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1.  How Evidence-Based Are the Recommendations in Evidence-Based Guidelines? 
PLoS Medicine  2007;4(8):e250.
Background
Treatment recommendations for the same condition from different guideline bodies often disagree, even when the same randomized controlled trial (RCT) evidence is cited. Guideline appraisal tools focus on methodology and quality of reporting, but not on the nature of the supporting evidence. This study was done to evaluate the quality of the evidence (based on consideration of its internal validity, clinical relevance, and applicability) underlying therapy recommendations in evidence-based clinical practice guidelines.
Methods and Findings
A cross-sectional analysis of cardiovascular risk management recommendations was performed for three different conditions (diabetes mellitus, dyslipidemia, and hypertension) from three pan-national guideline panels (from the United States, Canada, and Europe). Of the 338 treatment recommendations in these nine guidelines, 231 (68%) cited RCT evidence but only 105 (45%) of these RCT-based recommendations were based on high-quality evidence. RCT-based evidence was downgraded most often because of reservations about the applicability of the RCT to the populations specified in the guideline recommendation (64/126 cases, 51%) or because the RCT reported surrogate outcomes (59/126 cases, 47%).
Conclusions
The results of internally valid RCTs may not be applicable to the populations, interventions, or outcomes specified in a guideline recommendation and therefore should not always be assumed to provide high-quality evidence for therapy recommendations.
From an analysis of cardiovascular risk-management recommendations in guidelines produced by pan-national panels, McAlister and colleagues concluded that fewer than half were based on high-quality evidence.
Editors' Summary
Background.
Until recently, doctors largely relied on their own experience to choose the best treatment for their patients. Faced with a patient with high blood pressure (hypertension), for example, the doctor had to decide whether to recommend lifestyle changes or to prescribe drugs to reduce the blood pressure. If he or she chose the latter, he or she then had to decide which drug to prescribe, set a target blood pressure, and decide how long to wait before changing the prescription if this target was not reached. But, over the past decade, numerous clinical practice guidelines have been produced by governmental bodies and medical associations to help doctors make treatment decisions like these. For each guideline, experts have searched the medical literature for the current evidence about the diagnosis and treatment of a disease, evaluated the quality of that evidence, and then made recommendations based on the best evidence available.
Why Was This Study Done?
The recommendations made in different clinical practice guidelines vary, in part because they are based on evidence of varying quality. To help clinicians decide which recommendations to follow, some guidelines indicate the strength of their recommendations by grading them, based on the methods used to collect the underlying evidence. Thus, a randomized clinical trial (RCT)—one in which patients are randomly allocated to different treatments without the patient or clinician knowing the allocation—provides higher-quality evidence than a nonrandomized trial. Similarly, internally valid trials—in which the differences between patient groups are solely due to their different treatments and not to other aspects of the trial—provide high-quality evidence. However, grading schemes rarely consider the size of studies and whether they have focused on clinical or so-called “surrogate” measures. (For example, an RCT of a treatment to reduce heart or circulation [“cardiovascular”] problems caused by high blood pressure might have death rate as a clinical measure; a surrogate endpoint would be blood pressure reduction.) Most guidelines also do not consider how generalizable (applicable) the results of a trial are to the populations, interventions, and outcomes specified in the guideline recommendation. In this study, the researchers have investigated the quality of the evidence underlying recommendations for cardiovascular risk management in nine evidence-based clinical practice guides using these additional criteria.
What Did the Researchers Do and Find?
The researchers extracted the recommendations for managing cardiovascular risk from the current US, Canadian, and European guidelines for the management of diabetes, abnormal blood lipid levels (dyslipidemia), and hypertension. They graded the quality of evidence for each recommendation using the Canadian Hypertension Education Program (CHEP) grading scheme, which considers the type of study, its internal validity, its clinical relevance, and how generally applicable the evidence is considered to be. Of 338 evidence-based recommendations, two-thirds were based on evidence collected in internally valid RCTs, but only half of these RCT-based recommendations were based on high-quality evidence. The evidence underlying 64 of the guideline recommendations failed to achieve a high CHEP grade because the RCT data were collected in a population of people with different characteristics to those covered by the guideline. For example, a recommendation to use spironolactone to reduce blood pressure in people with hypertension was based on an RCT in which the participants initially had congestive heart failure with normal blood pressure. Another 59 recommendations were downgraded because they were based on evidence from RCTs that had not focused on clinical measures of effectiveness.
What Do These Findings Mean?
These findings indicate that although most of the recommendations for cardiovascular risk management therapies in the selected guidelines were based on evidence collected in internally valid RCTs, less than one-third were based on high-quality evidence applicable to the populations, treatments, and outcomes specified in guideline recommendations. A limitation of this study is that it analyzed a subset of recommendations in only a few guidelines. Nevertheless, the findings serve to warn clinicians that evidence-based guidelines are not necessarily based on high-quality evidence. In addition, they emphasize the need to make the evidence base underlying guideline recommendations more transparent by using an extended grading system like the CHEP scheme. If this were done, the researchers suggest, it would help clinicians apply guideline recommendations appropriately to their individual patients.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040250.
• Wikipedia contains pages on evidence-based medicine and on clinical practice guidelines (note: Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
• The National Guideline Clearinghouse provides information on US national guidelines
• The Guidelines International Network promotes the systematic development and application of clinical practice guidelines
• Information is available on the Canadian Hypertension Education Program (CHEP) (in French and English)
• See information on the Grading of Recommendations Assessment, Development and Evaluation (GRADE) working group, an organization that has developed an grading scheme similar to the CHEP scheme (in English, Spanish, French, German, and Italian)
doi:10.1371/journal.pmed.0040250
PMCID: PMC1939859  PMID: 17683197
2.  Threats to Validity in the Design and Conduct of Preclinical Efficacy Studies: A Systematic Review of Guidelines for In Vivo Animal Experiments 
PLoS Medicine  2013;10(7):e1001489.
Background
The vast majority of medical interventions introduced into clinical development prove unsafe or ineffective. One prominent explanation for the dismal success rate is flawed preclinical research. We conducted a systematic review of preclinical research guidelines and organized recommendations according to the type of validity threat (internal, construct, or external) or programmatic research activity they primarily address.
Methods and Findings
We searched MEDLINE, Google Scholar, Google, and the EQUATOR Network website for all preclinical guideline documents published up to April 9, 2013 that addressed the design and conduct of in vivo animal experiments aimed at supporting clinical translation. To be eligible, documents had to provide guidance on the design or execution of preclinical animal experiments and represent the aggregated consensus of four or more investigators. Data from included guidelines were independently extracted by two individuals for discrete recommendations on the design and implementation of preclinical efficacy studies. These recommendations were then organized according to the type of validity threat they addressed. A total of 2,029 citations were identified through our search strategy. From these, we identified 26 guidelines that met our eligibility criteria—most of which were directed at neurological or cerebrovascular drug development. Together, these guidelines offered 55 different recommendations. Some of the most common recommendations included performance of a power calculation to determine sample size, randomized treatment allocation, and characterization of disease phenotype in the animal model prior to experimentation.
Conclusions
By identifying the most recurrent recommendations among preclinical guidelines, we provide a starting point for developing preclinical guidelines in other disease domains. We also provide a basis for the study and evaluation of preclinical research practice.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
The development process for new drugs is lengthy and complex. It begins in the laboratory, where scientists investigate the causes of diseases and identify potential new treatments. Next, promising interventions undergo preclinical research in cells and in animals (in vivo animal experiments) to test whether the intervention has the expected effect and to support the generalization (extension) of this treatment–effect relationship to patients. Drugs that pass these tests then enter clinical trials, where their safety and efficacy is tested in selected groups of patients under strictly controlled conditions. Finally, the government bodies responsible for drug approval review the results of the clinical trials, and successful drugs receive a marketing license, usually a decade or more after the initial laboratory work. Notably, only 11% of agents that enter clinical testing (investigational drugs) are ultimately licensed.
Why Was This Study Done?
The frequent failure of investigational drugs during clinical translation is potentially harmful to trial participants. Moreover, the costs of these failures are passed onto healthcare systems in the form of higher drug prices. It would be good, therefore, to reduce the attrition rate of investigational drugs. One possible explanation for the dismal success rate of clinical translation is that preclinical research, the key resource for justifying clinical development, is flawed. To address this possibility, several groups of preclinical researchers have issued guidelines intended to improve the design and execution of in vivo animal studies. In this systematic review (a study that uses predefined criteria to identify all the research on a given topic), the authors identify the experimental practices that are commonly recommended in these guidelines and organize these recommendations according to the type of threat to validity (internal, construct, or external) that they address. Internal threats to validity are factors that confound reliable inferences about treatment–effect relationships in preclinical research. For example, experimenter expectation may bias outcome assessment. Construct threats to validity arise when researchers mischaracterize the relationship between an experimental system and the clinical disease it is intended to represent. For example, researchers may use an animal model for a complex multifaceted clinical disease that only includes one characteristic of the disease. External threats to validity are unseen factors that frustrate the transfer of treatment–effect relationships from animal models to patients.
