first patient: 15.09.2008
doi:10.1186/1745-6215-12-84
PMCID: PMC3072922  PMID: 21426543
18.  Effects of a nurse-based case management compared to usual care among aged patients with myocardial infarction: results from the randomized controlled KORINNA study 
BMC Geriatrics  2013;13:115.
Background
Transition from hospital to home is a critical period for older persons with acute myocardial infarction (AMI). Home-based secondary prevention programs led by nurses have been proposed to facilitate the patients’ adjustment to AMI after discharge. The objective of this study was to evaluate the effects of a nurse-based case management for elderly patients discharged after an AMI from a tertiary care hospital.
Methods
In a single-centre randomized two-armed parallel group trial of patients aged 65 years and older hospitalized with an AMI between September 2008 and May 2010 in the Hospital of Augsburg, Germany, patients were randomly assigned to a case management or a control group receiving usual care. The case-management intervention consisted of a nurse-based follow-up for one year including home visits and telephone calls. Key elements of the intervention were to detect problems or risks and to give advice regarding a wide range of aspects of disease management (e.g. nutrition, medication). Primary study endpoint was time to first unplanned readmission or death. Block randomization per telephone call to a biostatistical center, where the randomization list was kept, was performed. Persons who assessed one-year outcomes and validated readmission data were blinded. Statistical analysis was based on the intention-to-treat approach and included Cox Proportional Hazards models.
Results
Three hundred forty patients were allocated to receive case-management (n=168) or usual care (n=172). The analysis is based on 329 patients (intervention group: n=161; control group: n=168). Of these, 62% were men, mean age was 75.4 years, and 47.1% had at least either diabetes or chronic heart failure as a major comorbidity. The mean follow-up time for the intervention group was 273.6 days, and for the control group it was 320.6 days. During one year, in the intervention group there were 57 first unplanned readmissions and 5 deaths, while the control group had 75 first unplanned readmissions and 3 deaths. With respect to the endpoint there was no significant effect of the case management program after one year (Hazard Ratio 1.01, 95% confidence interval 0.72-1.41). This was also the case among subgroups according to sex, diabetes, living alone, and comorbidities.
Conclusions
A nurse-based management among elderly patients with AMI had no significant influence on the rate of first unplanned readmissions or death during a one-year follow-up. A possible long-term influence should be investigated by further studies.
Clinical trial registration
ISRCTN02893746
doi:10.1186/1471-2318-13-115
PMCID: PMC3871021  PMID: 24168465
Elderly; Randomized controlled trial; Case management; Myocardial infarction
19.  Randomized controlled trials in pediatric critical care: a scoping review 
Critical Care  2013;17(5):R256.
Introduction
Evidence from randomized controlled trials (RCTs) is required to guide treatment of critically ill children, but the number of RCTs available is limited and the publications are often difficult to find. The objectives of this review were to systematically identify RCTs in pediatric critical care and describe their methods and reporting.
Methods
We searched MEDLINE, EMBASE, LILACS and CENTRAL (from inception to April 16, 2013) and reference lists of included RCTs and relevant systematic reviews. We included published RCTs administering any intervention to children in a pediatric ICU. We excluded trials conducted in neonatal ICUs, those enrolling exclusively preterm infants, and individual patient crossover trials. Pairs of reviewers independently screened studies for eligibility, assessed risk of bias, and abstracted data. Discrepancies were resolved by consensus.
Results
We included 248 RCTs: 45 (18%) were multicentered and 14 (6%) were multinational. Trials most frequently enrolled both medical and surgical patients (43%) but postoperative cardiac surgery was the single largest population studied (19%). The most frequently evaluated types of intervention were medications (63%), devices (11%) and nutrition (8%). Laboratory or physiological measurements were the most frequent type of primary outcomes (18%). Half of these trials (50%) reported blinding. Of the 107 (43%) trials that reported an a priori sample size, 34 (32%) were stopped early. The median number of children randomized per trial was 49 and ranged from 6 to 4,947. The frequency of RCT publications increased at a mean rate of 0.7 RCTs per year (P<0.001) from 1 to 20 trials per year.