What Did the Researchers Do and Find?
The researchers identified 26 preclinical guidelines that met their predefined eligibility criteria. Twelve guidelines addressed preclinical research for neurological and cerebrovascular drug development; other disorders covered by guidelines included cardiac and circulatory disorders, sepsis, pain, and arthritis. Together, the guidelines offered 55 different recommendations for the design and execution of preclinical in vivo animal studies. Nineteen recommendations addressed threats to internal validity. The most commonly included recommendations of this type called for the use of power calculations to ensure that sample sizes are large enough to yield statistically meaningful results, random allocation of animals to treatment groups, and “blinding” of researchers who assess outcomes to treatment allocation. Among the 25 recommendations that addressed threats to construct validity, the most commonly included recommendations called for characterization of the properties of the animal model before experimentation and matching of the animal model to the human manifestation of the disease. Finally, six recommendations addressed threats to external validity. The most commonly included of these recommendations suggested that preclinical research should be replicated in different models of the same disease and in different species, and should also be replicated independently.
What Do These Findings Mean?
This systematic review identifies a range of investigational recommendations that preclinical researchers believe address threats to the validity of preclinical efficacy studies. Many of these recommendations are not widely implemented in preclinical research at present. Whether the failure to implement them explains the frequent discordance between the results on drug safety and efficacy obtained in preclinical research and in clinical trials is currently unclear. These findings provide a starting point, however, for the improvement of existing preclinical research guidelines for specific diseases, and for the development of similar guidelines for other diseases. They also provide an evidence-based platform for the analysis of preclinical evidence and for the study and evaluation of preclinical research practice. These findings should, therefore, be considered by investigators, institutional review bodies, journals, and funding agents when designing, evaluating, and sponsoring translational research.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001489.
The US Food and Drug Administration provides information about drug approval in the US for consumers and for health professionals; its Patient Network provides a step-by-step description of the drug development process that includes information on preclinical research
The UK Medicines and Healthcare Products Regulatory Agency (MHRA) provides information about all aspects of the scientific evaluation and approval of new medicines in the UK; its My Medicine: From Laboratory to Pharmacy Shelf web pages describe the drug development process from scientific discovery, through preclinical and clinical research, to licensing and ongoing monitoring
The STREAM website provides ongoing information about policy, ethics, and practices used in clinical translation of new drugs
The CAMARADES collaboration offers a “supporting framework for groups involved in the systematic review of animal studies” in stroke and other neurological diseases
doi:10.1371/journal.pmed.1001489
PMCID: PMC3720257  PMID: 23935460
3.  Prevalence and incidence density rates of chronic comorbidity in type 2 diabetes patients: an exploratory cohort study 
BMC Medicine  2012;10:128.
Background
Evidence-based diabetes guidelines generally neglect comorbidity, which may interfere with diabetes management. The prevalence of comorbidity described in patients with type 2 diabetes (T2D) shows a wide range depending on the population selected and the comorbid diseases studied. This exploratory study aimed to establish comorbidity rates in an unselected primary-care population of patients with T2D.
Methods
This was a cohort study of 714 adult patients with newly diagnosed T2D within the study period (1985-2007) in a practice-based research network in the Netherlands. The main outcome measures were prevalence and incidence density rates of chronic comorbid diseases and disease clusters. All chronic disease episodes registered in the practice-based research network were considered as comorbidities. We categorised comorbidity into 'concordant' (that is, shared aetiology, risk factors, and management plans with diabetes) and 'discordant' comorbidity. Prevalence and incidence density were assessed for both categories of comorbidity.
Results
The mean observation period was 17.3 years. At the time of diabetes diagnosis, 84.6% of the patients had one or more chronic comorbid disease of 'any type', 70.6% had one or more discordant comorbid disease, and 48.6% and 27.2% had three or more chronic comorbid diseases of 'any type' or of 'discordant only', respectively. A quarter of those without any comorbid disease at the time of their diabetes diagnosis developed at least one comorbid disease in the first year afterwards. Cardiovascular diseases (considered concordant comorbidity) were the most common, but there were also high rates of musculoskeletal and mental disease. Discordant comorbid diseases outnumbered concordant diseases.
Conclusions
We found high prevalence and incidence density rates for both concordant and discordant comorbidity. The latter may interfere with diabetes management, thus future research and clinical practice should take discordant comorbidity in patients with T2D into account.
doi:10.1186/1741-7015-10-128
PMCID: PMC3523042  PMID: 23106808
type 2 diabetes; comorbidity; primary care; prevalence; incidence
4.  Inclusion of Ethical Issues in Dementia Guidelines: A Thematic Text Analysis 
PLoS Medicine  2013;10(8):e1001498.
Background
Clinical practice guidelines (CPGs) aim to improve professionalism in health care. However, current CPG development manuals fail to address how to include ethical issues in a systematic and transparent manner. The objective of this study was to assess the representation of ethical issues in general CPGs on dementia care.
Methods and Findings
To identify national CPGs on dementia care, five databases of guidelines were searched and national psychiatric associations were contacted in August 2011 and in June 2013. A framework for the assessment of the identified CPGs' ethical content was developed on the basis of a prior systematic review of ethical issues in dementia care. Thematic text analysis and a 4-point rating score were employed to assess how ethical issues were addressed in the identified CPGs. Twelve national CPGs were included. Thirty-one ethical issues in dementia care were identified by the prior systematic review. The proportion of these 31 ethical issues that were explicitly addressed by each CPG ranged from 22% to 77%, with a median of 49.5%. National guidelines differed substantially with respect to (a) which ethical issues were represented, (b) whether ethical recommendations were included, (c) whether justifications or citations were provided to support recommendations, and (d) to what extent the ethical issues were explained.
Conclusions
Ethical issues were inconsistently addressed in national dementia guidelines, with some guidelines including most and some including few ethical issues. Guidelines should address ethical issues and how to deal with them to help the medical profession understand how to approach care of patients with dementia, and for patients, their relatives, and the general public, all of whom might seek information and advice in national guidelines. There is a need for further research to specify how detailed ethical issues and their respective recommendations can and should be addressed in dementia guidelines.
Please see later in the article for the Editors' Summary
Editors’ Summary
Background
In the past, doctors tended to rely on their own experience to choose the best treatment for their patients. Faced with a patient with dementia (a brain disorder that affects short-term memory and the ability tocarry out normal daily activities), for example, a doctor would use his/her own experience to help decide whether the patient should remain at home or would be better cared for in a nursing home. Similarly, the doctor might have to decide whether antipsychotic drugs might be necessary to reduce behavioral or psychological symptoms such as restlessness or shouting. However, over the past two decades, numerous evidence-based clinical practice guidelines (CPGs) have been produced by governmental bodies and medical associations that aim to improve standards of clinical competence and professionalism in health care. During the development of each guideline, experts search the medical literature for the current evidence about the diagnosis and treatment of a disease, evaluate the quality of that evidence, and then make recommendations based on the best evidence available.
Why Was This Study Done?
Currently, CPG development manuals do not address how to include ethical issues in CPGs. A health-care professional is ethical if he/she behaves in accordance with the accepted principles of right and wrong that govern the medical profession. More specifically, medical professionalism is based on a set of binding ethical principles—respect for patient autonomy, beneficence, non-malfeasance (the “do no harm” principle), and justice. In particular, CPG development manuals do not address disease-specific ethical issues (DSEIs), clinical ethical situations that are relevant to the management of a specific disease. So, for example, a DSEI that arises in dementia care is the conflict between the ethical principles of non-malfeasance and patient autonomy (freedom-to-move-at-will). Thus, healthcare professionals may have to decide to physically restrain a patient with dementia to prevent the patient doing harm to him- or herself or to someone else. Given the lack of guidance on how to address ethical issues in CPG development manuals, in this thematic text analysis, the researchers assess the representation of ethical issues in CPGs on general dementia care. Thematic text analysis uses a framework for the assessment of qualitative data (information that is word-based rather than number-based) that involves pinpointing, examining, and recording patterns (themes) among the available data.
What Did the Researchers Do and Find?
The researchers identified 12 national CPGs on dementia care by searching guideline databases and by contacting national psychiatric associations. They developed a framework for the assessment of the ethical content in these CPGs based on a previous systematic review of ethical issues in dementia care. Of the 31 DSEIs included by the researchers in their analysis, the proportion that were explicitly addressed by each CPG ranged from 22% (Switzerland) to 77% (USA); on average the CPGs explicitly addressed half of the DSEIs. Four DSEIs—adequate consideration of advanced directives in decision making, usage of GPS and other monitoring techniques, covert medication, and dealing with suicidal thinking—were not addressed in at least 11 of the CPGs. The inclusion of recommendations on how to deal with DSEIs ranged from 10% of DSEIs covered in the Swiss CPG to 71% covered in the US CPG. Overall, national guidelines differed substantially with respect to which ethical issues were included, whether ethical recommendations were included, whether justifications or citations were provided to support recommendations, and to what extent the ethical issues were clearly explained.
What Do These Findings Mean?