Conclusions
This scoping review identified the available RCTs in pediatric critical care and made them accessible to clinicians and researchers (http://epicc.mcmaster.ca). Most focused on medications and intermediate or surrogate outcomes, were single-centered and were conducted in North America and Western Europe. The results of this review underscore the need for trials with rigorous methodology, appropriate outcome measures, and improved quality of reporting to ensure that high quality evidence exists to support clinical decision-making in this vulnerable population.
doi:10.1186/cc13083
PMCID: PMC4057256  PMID: 24168782
20.  Double-blinded, randomized controlled trial comparing real versus placebo acupuncture to improve tolerance of diagnostic esophagogastroduodenoscopy without sedation: a study protocol 
Trials  2011;12:52.
Background
Sedation prior to performance of diagnostic esophagogastroduodenoscopy (EGDE) is widespread and increases patient comfort. But 98% of all serious adverse events during EGDEs are ascribed to sedation. The S3 guideline for sedation procedures in gastrointestinal endoscopy published in 2008 in Germany increases patient safety by standardization. These new regulations increase costs because of the need for more personnel and a prolonged discharge procedure after examinations with sedation. Many patients have difficulties to meet the discharge criteria regulated by the S3 guideline, e.g. the call for a second person to escort them home, to resign from driving and working for the rest of the day, resulting in a refusal of sedation. Therefore, we would like to examine if an acupuncture during elective, diagnostic EGDEs could increase the comfort of patients refusing systemic sedation.
Methods/Design
A single-center, double blinded, placebo controlled superiority trial to compare the success rates of elective, diagnostic EGDEs with real and placebo acupuncture. All patients aged 18 years or older scheduled for elective, diagnostic EGDE who refuse a systemic sedation are eligible. 354 patients will be randomized. The primary endpoint is the rate of successful EGDEs with the randomized technique. Intervention: Real or placebo acupuncture before and during EGDE. Duration of study: Approximately 24 months.
Discussion
Organisation/Responsibility The ACUPEND - Trial will be conducted in accordance with the protocol and in compliance with the moral, ethical, and scientific principles governing clinical research as set out in the Declaration of Helsinki (1989) and Good Clinical Practice (GCP). The Interdisciplinary Endoscopy Center (IEZ) of the University Hospital Heidelberg is responsible for design and conduct of the trial, including randomization and documentation of patients' data. Data management and statistical analysis will be performed by the independent Institute for Medical Biometry and Informatics (IMBI) and the Center of Clinical Trials (KSC) at the Department of General, Visceral and Transplantation Surgery, University of Heidelberg.
Trial registration
The trial is registered at Germanctr.de (DRKS00000164) on December 10th 2009. The first patient was randomized on February 2nd 2010.
doi:10.1186/1745-6215-12-52
PMCID: PMC3055829  PMID: 21345226
21.  A randomized trial to optimize HIV/TB care in South Africa: design of the Sizanani trial 
BMC Infectious Diseases  2013;13:390.
Background
Despite increases in HIV testing, only a fraction of people newly diagnosed with HIV infection enter the care system and initiate antiretroviral therapy (ART) in South Africa. We report on the design and initial enrollment of a randomized trial of a health system navigator intervention to improve linkage to HIV care and TB treatment completion in Durban, South Africa.
Methods/Design
We employed a multi-site randomized controlled trial design. Patients at 4 outpatient sites were enrolled prior to HIV testing. For all HIV-infected participants, routine TB screening with sputum for mycobacterial smear and culture were collected. HIV-infected participants were randomized to receive the health system navigator intervention or usual care. Participants in the navigator arm underwent a baseline interview using a strengths-based case management approach to assist in identifying barriers to entering care and devising solutions to best cope with perceived barriers. Over 4 months, participants in the navigator arm received scheduled phone and text messages. The primary outcome of the study is linkage and retention in care, assessed 9 months after enrollment. For ART-eligible participants without TB, the primary outcome is 3 months on ART as documented in the medical record; participants co-infected with TB are also eligible to meet the primary outcome of completion of 6 months of TB treatment, as documented by the TB clinic. Secondary outcomes include mortality, receipt of CD4 count and TB test results, and repeat CD4 counts for those not ART-eligible at baseline. We hypothesize that a health system navigator can help identify and positively affect modifiable patient factors, including self-efficacy and social support, that in turn can improve linkage to and retention in HIV and TB care.