These findings show that national CPGs on dementia care already address clinical ethical issues but that the extent to which the spectrum of DSEIs is considered varies widely within and between CPGs. They also indicate that recommendations on how to deal with DSEIs often lack the evidence that health-care professionals use to justify their clinical decisions. The researchers suggest that this situation can and should be improved, although more research is needed to determine how ethical issues and recommendations should be addressed in dementia guidelines. A more systematic and transparent inclusion of DSEIs in CPGs for dementia (and for other conditions) would further support the concept of medical professionalism as a core element of CPGs, note the researchers, but is also important for patients and their relatives who might turn to national CPGs for information and guidance at a stressful time of life.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001498.
Wikipedia contains a page on clinical practice guidelines (note: Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
The US National Guideline Clearinghouse provides information on national guidelines, including CPGs for dementia
The Guidelines International Network promotes the systematic development and application of clinical practice guidelines
The American Medical Association provides information about medical ethics; the British Medical Association provides information on all aspects of ethics and includes an essential tool kit that introduces common ethical problems and practical ways to deal with them
The UK National Health Service Choices website provides information about dementia, including a personal story about dealing with dementia
MedlinePlus provides links to additional resources about dementia and about Alzheimers disease, a specific type of dementia (in English and Spanish)
The UK Nuffield Council on Bioethics provides the report Dementia: ethical issues and additional information on the public consultation on ethical issues in dementia care
doi:10.1371/journal.pmed.1001498
PMCID: PMC3742442  PMID: 23966839
5.  Development of comorbidity-adapted exercise protocols for patients with knee osteoarthritis 
Background
Exercise therapy is generally recommended for patients with osteoarthritis (OA) of the knee. Comorbidity, which is highly prevalent in OA, may interfere with exercise therapy. To date, there is no evidence-based protocol for the treatment of patients with knee OA and comorbidity. Special protocols adapted to the comorbidity may facilitate the application of exercise therapy in patients with knee OA and one or more comorbidities.
Purpose
The purpose of this study was to develop comorbidity-adapted exercise protocols for patients with knee OA and comorbidity.
Method
Several steps were undertaken to develop comorbidity-adapted protocols: selection of highly prevalent comorbidities in OA, a literature search to identify restrictions and contraindications for exercise therapy for the various comorbid diseases, consultation of experts on each comorbid disease, and field testing of the protocol in eleven patients with knee OA and comorbidity.
Results
Based on literature and expert opinion, comorbidity-adapted protocols were developed for highly prevalent comorbidities in OA. Field testing showed that the protocols provided guidance in clinical decision making in both the diagnostic and the treatment phase. Because of overlap, the number of exercise protocols could be reduced to three: one for physiological adaptations (coronary disease, heart failure, hypertension, diabetes type 2, chronic obstructive pulmonary diseases, obesity), one for behavioral adaptations (chronic a-specific pain, nonspecific low back pain, depression), and one for environmental adaptations (visual or hearing impairments). Evaluation of patient outcome after treatment showed significant (P<0.05) and clinically relevant improvements in activity limitations and pain.
Conclusion
Comorbidity-adapted exercise protocols for patients with knee OA were developed, providing guidance in clinical reasoning with regard to diagnostics and treatment. To evaluate the effectiveness of treatment in line with our protocols, a randomized clinical trial should be performed.
doi:10.2147/CIA.S55705
PMCID: PMC4027930  PMID: 24868151
knee osteoarthritis; exercise therapy; comorbidity; rehabilitation; arthritis; coexisting disease
6.  Bariatric Surgery 
Executive Summary
Objective
To conduct an evidence-based analysis of the effectiveness and cost-effectiveness of bariatric surgery.
Background
Obesity is defined as a body mass index (BMI) of at last 30 kg/m2.1 Morbid obesity is defined as a BMI of at least 40 kg/m2 or at least 35 kg/m2 with comorbid conditions. Comorbid conditions associated with obesity include diabetes, hypertension, dyslipidemias, obstructive sleep apnea, weight-related arthropathies, and stress urinary incontinence. It is also associated with depression, and cancers of the breast, uterus, prostate, and colon, and is an independent risk factor for cardiovascular disease.
Obesity is also associated with higher all-cause mortality at any age, even after adjusting for potential confounding factors like smoking. A person with a BMI of 30 kg/m2 has about a 50% higher risk of dying than does someone with a healthy BMI. The risk more than doubles at a BMI of 35 kg/m2. An expert estimated that about 160,000 people are morbidly obese in Ontario. In the United States, the prevalence of morbid obesity is 4.7% (1999–2000).
In Ontario, the 2004 Chief Medical Officer of Health Report said that in 2003, almost one-half of Ontario adults were overweight (BMI 25–29.9 kg/m2) or obese (BMI ≥ 30 kg/m2). About 57% of Ontario men and 42% of Ontario women were overweight or obese. The proportion of the population that was overweight or obese increased gradually from 44% in 1990 to 49% in 2000, and it appears to have stabilized at 49% in 2003. The report also noted that the tendency to be overweight and obese increases with age up to 64 years. BMI should be used cautiously for people aged 65 years and older, because the “normal” range may begin at slightly above 18.5 kg/m2 and extend into the “overweight” range.
The Chief Medical Officer of Health cautioned that these data may underestimate the true extent of the problem, because they were based on self reports, and people tend to over-report their height and under-report their weight. The actual number of Ontario adults who are overweight or obese may be higher.
Diet, exercise, and behavioural therapy are used to help people lose weight. The goals of behavioural therapy are to identify, monitor, and alter behaviour that does not help weight loss. Techniques include self-monitoring of eating habits and physical activity, stress management, stimulus control, problem solving, cognitive restructuring, contingency management, and identifying and using social support. Relapse, when people resume old, unhealthy behaviour and then regain the weight, can be problematic.
Drugs (including gastrointestinal lipase inhibitors, serotonin norepinephrine reuptake inhibitors, and appetite suppressants) may be used if behavioural interventions fail. However, estimates of efficacy may be confounded by high rates of noncompliance, in part owing to the side effects of the drugs. In addition, the drugs have not been approved for indefinite use, despite the chronic nature of obesity.
The Technology
Morbidly obese people may be eligible for bariatric surgery. Bariatric surgery for morbid obesity is considered an intervention of last resort for patients who have attempted first-line forms of medical management, such as diet, increased physical activity, behavioural modification, and drugs.
There are various bariatric surgical procedures and several different variations for each of these procedures. The surgical interventions can be divided into 2 general types: malabsorptive (bypassing parts of the gastrointestinal tract to limit the absorption of food), and restrictive (decreasing the size of the stomach so that the patient is satiated with less food). All of these may be performed as either open surgery or laparoscopically. An example of a malabsorptive technique is Roux-en-Y gastric bypass (RYGB). Examples of restrictive techniques are vertical banded gastroplasty (VBG) and adjustable gastric banding (AGB).
The Ontario Health Insurance Plan (OHIP) Schedule of Benefits for Physician Services includes fee code “S120 gastric bypass or partition, for morbid obesity” as an insured service. The term gastric bypass is a general term that encompasses a variety of surgical methods, all of which involve reconfiguring the digestive system. The term gastric bypass does not include AGB. The number of gastric bypass procedures funded and done in Ontario, and funded as actual out-of-country approvals,2 is shown below.
Number of Gastric Bypass Procedures by Fiscal Year: Ontario and Actual Out-of-Country (OOC) Approvals
Data from Provider Services, MOHLTC
Courtesy of Provider Services, Ministry of Health and Long Term Care
Review Strategy
The Medical Advisory Secretariat reviewed the literature to assess the effectiveness, safety, and cost-effectiveness of bariatric surgery to treat morbid obesity. It used its standard search strategy to retrieve international health technology assessments and English-language journal articles from selected databases. The interventions of interest were bariatric surgery and, for the controls, either optimal conventional management or another type of bariatric procedure. The outcomes of interest were improvement in comorbid conditions (e.g., diabetes, hypertension); short- and long-term weight loss; quality of life; adverse effects; and economic analysis data. The databases yielded 15 international health technology assessments or systematic reviews on bariatric surgery.
Subsequently, the Medical Advisory Secretariat searched MEDLINE and EMBASE from April 2004 to December 2004, after the search cut-off date of April, 2004, for the most recent systematic reviews on bariatric surgery. Ten studies met the inclusion criteria. One of those 10 was the Swedish Obese Subjects study, which started as a registry and intervention study, and then published findings on people who had been enrolled for at least 2 years or at least 10 years. In addition to the literature review of economic analysis data, the Medical Advisory Secretariat also did an Ontario-based economic analysis.
Summary of Findings
Bariatric surgery generally is effective for sustained weight loss of about 16% for people with BMIs of at least 40 kg/m2 or at least 35 kg/m2 with comorbid conditions (including diabetes, high lipid levels, and hypertension). It also is effective at resolving the associated comorbid conditions. This conclusion is largely based on level 3a evidence from the prospectively designed Swedish Obese Subjects study, which recently published 10-year outcomes for patients who had bariatric surgery compared with patients who received nonsurgical treatment. (1)
Regarding specific procedures, there is evidence that malabsorptive techniques are better than other banding techniques for weight loss and resolution of comorbid illnesses. However, there are no published prospective, long-term, direct comparisons of these techniques available.
Surgery for morbid obesity is considered an intervention of last resort for patients who have attempted first-line forms of medical management, such as diet, increased physical activity, behavioural modification, and drugs. In the absence of direct comparisons of active nonsurgical intervention via caloric restriction with bariatric techniques, the following observations are made:
A recent systematic review examining the efficacy of major commercial and organized self-help weight loss programs in the United States concluded that the evidence to support the use of such programs was suboptimal, except for one trial on Weight Watchers. Furthermore, the programs were associated with high costs, attrition rates, and probability of regaining at least 50% of the lost weight in 1 to 2 years. (2)
A recent randomized controlled trial reported 1-year outcomes comparing weight loss and metabolic changes in severely obese patients assigned to either a low-carbohydrate diet or a conventional weight loss diet. At 1 year, weight loss was similar for patients in each group (mean, 2–5 kg). There was a favourable effect on triglyceride levels and glycemic control in the low-carbohydrate diet group. (3)
A decision-analysis model showed bariatric surgery results in increased life expectancy in morbidly obese patients when compared to diet and exercise. (4)
A cost-effectiveness model showed bariatric surgery is cost-effective relative to nonsurgical management. (5)
Extrapolating from 2003 data from the United States, Ontario would likely need to do 3,500 bariatric surgeries per year. It currently does 508 per year, including out-of-country surgeries.
PMCID: PMC3382415  PMID: 23074460
7.  Comorbidity and dementia: a scoping review of the literature 
BMC Medicine  2014;12(1):192.
Background
Evidence suggests that amongst people with dementia there is a high prevalence of comorbid medical conditions and related complaints. The presence of dementia may complicate clinical care for other conditions and undermine a patient’s ability to manage a chronic condition. The aim of this study was to scope the extent, range and nature of research activity around dementia and comorbidity.
Methods
We undertook a scoping review including all types of research relating to the prevalence of comorbidities in people with dementia; current systems, structures and other issues relating to service organisation and delivery; patient and carer experiences; and the experiences and attitudes of service providers. We searched AMED, Cochrane Library, CINAHL, PubMed, NHS Evidence, Scopus, Google Scholar (searched 2012, Pubmed updated 2013), checked reference lists and performed citation searches on PubMed and Google Scholar (ongoing to February 2014).
Results
We included 54 primary studies, eight reviews and three guidelines. Much of the available literature relates to the prevalence of comorbidities in people with dementia or issues around quality of care. Less is known about service organisation and delivery or the views and experiences of people with dementia and their family carers. There is some evidence that people with dementia did not have the same access to treatment and monitoring for conditions such as visual impairment and diabetes as those with similar comorbidities but without dementia.
Conclusions
The prevalence of comorbid conditions in people with dementia is high. Whilst current evidence suggests that people with dementia may have poorer access to services the reasons for this are not clear. There is a need for more research looking at the ways in which having dementia impacts on clinical care for other conditions and how the process of care and different services are adapting to the needs of people with dementia and comorbidity. People with dementia should be included in the debate about the management of comorbidities in older populations and there needs to be greater consideration given to including them in studies that focus on age-related healthcare issues.
Electronic supplementary material
The online version of this article (doi:10.1186/s12916-014-0192-4) contains supplementary material, which is available to authorized users.
doi:10.1186/s12916-014-0192-4
PMCID: PMC4229610  PMID: 25358236
Dementia; Comorbidity; Diabetes; Stroke; Visual impairment; Scoping review
8.  The Impact of Comorbidity Type on Measures of Quality for Diabetes Care 
Medical Care  2011;49(6):605-610.
Objective
Studies provide conflicting results about the impact of comorbid conditions on the quality of chronic illness care. We assessed the effect of comorbidity type (concordant, discordant, or both) on the receipt of guideline-recommended care among patients with diabetes.
Research Design
Patients were assigned to 1 of 4 condition groups: diabetes-concordant (hypertension, ischemic heart disease, hyperlipidemia), and/or -discordant (arthritis, depression, chronic obstructive pulmonary disease) conditions, or neither. We evaluated hemoglobin (Hb) A1c, blood pressure, and low-density lipoprotein cholesterol (LDL-C) readings at index and measured overall good quality of diabetes care, including a 6-month follow-up interval. We assessed the effect of condition group on overall good quality of care with logistic regression and generalized ordered logistic regression.
Results
We assigned 35,872 patients to the diabetes comorbid condition groups, ranging from 2.0% in the discordant-only group to 58.0% in the concordant-only group. Patients with both types of conditions were more likely than those with no comorbidities to receive overall good quality for glycemic [odds ratio (OR), 2.13; 95% confidence interval (CI), 1.86-2.41], blood pressure (OR, 1.62; 95% CI, 1.40-1.84) and LDL-C (OR, 3.57; 95% CI, 3.08-4.05) control within 6 months of an index visit. They were also more likely to receive overall good quality for all 3 quality measures combined (OR, 2.17; 95% CI, 1.96-2.39).
Conclusions
Patients with the greatest clinical complexity were more likely than less complex patients to receive high quality diabetes care, suggesting that increased complexity does not necessarily predispose chronically ill patients to receiving poorer care. However, caution should be used in treating certain patient groups, such as the elderly, for whom adherence to multiple condition-specific guidelines may lack benefit or cause harm.
doi:10.1097/MLR.0b013e31820f0ed0
PMCID: PMC3366691  PMID: 21422952
diabetes mellitus; quality of health care; comorbidity
9.  Chiropractic clinical practice guideline: evidence-based treatment of adult neck pain not due to whiplash 
OBJECTIVE
To provide an evidence-based clinical practice guideline for the chiropractic cervical treatment of adults with acute or chronic neck pain not due to whiplash. This is a considerable health concern considered to be a priority by stakeholders, and about which the scientific information was poorly organized.
OPTIONS
Cervical treatments: manipulation, mobilization, ischemic pressure, clinic- and home-based exercise, traction, education, low-power laser, massage, transcutaneous electrical nerve stimulation, pillows, pulsed electromagnetic therapy, and ultrasound.
OUTCOMES
The primary outcomes considered were improved (reduced and less intrusive) pain and improved (increased and easier) ranges of motion (ROM) of the adult cervical spine.
EVIDENCE
An “extraction” team recorded evidence from articles found by literature search teams using 4 separate literature searches, and rated it using a Table adapted from the Oxford Centre for Evidence-based Medicine. The searches were 1) Treatment; August, 2003, using MEDLINE, CINAHL, AMED, MANTIS, ICL, The Cochrane Library (includes CENTRAL), and EBSCO, identified 182 articles. 2) Risk management (adverse events); October, 2004, identified 230 articles and 2 texts. 3) Risk management (dissection); September, 2003, identified 79 articles. 4) Treatment update; a repeat of the treatment search for articles published between September, 2003 and November, 2004 inclusive identified 121 articles.
VALUES
To enable the search of the literature, the authors (Guidelines Development Committee [GDC]) regarded chiropractic treatment as including elements of “conservative” care in the search strategies, but not in the consideration of the range of chiropractic practice. Also, knowledge based only on clinical experience was considered less valid and reliable than good-caliber evidence, but where the caliber of the relevant evidence was low or it was non-existent, unpublished clinical experience was considered to be equivalent to, or better than the published evidence.
REPORTED BENEFITS, HARMS AND COSTS
The expected benefits from the recommendations include more rapid recovery from pain, impairment and disability (improved pain and ROM). The GDC identified evidence-based pain benefits from 10 unimodal treatments and more than 7 multimodal treatments. There were no pain benefits from magnets in necklaces, education or relaxation alone, occipital release alone, or head retraction-extension exercise combinations alone. The specificity of the studied treatments meant few studies could be generalized to more than a minority of patients.
Adverse events were not addressed in most studies, but where they were, there were none or they were minor. The theoretic harm of vertebral artery dissection (VAD) was not reported, but an analysis suggested that 1 VAD may occur subsequent to 1 million cervical manipulations.
Costs were not analyzed in this guideline, but it is the understanding of the GDC that recommendations limiting ineffective care and promoting a more rapid return of patients to full functional capacity will reduce patient costs, as well as increase patient safety and satisfaction.
For simplicity, this version of the guideline includes primarily data synthesized across studies (evidence syntheses), whereas the technical and the interactive versions of this guideline (http://ccachiro.org/cpg) also include relevant data from individual studies (evidence extractions).
RECOMMENDATIONS
The GDC developed treatment, risk-management and research recommendations using the available evidence. Treatment recommendations addressing 13 treatment modalities revolved around a decision algorithm comprising diagnosis (or assessment leading to diagnosis), treatment and reassessment. Several specific variations of modalities of treatment were not recommended.