Discussion
We are currently evaluating the clinical impact of a novel health system navigator intervention to promote entry to and retention in HIV and TB care for people newly diagnosed with HIV. The details of this study protocol will inform clinicians, investigators, and policy makers of strategies to best support HIV-infected patients in resource-limited settings.
Trial registration
Clinicaltrials.gov. unique identifier: NCT01188941.
doi:10.1186/1471-2334-13-390
PMCID: PMC3765953  PMID: 23972276
(3-10): HIV/AIDS; Tuberculosis; South Africa; Linkage to care; SMS reminders; Randomized controlled trial; Counseling/Support
22.  Community-Based Care for Chronic Wound Management 
Executive Summary
In August 2008, the Medical Advisory Secretariat (MAS) presented a vignette to the Ontario Health Technology Advisory Committee (OHTAC) on a proposed targeted health care delivery model for chronic care. The proposed model was defined as multidisciplinary, ambulatory, community-based care that bridged the gap between primary and tertiary care, and was intended for individuals with a chronic disease who were at risk of a hospital admission or emergency department visit. The goals of this care model were thought to include: the prevention of emergency department visits, a reduction in hospital admissions and re-admissions, facilitation of earlier hospital discharge, a reduction or delay in long-term care admissions, and an improvement in mortality and other disease-specific patient outcomes.
OHTAC approved the development of an evidence-based assessment to determine the effectiveness of specialized community based care for the management of heart failure, Type 2 diabetes and chronic wounds.
Please visit the Medical Advisory Secretariat Web site at: www.health.gov.on.ca/ohtas to review the following reports associated with the Specialized Multidisciplinary Community-Based care series.
Specialized multidisciplinary community-based care series: a summary of evidence-based analyses
Community-based care for the specialized management of heart failure: an evidence-based analysis
Community-based care for chronic wound management: an evidence-based analysis
Please note that the evidence-based analysis of specialized community-based care for the management of diabetes titled: “Community-based care for the management of type 2 diabetes: an evidence-based analysis” has been published as part of the Diabetes Strategy Evidence Platform at this URL: http://www.health.gov.on.ca/english/providers/program/mas/tech/ohtas/tech_diabetes_20091020.html
Please visit the Toronto Health Economics and Technology Assessment Collaborative Web site at: http://theta.utoronto.ca/papers/MAS_CHF_Clinics_Report.pdf to review the following economic project associated with this series:
Community-based Care for the specialized management of heart failure: a cost-effectiveness and budget impact analysis.
Objective
The objective of this evidence-based review is to determine the effectiveness of a multidisciplinary wound care team for the management of chronic wounds.
Clinical Need: Condition and Target Population
Chronic wounds develop from various aetiologies including pressure, diabetes, venous pathology, and surgery. A pressure ulcer is defined as a localized injury to the skin/and or underlying tissue occurring most often over a bony prominence and caused, alone or in combination, by pressure, shear, or friction. Up to three fifths of venous leg ulcers are due to venous aetiology.
Approximately 1.5 million Ontarians will sustain a pressure ulcer, 111,000 will develop a diabetic foot ulcer, and between 80,000 and 130,000 will develop a venous leg ulcer. Up to 65% of those afflicted by chronic leg ulcers report experiencing decreased quality of life, restricted mobility, anxiety, depression, and/or severe or continuous pain.
Multidisciplinary Wound Care Teams
The term ‘multidisciplinary’ refers to multiple disciplines on a team and ‘interdisciplinary’ to such a team functioning in a coordinated and collaborative manner. There is general consensus that a group of multidisciplinary professionals is necessary for optimum specialist management of chronic wounds stemming from all aetiologies. However, there is little evidence to guide the decision of which professionals might be needed form an optimal wound care team.