For adverse events not associated with a treatment modality, but that occur in the clinical setting, there was evidence to recommend reconsideration of treatment options or referral to the appropriate health services. For adverse events associated with a treatment modality, but not a known or observable risk factor, there was evidence to recommend heightened vigilance when a relevant treatment is planned or administered. For adverse events associated with a treatment modality and predicted by an observable risk factor, there was evidence to recommend absolute contraindications, and requirements for treatment modality modification or caution to minimize harm and maximize benefit. For managing the theoretic risk of dissection, there was evidence to recommend a systematic risk-management approach. For managing the theoretic risk of stroke, there was support to recommend minimal rotation in administering any modality of upper-cervical spine treatment, and to recommend caution in treating a patient with hyperhomocysteinemia, although the evidence was especially ambiguous in both of these areas.
Research recommendations addressed the poor caliber of many of the studies; the GDC concluded that the scientific base for chiropractic cervical treatment of neck pain was not of sufficient quality or scope to “cover” current chiropractic practice comprehensively, although this should not suggest other disciplines are more evidence-based.
VALIDATION
This guideline was authored by the 10 members of the GDC (Elizabeth Anderson-Peacock, Jean-Sébastien Blouin, Roland Bryans, Normand Danis, Andrea Furlan, Henri Marcoux, Brock Potter, Rick Ruegg, Janice Gross Stein, Eleanor White) based on the work of 3 literature search teams and an evidence extraction team, and in light of feedback from a commentator (Donald R Murphy), a 5-person review panel (Robert R Burton, Andrea Furlan, Richard Roy, Steven Silk, Roy Till), a 6-person Task Force (Grayden Bridge, H James Duncan, Wanda Lee MacPhee, Bruce Squires, Greg Stewart, Dean Wright), and 2 national profession-wide critiques of complete drafts. Two professional editors with extensive guidelines experience were contracted (Thor Eglington, Bruce P Squires). Key contributors to the guideline included individuals with specialties or expert knowledge in chiropractic, medicine, research processes, literature analysis processes, clinical practice guideline processes, protective association affairs, regulatory affairs, and the public interest. This guideline has been formally peer reviewed.
PMCID: PMC1839918  PMID: 17549134
chiropractic; guideline; evidence-based; neck pain
10.  Protein localization as a principal feature of the etiology and comorbidity of genetic diseases 
Proteins localized within the same subcellular compartment tend to be functionally associated. This study shows that subcellular localization and network distance between disease-associated proteins provide complementary information explaining patterns of disease comorbidity.
A positive correlation was found between subcellular localization of disease-associated protein pairs and measures of comorbidity.A higher comorbidity tendency was found for disease-associated protein pairs that are positioned within a shorter distance in the protein interaction network.The integration of subcellular localization information with protein interaction network sheds light onto the potential molecular connections underlying comorbidity patterns and will help to understand the mechanisms of human disease.
It was shown that the emergence of phenotypically similar diseases are triggered as a result of molecular connections between disease-causing genes (Oti and Brunner, 2007; Zaghloul and Katsanis, 2010). From a genetics, perspective diseases are associated with certain genes (Goh et al, 2007; Feldman et al, 2008), whereas from a proteomics perspective phenotypically similar diseases are connected via biological modules such as protein–protein interactions (PPIs) or molecular pathways (Lage et al, 2007; Jiang et al, 2008; Wu et al, 2008; Linghu et al, 2009; Suthram et al, 2010). These molecular connections between diseases were observed on the population level as well: diseases connected through molecular connections such as shared genes, PPIs, and metabolic pathways tend to show elevated comorbidity (Rzhetsky et al, 2007; Lee et al, 2008; Zhernakova et al, 2009; Park et al, 2009a, 2009b). While these findings constitute a step toward improving our understanding of the mechanism of disease progression, there are still many more molecule-level connections between disease pairs that need to be explored in order to establish a firmer comorbidity association.
Subcellular localization provides spatial information of proteins in the cell; proteins target subcellular localizations to interact with appropriate partners and form functional complexes in signaling pathways and metabolic processes (Au et al, 2007). Abnormal protein localizations are known to lead to the loss of functional effects in diseases (Luheshi et al, 2008; Laurila and Vihinen, 2009). For example, mis-localizations of nuclear/cytoplasmic transport have been detected in many types of carcinoma cells (Kau et al, 2004). A proper identification of protein subcellular localization can hence be useful in discovering disease-associated proteins (Giallourakis et al, 2005; Calvo and Mootha, 2010). With this understanding, we postulate that disease-associated proteins connected by subcellular localizations could also explain the phenotypic similarities between diseases. Furthermore, such connections may also couple to disease progressions that contribute to multiple disease manifestation, that is, comorbidity.
Protein subcellular localization has been extensively studied through various methods to determine a variety of protein functions. To the best of our knowledge, the connection between diseases and subcellular localizations are yet to be studied systematically. To resolve this we constructed, for the first time, a human Disease-associated Protein and subcellular Localization (DPL) matrix (top panel in Box 1). Our DPL matrix provides the ‘cellular localization map of diseases' that represents the spatial index of diseases in the cell. We found that each disease shows unique characteristics of subcellular localization profile in the DPL matrix. We were interested in determining whether subsets of 1284 human diseases exhibit distinct enrichment profiles across subcellular localizations. We calculated pairwise correlations and performed a hierarchical clustering of the enrichments of the 1284 diseases across 10 different subcellular localizations.
Our DPL matrix revealed that 778 diseases (∼62%, P=1.40 × 10−3) are enriched in a single localization and 273 diseases (∼21%, P=3.45 × 10−3) are enriched in dual localizations. In the DPL matrix, certain disease-associated proteins are likely to be found in membrane-bounded organelles such as mitochondria, lysosome, and peroxisome, indicating that the mutations of proteins localized to these compartments are connected to the pathophysiological conditions of those organelles. Meanwhile, certain disease-associated proteins in the DPL matrix are enriched in dual localizations, such as extracellular/plasma membrane or endoplasmic reticulum/Golgi. Although these two pairs of subcellular localizations appear to be distinct compartments at first, they are functionally related compartments in close proximity during protein translocation process in the cell, and thus are likely to share interacting protein partners (Gandhi et al, 2006).
Comorbidity represents the co-occurrence of multiple diseases in the same individual (Lee et al, 2008; Hidalgo et al, 2009; Park et al, 2009a). Many comorbid disease pairs have been shown to share common genes in the human disease network. For example, Diabetes and Alzheimer's disease share a risk factor in angiotensin I converting enzyme, and frequently occur together in an individual. In such instances, comorbidity can be partially attributed to the disease connections on the molecular level. To explore the impact of protein subcellular localization on comorbidity, we hypothesized that certain disease pairs could also be connected via subcellular localization by the molecular connections between the disease-associated proteins (bottom panel in Box 1).
We found a positive correlation between subcellular localization similarity and relative risk (Figure 3B, Pearson's correlation coefficient between relative risk and subcellular localization similarity=0.81, P=2.96 × 10−5). The subcellular localization similarity represents the correlation of subcellular localization profiles between disease pairs. To our surprise, when we compared the relative risk of disease pairs linked via various molecular connections, we found that disease pairs connected by subcellular localization showed a near three-fold higher comorbidity tendency (with link distances equal to 2 or 3) when compared with random pairs (Figure 3E).
We then assessed quantitatively the impact of network distances and subcellular localizations on the comorbidity tendency of disease pairs. We expected the proteins associated with comorbid disease pairs to be located closely in the protein interaction network via fewer links compared with random disease pairs. Indeed, a higher comorbidity tendency was found when two disease-associated proteins were positioned within a shorter distance (gray plots in Figure 3F). Moreover, when subcellular localization information was combined with small network distances, the comorbidity tendency increased dramatically (orange plots in Figure 3F). It suggests that subcellular localization and close network distances, two conceptually distinct molecular connections, contributed synergistically to the comorbidity tendency.
Disease progression is not restricted to the mutation of disease-causing genes, but also affected by molecular connections in ‘disease modules,' resulting in comorbidity (Fraser, 2006; Lee et al, 2008). In this study, for the first time we applied subcellular localization information to elucidate the molecular connections between comorbid diseases. We believe that, based on our finding, our approach helps to define the boundaries of ‘disease modules.' Taken together, integration of diverse molecular connections should improve the molecular level understanding of hitherto unexplained comorbid disease pairs and help us in expanding the scope of our knowledge of the mechanism of human disease progression.
Proteins targeting the same subcellular localization tend to participate in mutual protein–protein interactions (PPIs) and are often functionally associated. Here, we investigated the relationship between disease-associated proteins and their subcellular localizations, based on the assumption that protein pairs associated with phenotypically similar diseases are more likely to be connected via subcellular localization. The spatial constraints from subcellular localization significantly strengthened the disease associations of the proteins connected by subcellular localizations. In particular, certain disease types were more prevalent in specific subcellular localizations. We analyzed the enrichment of disease phenotypes within subcellular localizations, and found that there exists a significant correlation between disease classes and subcellular localizations. Furthermore, we found that two diseases displayed high comorbidity when disease-associated proteins were connected via subcellular localization. We newly explained 7584 disease pairs by using the context of protein subcellular localization, which had not been identified using shared genes or PPIs only. Our result establishes a direct correlation between protein subcellular localization and disease association, and helps to understand the mechanism of human disease progression.
doi:10.1038/msb.2011.29
PMCID: PMC3130560  PMID: 21613983
cellular networks; comorbidity; human disease; subcellular localization
11.  Canadian guidelines for clinical practice: an analysis of their quality and relevance to the care of adults with comorbidity 
BMC Family Practice  2011;12:74.