Evidence-Based Analysis Methods
Literature Search
A literature search was performed on July 7, 2009 using OVID MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, OVID EMBASE, Wiley Cochrane, Centre for Reviews and Dissemination/International Agency for Health Technology Assessment, and on July 13, 2009 using the Cumulative Index to Nursing & Allied Health Literature (CINAHL), and the International Agency for Health Technology Assessment (INAHTA) for studies pertaining to leg and foot ulcers. A similar literature search was conducted on July 29’ 2009 for studies pertaining to pressure ulcers. 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
Randomized controlled trials and Controlled clinical Trials (CCT)
Systematic review with meta analysis
Population includes persons with pressure ulcers (anywhere) and/or leg and foot ulcers
The intervention includes a multidisciplinary (two or more disciplines) wound care team.
The control group does not receive care by a wound care team
Studies published in the English language between 2004 and 2009
Exclusion Criteria
Single centre retrospective observational studies
Outcomes of Interest
Proportion of persons and/or wounds completely healed
Time to complete healing
Quality of Life
Pain assessment
Summary of Findings
Two studies met the inclusion and exclusion criteria, one a randomized controlled trial (RCT), the other a CCT using a before and after study design. There was variation in the setting, composition of the wound care team, outcome measures, and follow up periods between the studies. In both studies, however, the wound care team members received training in wound care management and followed a wound care management protocol.
In the RCT, Vu et al. reported a non-significant difference between the proportion of wounds healed in 6 months using a univariate analysis (61.7% for treatment vs. 52.5% for control; p=0.074, RR=1.19) There was also a non-significant difference in the mean time to healing in days (82 for treatment vs. 101 for control; p=0.095). More persons in the intervention group had a Brief Pain Inventory (BPI) score equal to zero (better pain control) at 6 months when compared with the control group (38.6% for intervention vs. 24.4% for control; p=0.017, RR=1.58). By multivariate analysis a statistically significant hazard ratio was reported in the intervention group (1.73, 95% CI 1.20-1.50; p=0.003).
In the CCT, Harrison et al. reported a statistically significant difference in healing rates between the pre (control) and post (intervention) phases of the study. Of patients in the pre phase, 23% had healed ulcers 3 months after study enrolment, whereas 56% were healed in the post phase (P<0.001, OR=4.17) (Figure 3). Furthermore, 27% of patients were treated daily or more often in the pre phase whereas only 6% were treated at this frequency in the post phase (P<0.001), equal to a 34% relative risk reduction in frequency of daily treatments. The authors did not report the results of pain relief assessment.
The body of evidence was assessed using the GRADE methodology for 4 outcomes: proportion of wounds healed, proportion of persons with healed wounds, wound associated pain relief, and proportion of persons needing daily wound treatments. In general, the evidence was found to be low to very low quality.
Conclusion
The evidence supports that managing chronic wounds with a multidisciplinary wound care team significantly increases wound healing and reduces the severity of wound-associated pain and the required daily wound treatments compared to persons not managed by a wound care team. The quality of evidence supporting these outcomes is low to very low meaning that further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
PMCID: PMC3377537  PMID: 23074522
23.  Effectiveness of Chest Physiotherapy in Infants Hospitalized with Acute Bronchiolitis: A Multicenter, Randomized, Controlled Trial 
PLoS Medicine  2010;7(9):e1000345.
Vincent Gajdos and colleagues report results of a randomized trial conducted among hospitalized infants with bronchiolitis. They show that a physiotherapy technique (increased exhalation and assisted cough) commonly used in France does not reduce time to recovery in this population.
Background
Acute bronchiolitis treatment in children and infants is largely supportive, but chest physiotherapy is routinely performed in some countries. In France, national guidelines recommend a specific type of physiotherapy combining the increased exhalation technique (IET) and assisted cough (AC). Our objective was to evaluate the efficacy of chest physiotherapy (IET + AC) in previously healthy infants hospitalized for a first episode of acute bronchiolitis.
Methods and Findings
We conducted a multicenter, randomized, outcome assessor-blind and parent-blind trial in seven French pediatric departments. We recruited 496 infants hospitalized for first-episode acute bronchiolitis between October 2004 and January 2008. Patients were randomly allocated to receive from physiotherapists three times a day, either IET + AC (intervention group, n = 246) or nasal suction (NS, control group, n = 250). Only physiotherapists were aware of the allocation group of the infant. The primary outcome was time to recovery, defined as 8 hours without oxygen supplementation associated with minimal or no chest recession, and ingesting more than two-thirds of daily food requirements. Secondary outcomes were intensive care unit admissions, artificial ventilation, antibiotic treatment, description of side effects during procedures, and parental perception of comfort. Statistical analysis was performed on an intent-to-treat basis. Median time to recovery was 2.31 days, (95% confidence interval [CI] 1.97–2.73) for the control group and 2.02 days (95% CI 1.96–2.34) for the intervention group, indicating no significant effect of physiotherapy (hazard ratio [HR]  = 1.09, 95% CI 0.91–1.31, p = 0.33). No treatment by age interaction was found (p = 0.97). Frequency of vomiting and transient respiratory destabilization was higher in the IET + AC group during the procedure (relative risk [RR]  = 10.2, 95% CI 1.3–78.8, p = 0.005 and RR  = 5.4, 95% CI 1.6–18.4, p = 0.002, respectively). No difference between groups in bradycardia with or without desaturation (RR  = 1.0, 95% CI 0.2–5.0, p = 1.00 and RR  = 3.6, 95% CI 0.7–16.9, p = 0.10, respectively) was found during the procedure. Parents reported that the procedure was more arduous in the group treated with IET (mean difference  = 0.88, 95% CI 0.33–1.44, p = 0.002), whereas there was no difference regarding the assessment of the child's comfort between both groups (mean difference  = −0.07, 95% CI −0.53 to 0.38, p = 0.40). No evidence of differences between groups in intensive care admission (RR  = 0.7, 95% CI 0.3–1.8, p = 0.62), ventilatory support (RR  = 2.5, 95% CI 0.5–13.0, p = 0.29), and antibiotic treatment (RR  = 1.0, 95% CI 0.7–1.3, p = 1.00) was observed.
Conclusions
IET + AC had no significant effect on time to recovery in this group of hospitalized infants with bronchiolitis. Additional studies are required to explore the effect of chest physiotherapy on ambulatory populations and for infants without a history of atopy.
Trial registration
ClinicalTrials.gov NCT00125450
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Bronchiolitis, which is usually caused by the respiratory syncytial virus (RSV), is the commonest infection of the lower respiratory tract (the lungs and the passages through which air enters the lungs) in infants. A third of all children have bronchiolitis during their first year of life. The illness begins with stuffiness, a runny nose, a mild cough, and mild fever. Then, as the smallest airways in the lung (the bronchioles) become inflamed (swell) and blocked with mucus, the cough worsens, and the infant may develop a wheeze, shallow breathing, and a rapid heartbeat. Most cases of bronchiolitis are mild and clear up within two weeks without any treatment but some infants develop severe disease. Such infants struggle to get enough air into their lungs, drawing in their chest with each breath (chest recession). They have trouble eating and drinking, and the oxygen level in their blood can drop dangerously low. About 1% of previously healthy infants need hospitalization because of severe bronchiolitis. These severely affected infants are not normally given any medications but, where necessary, they are given oxygen therapy, fed through a tube into their stomach, and given fluids through a vein.
Why Was This Study Done?