Background
Clinical guidelines have been the subject of much criticism in primary care literature partly due to potential conflicts in their implementation among patients with multiple chronic conditions. We assessed the relevance of selected Canadian clinical guidelines on chronic diseases for patients with comorbidity and examined their quality.
Methods
We selected 16 chronic medical conditions according to their frequency of occurrence, complexity of treatment, and pertinence to primary care. Recent Canadian clinical guidelines (2004 - 2009) on these conditions, published in English or French, were retrieved. We assessed guideline relevance to the care of patients with comorbidity with a tool developed by Boyd and colleagues. Quality was assessed using the Appraisal of Guidelines Research and Evaluation (AGREE) instrument.
Results
Regarding relevance, 56.2% of guidelines addressed treatment for patients with multiple chronic conditions and 18.8% addressed the issue for older patients. Fifteen guidelines (93.8%) included specific recommendations for patients with one concurrent condition; only three guidelines (18.8%) addressed specific recommendations for patients with two comorbid conditions and one for more than two concurrent comorbid conditions. Quality of the evaluated guidelines was good to very good in four out of the six domains measured using the AGREE instrument. The domains with lower mean scores were Stakeholder Involvement and Applicability.
Conclusions
The quality of the Canadian guidelines examined is generally good, yet their relevance for patients with two or more chronic conditions is very limited and there is room for improvement in this respect.
doi:10.1186/1471-2296-12-74
PMCID: PMC3146414  PMID: 21752267
12.  The 2007 Canadian Hypertension Education Program recommendations for the management of hypertension: Part 2 – therapy 
OBJECTIVE:
To provide updated, evidence-based recommendations for the prevention and management of hypertension in adults.
OPTIONS AND OUTCOMES:
For lifestyle and pharmacological interventions, evidence was reviewed from randomized controlled trials and systematic reviews of trials. Changes in cardiovascular morbidity and mortality were the primary outcomes of interest. However, for lifestyle interventions, blood pressure lowering was accepted as a primary outcome given the lack of long-term morbidity and mortality data in this field. For treatment of patients with kidney disease, the progression of kidney dysfunction was also accepted as a clinically relevant primary outcome.
EVIDENCE:
A Cochrane collaboration librarian conducted an independent MEDLINE search from 2005 to August 2006 to update the 2006 Canadian Hypertension Education Program recommendations. In addition, reference lists were scanned and experts were contacted to identify additional published studies. All relevant articles were reviewed and appraised independently by both content and methodological experts using prespecified levels of evidence.
RECOMMENDATIONS:
Dietary lifestyle modifications for prevention of hypertension, in addition to a well-balanced diet, include a dietary sodium intake of less than 100 mmol/day. In hypertensive patients, the dietary sodium intake should be limited to 65 mmol/day to 100 mmol/day. Other lifestyle modifications for both normotensive and hypertensive patients include: performing 30 min to 60 min of aerobic exercise four to seven days per week; maintaining a healthy body weight (body mass index of 18.5 kg/m2 to 24.9 kg/m2) and waist circumference (less than 102 cm in men and less than 88 cm in women); limiting alcohol consumption to no more than 14 units per week in men or nine units per week in women; following a diet reduced in saturated fat and cholesterol, and one that emphasizes fruits, vegetables and low-fat dairy products, dietary and soluble fibre, whole grains and protein from plant sources; and considering stress management in selected individuals with hypertension.
For the pharmacological management of hypertension, treatment thresholds and targets should take into account each individual’s global atherosclerotic risk, target organ damage and any comorbid conditions: blood pressure should be lowered to lower than 140/90 mmHg in all patients and lower than 130/80 mmHg in those with diabetes mellitus or chronic kidney disease. Most patients require more than one agent to achieve these blood pressure targets. In adults without compelling indications for other agents, initial therapy should include thiazide diuretics; other agents appropriate for first-line therapy for diastolic and/or systolic hypertension include angiotensin-converting enzyme (ACE) inhibitors (except in black patients), long-acting calcium channel blockers (CCBs), angiotensin receptor blockers (ARBs) or beta-blockers (in those younger than 60 years of age). First-line therapy for isolated systolic hypertension includes long-acting dihydropyridine CCBs or ARBs. Certain comorbid conditions provide compelling indications for first-line use of other agents: in patients with angina, recent myocardial infarction, or heart failure, beta-blockers and ACE inhibitors are recommended as first-line therapy; in patients with cerebrovascular disease, an ACE inhibitor plus diuretic combination is preferred; in patients with nondiabetic chronic kidney disease, ACE inhibitors are recommended; and in patients with diabetes mellitus, ACE inhibitors or ARBs (or, in patients without albuminuria, thiazides or dihydropyridine CCBs) are appropriate first-line therapies. All hypertensive patients with dyslipidemia should be treated using the thresholds, targets and agents outlined in the Canadian Cardiovascular Society position statement (recommendations for the diagnosis and treatment of dyslipidemia and prevention of cardiovascular disease). Selected high-risk patients with hypertension who do not achieve thresholds for statin therapy according to the position paper should nonetheless receive statin therapy. Once blood pressure is controlled, acetylsalicylic acid therapy should be considered.
VALIDATION:
All recommendations were graded according to strength of the evidence and voted on by the 57 members of the Canadian Hypertension Education Program Evidence-Based Recommendations Task Force. All recommendations reported here achieved at least 95% consensus. These guidelines will continue to be updated annually.
PMCID: PMC2650757  PMID: 17534460
Antihypertensive drugs; Blood pressure; Guidelines; High blood pressure; Hypertension; Lifestyle interventions
13.  The 2006 Canadian Hypertension Education Program recommendations for the management of hypertension: Part II – Therapy 
OBJECTIVE
To provide updated, evidence-based recommendations for the management of hypertension in adults.
OPTIONS AND OUTCOMES
For lifestyle and pharmacological interventions, evidence from randomized, controlled trials and systematic reviews of trials was preferentially reviewed. Changes in cardiovascular morbidity and mortality were the primary outcomes of interest. For lifestyle interventions, blood pressure (BP) lowering was accepted as a primary outcome given the lack of long-term morbidity/mortality data in this field. For treatment of patients with kidney disease, the development of proteinuria or worsening of kidney function was also accepted as a clinically relevant primary outcome.
EVIDENCE
MEDLINE searches were conducted from November 2004 to October 2005 to update the 2005 recommendations. In addition, reference lists were scanned and experts were contacted to identify additional published studies. All relevant articles were reviewed and appraised independently by content and methodological experts using prespecified levels of evidence.
RECOMMENDATIONS
Lifestyle modifications to prevent and/or treat hypertension include the following: perform 30 min to 60 min of aerobic exercise four to seven days per week; maintain a healthy body weight (body mass index of 18.5 kg/m2 to 24.9 kg/m2) and waist circumference (less than 102 cm for men and less than 88 cm for women); limit alcohol consumption to no more than 14 standard drinks per week in men or nine standard drinks per week in women; follow a diet that is reduced in saturated fat and cholesterol and that emphasizes fruits, vegetables and low-fat dairy products; restrict salt intake; and consider stress management in selected individuals. Treatment thresholds and targets should take into account each individual’s global atherosclerotic risk, target organ damage and comorbid conditions. BP should be lowered to less than 140/90 mmHg in all patients, and to less than 130/80 mmHg in those with diabetes mellitus or chronic kidney disease (regardless of the degree of proteinuria). Most adults with hypertension require more than one agent to achieve these target BPs. For adults without compelling indications for other agents, initial therapy should include thiazide diuretics. Other agents appropriate for first-line therapy for diastolic hypertension with or without systolic hypertension include beta-blockers (in those younger than 60 years), angiotensin-converting enzyme (ACE) inhibitors (in nonblack patients), long-acting calcium channel blockers or angiotensin receptor antagonists. Other agents for first-line therapy for isolated systolic hypertension include long-acting dihydropyridine calcium channel blockers or angiotensin receptor antagonists. Certain comorbid conditions provide compelling indications for first-line use of other agents: in patients with angina, recent myocardial infarction or heart failure, beta-blockers and ACE inhibitors are recommended as first-line therapy; in patients with diabetes mellitus, ACE inhibitors or angiotensin receptor antagonists (or in patients without albuminuria, thiazides or dihydropyridine calcium channel blockers) are appropriate first-line therapies; and in patients with nondiabetic chronic kidney disease, ACE inhibitors are recommended. All hypertensive patients should have their fasting lipids screened, and those with dyslipidemia should be treated using the thresholds, targets and agents recommended by the Canadian Hypertension Education Program Working Group on the management of dyslipidemia and the prevention of cardiovascular disease. Selected patients with hypertension, but without dyslipidemia, should also receive statin therapy and/or acetylsalicylic acid therapy.
VALIDATION
All recommendations were graded according to strength of the evidence and voted on by the 45 members of the Canadian Hypertension Education Program Evidence-Based Recommendations Task Force. All recommendations reported here achieved at least 95% consensus. These guidelines will continue to be updated annually.
PMCID: PMC2560865  PMID: 16755313
Blood pressure; Drugs; Guidelines; High blood pressure; Hypertension; Lifestyle interventions
14.  Guideline Compliance in Chronic Heart Failure Patients with Multiple Comorbid Diseases: Evaluation of an Individualised Multidisciplinary Model of Care 
PLoS ONE  2014;9(4):e93129.
Objective
To assess the impact of individualised, reconciled evidence-based recommendations (IRERs) and multidisciplinary care in patients with chronic heart failure (CHF) on clinical guideline compliance for CHF and common comorbid conditions.
Design and setting
A retrospective hospital clinical audit conducted between 1st July 2006 and February 2011.
Participants
A total of 255 patients with a diagnosis of CHF who attended the Multidisciplinary Ambulatory Consulting Services (MACS) clinics, at the Royal Adelaide Hospital, were included.
Main outcome measures
Compliance with Australian clinical guideline recommendations for CHF, atrial fibrillation, diabetes mellitus and ischaemic heart disease.
Results
Study participants had a median of eight medical conditions (IQR 6–10) and were on an average of 10 (±4) unique medications. Compliance with clinical guideline recommendations for pharmacological therapy for CHF, comorbid atrial fibrillation, diabetes or ischaemic heart disease was high, ranging from 86% for lipid lowering therapy to 98% anti-platelet agents. For all conditions, compliance with lifestyle recommendations was lower than pharmacological therapy, ranging from no podiatry reviews for CHF patients with comorbid diabetes to 75% for heart failure education. Concordance with many guideline recommendations was significantly associated if the patient had IRERs determined, a greater number of recommendations, more clinic visits or if patients participated in a heart failure program.
Conclusions
Despite the high number of comorbid conditions and resulting complexity of the management, high compliance to clinical guideline recommendations was associated with IRER determination in older patients with CHF. Importantly these recommendations need to be communicated to the patient’s general practitioner, regularly monitored and adjusted at clinic visits.
doi:10.1371/journal.pone.0093129
PMCID: PMC3979669  PMID: 24714369
15.  Alemtuzumab in chronic lymphocytic leukemia 
Current Oncology  2007;14(3):96-109.
Questions
With respect to outcomes such as survival, response rate, response duration, time to progression, and quality of life, is alemtuzumab a beneficial treatment option for patients with B-cell chronic lymphocytic leukemia (cll)?
What toxicities are associated with the use of alemtuzumab?
Which patients are more likely—or less likely—to benefit from treatment with alemtuzumab?
Perspectives
Evidence was selected and reviewed by one member of the Hematology Disease Site Group (dsg) of Cancer Care Ontario’s Program in Evidence-Based Care (pebc) and by methodologists. The practice guideline report was reviewed and approved by the Hema-tology dsg, which comprises hematologists, medical and radiation oncologists, and a patient representative. As part of an external review process, the report was disseminated to obtain feedback from practitioners in Ontario.
Outcomes
Outcomes of interest were overall survival, quality of life, response rates and duration, and adverse event rates.
Methodology
A systematic review of the medline, embase, HealthStar, cinahl, and Cochrane Library databases was conducted to search for primary articles and practice guidelines. The evidence informed the development of clinical practice recommendations. The evidence review and recommendations were appraised by a sample of practitioners from Ontario, Canada, and were modified in response to the feedback received. The systematic review and modified recommendations were approved by a review body within the pebc.
Results
The literature review found no published randomized controlled trials (rcts) that evaluated alem-tuzumab alone or in combination with other chemotherapeutic agents for the treatment of relapsed or refractory cll.
One rct evaluated alemtuzumab administered to consolidate a complete or partial response to first-line fludarabine-containing chemotherapy. That study was stopped early because of excessive grades 3 and 4 infection-related toxicity in the alemtuzumab arm. Patients receiving alemtuzumab experienced significantly improved progression-free survival as compared with patients undergoing observation.
Six single-arm studies evaluated disease response with administration of alemtuzumab as a single agent in the treatment of patients with relapsed or refractory cll post-fludarabine. The pooled overall response rate was 38% (complete response: 6%; partial response: 32%). Adverse events associated with the use of alemtuzumab were commonly reported and included serious infusion-related, hematologic, and infection-related toxicities.
Recommendation
This evidence-based recommendation applies to adult patients with B-cell cll.
Treatment with alemtuzumab is a reasonable option for patients with progressive and symptomatic cll that is refractory to both alkylator-based and fludarabine-based regimens.
Qualifying Statements
The evidence supporting treatment with alemtuzumab comes principally from case series that evaluated disease response as the primary outcome measure. Patients should be informed that any possible beneficial effect of alemtuzumab on other outcome measures such as duration of response, quality of life, and overall survival are not supported in evidence and currently remain speculative.
Treatment with alemtuzumab is associated with significant and potentially serious treatment-related toxicities. Patients must be carefully informed of the uncertain balance between potential risks of harm and the chance for benefit reported in studies. Given the current substantial uncertainty in this balance, patient preferences will likely play a large role in determining the appropriate treatment choice.
Given the potential toxicities associated with alemtuzumab, and given the limited nature of the agent’s testing in clinical trials in broad populations of patients with cll, the use of alemtuzumab in patients with important comorbidities may be associated with excessive risks.
PMCID: PMC1899355  PMID: 17593982
Alemtuzumab; Campath; chronic lymphocytic leukemia; systematic review; clinical practice guideline
16.  Rational Prescribing in Primary Care (RaPP): A Cluster Randomized Trial of a Tailored Intervention 
PLoS Medicine  2006;3(6):e134.
Background
A gap exists between evidence and practice regarding the management of cardiovascular risk factors. This gap could be narrowed if systematically developed clinical practice guidelines were effectively implemented in clinical practice. We evaluated the effects of a tailored intervention to support the implementation of systematically developed guidelines for the use of antihypertensive and cholesterol-lowering drugs for the primary prevention of cardiovascular disease.
Methods and Findings
We conducted a cluster-randomized trial comparing a tailored intervention to passive dissemination of guidelines in 146 general practices in two geographical areas in Norway. Each practice was randomized to either the tailored intervention (70 practices; 257 physicians) or control group (69 practices; 244 physicians). Patients started on medication for hypertension or hypercholesterolemia during the study period and all patients already on treatment that consulted their physician during the trial were included. A multifaceted intervention was tailored to address identified barriers to change. Key components were an educational outreach visit with audit and feedback, and computerized reminders linked to the medical record system. Pharmacists conducted the visits. Outcomes were measured for all eligible patients seen in the participating practices during 1 y before and after the intervention. The main outcomes were the proportions of (1) first-time prescriptions for hypertension where thiazides were prescribed, (2) patients assessed for cardiovascular risk before prescribing antihypertensive or cholesterol-lowering drugs, and (3) patients treated for hypertension or hypercholesterolemia for 3 mo or more who had achieved recommended treatment goals.
The intervention led to an increase in adherence to guideline recommendations on choice of antihypertensive drug. Thiazides were prescribed to 17% of patients in the intervention group versus 11% in the control group (relative risk 1.94; 95% confidence interval 1.49–2.49, adjusted for baseline differences and clustering effect). Little or no differences were found for risk assessment prior to prescribing and for achievement of treatment goals.
Conclusions
Our tailored intervention had a significant impact on prescribing of antihypertensive drugs, but was ineffective in improving the quality of other aspects of managing hypertension and hypercholesterolemia in primary care.
Editors' Summary
Background.
An important issue in health care is “getting research into practice,” in other words, making sure that, when evidence from research has established the best way to treat a disease, doctors actually use that approach with their patients. In reality, there is often a gap between evidence and practice.
  An example concerns the treatment of people who have high blood pressure (hypertension) and/or high cholesterol. These are common conditions, and both increase the risk of having a heart attack or a stroke. Research has shown that the risks can be lowered if patients with these conditions are given drugs that lower blood pressure (antihypertensives) and drugs that lower cholesterol. There are many types of these drugs now available. In many countries, the health authorities want family doctors (general practitioners) to make better use of these drugs. They want doctors to prescribe them to everyone who would benefit, using the type of drugs found to be most effective. When there is a choice of drugs that are equally effective, they want doctors to use the cheapest type. (In the case of antihypertensives, an older type, known as thiazides, is very effective and also very cheap, but many doctors prefer to give their patients newer, more expensive alternatives.) Health authorities have issued guidelines to doctors that address these issues. However, it is not easy to change prescribing practices, and research in several countries has shown that issuing guidelines has only limited effects.
Why Was This Study Done?
The researchers wanted—in two parts of Norway—to compare the effects on prescribing practices of what they called the “passive dissemination of guidelines” with a more active approach, where the use of the guidelines was strongly promoted and encouraged.
What Did the Researchers Do and Find?