In some countries, chest physiotherapy is routinely given to infants with bronchiolitis even though this is not a recommended treatment internationally. In France, for example, virtually all outpatients with bronchiolitis receive a form of chest physiotherapy known as increased exhalation technique with assisted cough (IET + AC). IET—manual chest compression—is designed to clear mucus from the bronchioles whereas AC—coughing triggered by applying pressure to the top of the breastbone—facilitates clearance of the large airways. But is IET + AC an effective treatment for bronchiolitis? In this study, the researchers undertook a multicenter, randomized, controlled trial to answer this question. A randomized trial is a study in which patients are randomly allocated to receive either the treatment under study or a control treatment. Usually in such trials, noone is aware of the treatment allocations until the trial has been completed. This is called blinding and avoids unconscious biases being introduced into the results. In this trial, although the parents, caregivers, and outcome assessors were blinded, the physiotherapists and the infants were aware of treatment allocations. The physiotherapists were not involved in patient assessment, however, and the infants were sufficiently young that their knowledge of their treatment was unlikely to bias the results.
What Did the Researchers Do and Find?
The researchers enrolled nearly 500 children aged 15 days to 2 years who were admitted to seven French hospitals for a first episode of acute bronchiolitis. They randomly allocated the patients to receive IET + AC (intervention group) or nasal suction (control group) three times a day from a physiotherapist working alone in a room with blacked-out windows. The primary outcome of the trial was the patients' time to recovery. Infants were judged to have recovered if they had not had oxygen therapy or showed signs of chest recession for 8 hours and had ingested more than two-thirds of their daily food requirement. Infants in the control group took an average of 2.31 days to recover whereas those in the intervention group took 2.02 days. However, this difference in recovery time was not statistically significant. That is, it could have happened by chance. The researchers also recorded several secondary outcomes such as admission to an intensive care unit, help with breathing, antibiotic treatment, and parental perceptions of their child's comfort. There were no significant differences between the two treatment groups for any of these secondary outcomes, although the parents did report that the IET + AC treatment was harder on their children than nasal suction while not reducing their overall comfort.
What Do These Findings Mean?
These findings show that IET + AC had no significant effect on the time to recovery of a large population of French infants admitted to hospital with severe bronchiolitis. These results cannot be extrapolated, however, to infants with mild or moderate bronchiolitis, and further studies are needed to assess whether chest physiotherapy is of any benefit in an outpatient setting. Three small trials of a different form of chest physiotherapy have also previously failed to find any effect of chest physiotherapy on recovery time. Thus, none of the currently available results support the routine use of chest physiotherapy in infants admitted to a hospital for severe bronchiolitis.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000345
The UK National Health Service Choices Web site provides detailed information on all aspects of bronchiolitis
Kidshealth, a resource maintained by the Nemours Foundation (a not-for-profit organization for children's health) provides information for parents on bronchiolitis schizophrenia and on respiratory syncytial virus (in English and Spanish)
The British Lung Foundation also provides information on bronchiolitis schizophrenia and on respiratory syncytial virus
The MedlinePlus encyclopedia has a page on bronchiolitis schizophrenia (in English and Spanish)
The US Centers for Disease Control and Prevention has detailed information on respiratory syncytial virus
doi:10.1371/journal.pmed.1000345
PMCID: PMC2946956  PMID: 20927359
24.  No Treatment versus 24 or 60 Weeks of Antiretroviral Treatment during Primary HIV Infection: The Randomized Primo-SHM Trial 
PLoS Medicine  2012;9(3):e1001196.
In a three-arm randomized trial conducted among adult patients in HIV treatment centers in The Netherlands, Marlous Grijsen and colleagues examine the effects of temporary combination antiretroviral therapy during primary HIV infection.
Background
The objective of this study was to assess the benefit of temporary combination antiretroviral therapy (cART) during primary HIV infection (PHI).
Methods and Findings
Adult patients with laboratory evidence of PHI were recruited in 13 HIV treatment centers in the Netherlands and randomly assigned to receive no treatment or 24 or 60 wk of cART (allocation in a 1∶1∶1 ratio); if therapy was clinically indicated, participants were randomized over the two treatment arms (allocation in a 1∶1 ratio). Primary end points were (1) viral set point, defined as the plasma viral load 36 wk after randomization in the no treatment arm and 36 wk after treatment interruption in the treatment arms, and (2) the total time that patients were off therapy, defined as the time between randomization and start of cART in the no treatment arm, and the time between treatment interruption and restart of cART in the treatment arms. cART was (re)started in case of confirmed CD4 cell count <350 cells/mm3 or symptomatic HIV disease. In total, 173 participants were randomized. The modified intention-to-treat analysis comprised 168 patients: 115 were randomized over the three study arms, and 53 randomized over the two treatment arms. Of the 115 patients randomized over the three study arms, mean viral set point was 4.8 (standard deviation 0.6) log10 copies/ml in the no treatment arm, and 4.0 (1.0) and 4.3 (0.9) log10 copies/ml in the 24- and 60-wk treatment arms (between groups: p<0.001). The median total time off therapy in the no treatment arm was 0.7 (95% CI 0.0–1.8) y compared to 3.0 (1.9–4.2) and 1.8 (0.5–3.0) y in the 24- and 60-wk treatment arms (log rank test, p<0.001). In the adjusted Cox analysis, both 24 wk (hazard ratio 0.42 [95% CI 0.25–0.73]) and 60 wk of early treatment (hazard ratio 0.55 [0.32–0.95]) were associated with time to (re)start of cART.
Conclusions
In this trial, temporary cART during PHI was found to transiently lower the viral set point and defer the restart of cART during chronic HIV infection.
Trial registration
Current Controlled Trials ISRCTN59497461
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Every year, nearly three million people become infected with HIV, the virus that causes AIDS. The first stage of HIV infection—primary HIV infection—lasts a few weeks and often goes undetected, although most individuals develop a short, flu-like illness. During this stage of infection, the immune system begins to make antibodies to HIV. The second stage of HIV infection, which lasts many years, also has no major symptoms but, during this stage, HIV slowly destroys immune system cells, including CD4 cells, a type of lymphocyte. Eventually, the immune system is unable to fight off other infections and patients enter the third phase of HIV infection—symptomatic HIV infection. The final stage—AIDS—is characterized by the occurrence of one or more AIDS-defining conditions, which include severe but unusual infections and several types of cancer. Early in the AIDS epidemic, most HIV-positive people died within ten years of infection. Nowadays, although there is still no cure for HIV infection, HIV has become a chronic disease because of the availability of combination antiretroviral therapy (cART; cocktails of several powerful drugs). This means that many HIV-positive people have a near-normal life span.
Why Was This Study Done?
It is currently recommended that people start cART when their CD4 count falls below 350 CD4 cells per cubic milliliter (cells/mm3) of blood, when they develop severe constitutional symptoms such as fever lasting longer than a month, or when they develop an AIDS-defining condition. But could a short course of cART during primary HIV infection be clinically beneficial? Some, but not all, nonrandomized studies have shown that such treatment reduces the viral set point (the stabilized viral load that is reached after the immune system begins to make antibodies to HIV; the viral load is the amount of virus in the blood) and slows the decline of CD4 cell count in patients. In this randomized trial (the Primo-SHM trial), the researchers assess the clinical benefit of temporary cART initiated during primary HIV infection by measuring its effects on the viral set point and on when patients have to restart cART during chronic HIV infection. In a randomized controlled trial, patients are assigned by the play of chance to receive different treatments and then followed to compare the effects of these treatments.
What Did the Researchers Do and Find?
The researchers assigned 168 patients with primary HIV infection to receive no treatment, 24 weeks of cART, or 60 weeks of cART. They measured the viral set point (the viral load in the blood 36 weeks after randomization in the no treatment arm and 36 weeks after cART interruption in the treatment arms) and determined the time off therapy (the time between randomization and the start of cART in the no treatment arm, and the time between treatment interruption and restart of cART in the treatment arms) for each patient. cART was (re)started following two consecutive CD4 counts below 350 cells/mm3 or when symptomatic HIV disease developed. The average viral set point was lower in the patients who received early cART than in those who had no treatment. Moreover, on average, the patients in the no treatment arm started cART 0.7 years after randomization whereas those in the 24- and 60-week treatment arms restarted cART after 3.0 and 1.8 years, respectively. There was no statistically significant difference between the 24-week and 60-week treatment arms in time off therapy.
What Do These Findings Mean?
These findings suggest that temporary cART during primary HIV infection can transiently lower the viral set point and can delay the need to restart cART during chromic HIV infection. They also suggest that 24 weeks of cART during primary HIV is as effective as 60 weeks of treatment. These findings need to be confirmed in other settings, and follow-up studies are needed to evaluate the long-term benefits of early temporary cART, but given the short time between cART interruption and treatment restart, the researchers suggest that not interrupting early cART, but instead continuing it for life, should be considered. However, they add, because patients are often physically and emotionally distressed at this stage of HIV infection, adherence to cART during primary HIV infection may be suboptimal, and so patients with primary HIV infection should be advised to start cART only when they feel ready to start treatment.
Additional Information
Please access these web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001196.
Information is available from the US National Institute of Allergy and infectious diseases on HIV infection and AIDS, including information on the clinical progression of HIV infection
NAM/aidsmap provides information about HIV/AIDS, including a factsheet on primary infection
Information is available from Avert, an international AIDS charity on many aspects of HIV/AIDS, including detailed information on HIV treatment and care and on the stages of HIV infection (in English and Spanish)
The World Health Organization's 2010 antiretroviral therapy guidelines provide recommendations on when to initiate cART
Information about Primo-SHM is available
Patient stories about living with HIV/AIDS are available through Avert and through the charity website Healthtalkonline
doi:10.1371/journal.pmed.1001196
PMCID: PMC3313945  PMID: 22479156
25.  Prevention of low back pain: effect, cost-effectiveness, and cost-utility of maintenance care – study protocol for a randomized clinical trial 
Trials  2014;15:102.
Background
Low back pain (LBP) is a prevalent condition and a socioeconomic problem in many countries. Due to its recurrent nature, the prevention of further episodes (secondary prevention), seems logical. Furthermore, when the condition is persistent, the minimization of symptoms and prevention of deterioration (tertiary prevention), is equally important. Research has largely focused on treatment methods for symptomatic episodes, and little is known about preventive treatment strategies.
Methods/Design
This study protocol describes a randomized controlled clinical trial in a multicenter setting investigating the effect and cost-effectiveness of preventive manual care (chiropractic maintenance care) in a population of patients with recurrent or persistent LBP.
Four hundred consecutive study subjects with recurrent or persistent LBP will be recruited from chiropractic clinics in Sweden. The primary outcome is the number of days with bothersome pain over 12 months. Secondary measures are self-rated health (EQ-5D), function (the Roland Morris Disability Questionnaire), psychological profile (the Multidimensional Pain Inventory), pain intensity (the Numeric Rating Scale), and work absence.
The primary utility measure of the study is quality-adjusted life years and will be calculated using the EQ-5D questionnaire. Direct medical costs as well as indirect costs will be considered.
Subjects are randomly allocated into two treatment arms: 1) Symptom-guided treatment (patient controlled), receiving care when patients feel a need. 2) Preventive treatment (clinician controlled), receiving care on a regular basis. Eligibility screening takes place in two phases: first, when assessing the primary inclusion/exclusion criteria, and then to only include fast responders, i.e., subjects who respond well to initial treatment. Data are collected at baseline and at follow-up as well as weekly, using SMS text messages.
Discussion
This study investigates a manual strategy (chiropractic maintenance care) for recurrent and persistent LBP and aims to answer questions regarding the effect and cost-effectiveness of this preventive approach. Strict inclusion criteria should ensure a suitable target group and the use of frequent data collection should provide an accurate outcome measurement. The study utilizes normal clinical procedures, which should aid the transferability of the results.
Trial registration
Clinical trials.gov; NCT01539863, February 22, 2012. The first patient was randomized into the study on April 13th 2012.
doi:10.1186/1745-6215-15-102
PMCID: PMC3984260  PMID: 24690201
Chiropractic; Low back pain; Maintenance care; Manual therapy; Prevention; Randomized controlled trial; Secondary prevention; Spinal manipulation; Tertiary prevention

Results 1-25 (1356241)