They worked with 146 general practices. In half of them the guidelines were actively promoted. The remaining were regarded as a control group; they were given the guidelines but no special efforts were made to encourage their use. It was decided at random which practices would be in which group; this approach is called a randomized controlled trial. The methods used to actively promote use of the guidelines included personal visits to the practices by pharmacists and use of a computerized reminder system. Information was then collected on the number of patients who, when first treated for hypertension, were prescribed a thiazide. Other information collected included whether patients had been properly assessed for their level of risk (for strokes and heart attacks) before antihypertensive or cholesterol-lowering drugs were given. In addition, the researchers recorded whether the recommended targets for improvement in blood pressure and cholesterol level had been reached.
Only 11% of those patients visiting the control group of practices who should have been prescribed thiazides, according to the guidelines, actually received them. Of those seen by doctors in the practices where the guidelines were actively promoted, 17% received thiazides. According to statistical analysis, the increase achieved by active promotion is significant. Little or no differences were found for risk assessment prior to prescribing and for achievement of treatment goals.
What Do These Findings Mean?
Even in the active promotion group, the great majority of patients (83%) were still not receiving treatment according to the guidelines. However, active promotion of guidelines is more effective than simply issuing the guidelines by themselves. The study also demonstrates that it is very hard to change prescribing practices. The efforts made here to encourage the doctors to change were considerable, and although the results were significant, they were still disappointing. Also disappointing is the fact that achievement of treatment goals was no better in the active-promotion group. These issues are discussed further in a Perspective about this study (DOI: 10.1371/journal.pmed.0030229).
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0030134.
• The Web site of the American Academy of Family Physicians has a page on heart disease
• The MedlinePlus Medical Encyclopedia's pages on heart diseases and vascular diseases
• Information from NHS Direct (UK National Health Service) about heart attack and stroke
• Another PLoS Medicine article has also addressed trends in thiazide prescribing
Passive dissemination of management guidelines for hypertension and hypercholesterolaemia was compared with active promotion. Active promotion led to significant improvement in antihypertensive prescribing but not other aspects of management.
doi:10.1371/journal.pmed.0030134
PMCID: PMC1472695  PMID: 16737346
17.  Epidemiological strategies for adapting clinical practice guidelines to the needs of multimorbid patients 
Background
Clinical practice guidelines have been developed to improve the quality of health care. However, adherence to current monomorbidity-focused, mono-disciplinary guidelines may result in undesirable effects for persons with several comorbidities, in adverse interactions between drugs and diseases, conflicting management strategies, and polypharmacy. This is why new types of guidelines that address the problem of interacting medical interventions and conditions in multimorbid patients are needed.
Discussion
Previous research projects investigated patterns of multimorbidity and were able to identify combinations of the most prevalent chronic conditions, or clusters of comorbidities. These results represent potential methodological starting points for the development of guidelines that account for multimorbidity. The objective of these efforts is to identify frequent reasons for interactions and adverse events that may occur when the current type of guideline is rigorously applied in multimorbid patients.
Summary
The epidemiologic approaches described above may help guideline developers as a kind of check list of disease combinations that should systematically be considered during guideline development. Given the risk of worse outcomes in a huge group of vulnerable patients, researchers, guideline developers, and funding institutions should give first priority to the development of guidelines more appropriate for use in multimorbid persons.
doi:10.1186/1472-6963-13-352
PMCID: PMC3848618  PMID: 24041153
Clinical practice guideline; Multimorbidity; Chronic conditions
18.  The Effects of Comorbidity on the Benefits and Harms of Treatment for Chronic Disease: A Systematic Review 
PLoS ONE  2014;9(11):e112593.
Background
There are concerns about the potential for unintentional harms when clinical practice guidelines are applied to patients with multimorbidity. The objective was to summarize the evidence regarding the effect(s) of comorbidity on the outcomes of medication for an index chronic condition.
Methods
A systematic review was conducted of studies published in MEDLINE and Cochrane Trials before May 2012. The search strategy was constructed to identify articles indexed with “comorbidity” or a related term or by a given condition and one or more additional specified comorbid conditions. The search yielded 3252 articles, of which 37 passed the title/abstract screening process, and 22 were included after full-text review. An additional 23 articles were identified by screening the reference lists for included articles. Information was extracted on study design; population; therapy; comparison groups; outcome(s); main findings.
Findings
Indexing of articles was inconsistent, with no term for “multimorbidity,” and rare use of “comorbidity”. Only one article examined the effects of comorbidity per se, finding no benefit of tight control of DM among persons with high comorbidity, defined using a comorbidity index. The remainder examined pairs of conditions, the majority of which were post-hoc analyses of randomized controlled trials and which found no difference in outcomes according to whether a comorbid condition was present. Several demonstrated no difference or an increased risk of adverse outcome among persons with DM and tight control of HTN as compared to usual control. Several demonstrated lack of benefit of statins among persons with end-stage renal disease.
Conclusions
There is limited evidence regarding the effects of multiple comorbidities on treatment outcomes. The majority of studies demonstrated no effect of a single comorbid condition on outcomes. Additional studies examining a broad range of comorbidity are required, along with clear and consistent indexing to allow for improved synthesis of the evidence.
doi:10.1371/journal.pone.0112593
PMCID: PMC4234418  PMID: 25402463
19.  Prevalence of comorbidity of chronic diseases in Australia 
BMC Public Health  2008;8:221.
Background
The prevalence of comorbidity is high, with 80% of the elderly population having three or more chronic conditions. Comorbidity is associated with a decline in many health outcomes and increases in mortality and use of health care resources. The aim of this study was to identify, review and summarise studies reporting the prevalence of comorbidity of chronic diseases in Australia.
Methods
A systematic review of Australian studies (1996 – May 2007) was conducted. The review focused specifically on the chronic diseases included as national health priorities; arthritis, asthma, cancer, cardiovascular disease (CVD), diabetes mellitus and mental health problems.
Results
A total of twenty five studies met our inclusion criteria. Over half of the elderly patients with arthritis also had hypertension, 20% had CVD, 14% diabetes and 12% mental health problem. Over 60% of patients with asthma reported arthritis as a comorbidity, 20% also had CVD and 16% diabetes. Of those with CVD, 60% also had arthritis, 20% diabetes and 10% had asthma or mental health problems.
Conclusion
There are comparatively few Australian studies that focused on comorbidity associated with chronic disease. However, they do show high prevalence of comorbidity across national health priority areas. This suggests integration and co-ordination of the national health priority areas is critical. A greater awareness of the importance of managing a patients' overall health status within the context of comorbidity is needed together with, increased research on comorbidity to provide an appropriate scientific basis on which to build evidence based care guidelines for these multimorbid patients.
doi:10.1186/1471-2458-8-221
PMCID: PMC2474682  PMID: 18582390
20.  Informing Evidence-Based Decision-Making for Patients with Comorbidity: Availability of Necessary Information in Clinical Trials for Chronic Diseases 
PLoS ONE  2012;7(8):e41601.
Background
The population with multiple chronic conditions is growing. Prior studies indicate that patients with comorbidities are frequently excluded from trials but do not address whether information is available in trials to draw conclusions about treatment effects for these patients.
Methods and Findings
We conducted a literature survey of trials from 11 Cochrane Reviews for four chronic diseases (diabetes, heart failure, chronic obstructive pulmonary disease, and stroke). The Cochrane Reviews systematically identified and summarized trials on the effectiveness of diuretics, metformin, anticoagulants, longacting beta-agonists alone or in combination with inhaled corticosteroids, lipid lowering agents, exercise and diet. Eligible studies were reports of trials included in the Cochrane reviews and additional papers that described the methods of these trials. We assessed the exclusion and inclusion of people with comorbidities, the reporting of comorbidities, and whether comorbidities were considered as potential modifiers of treatment effects. Overall, the replicability of both the inclusion criteria (mean [standard deviation (SD)]: 6.0 (2.1), range (min-max): 1–9.5) and exclusion criteria(mean(SD): 5.3 (2.1), range: 1–9.5) was only moderate. Trials excluded patients with many common comorbidities. The proportion of exclusions for comorbidities ranged from 0–42 percent for heart failure, 0–55 percent for COPD, 0–44 percent for diabetes, and 0–39 percent for stroke. Seventy of the 161 trials (43.5%) described the prevalence of any comorbidity among participants with the index disease. The reporting of comorbidities in trials was very limited, in terms of reporting an operational definition and method of ascertainment for the presence of comorbidity and treatments for the comorbidity. It was even less common that the trials assessed whether comorbidities were potential modifiers of treatment effects.
Conclusions
Comorbidities receive little attention in chronic disease trials. Given the public health importance of people with multiple chronic conditions, trials should better report on comorbidities and assess the effect comorbidities have on treatment outcomes.
doi:10.1371/journal.pone.0041601
PMCID: PMC3411714  PMID: 22870234
21.  Treatment of depression in cancer patients 
Current Oncology  2007;14(5):180-188.
Question
What is the efficacy of pharmacologic and non-pharmacologic treatments for major depression and other depressive disorders in cancer populations?
Perspectives
Depression occurs at an increased rate in medically ill populations, including patients with cancer. In the general population, depression has been shown to be responsive to structured forms of psychotherapy and to pharmacologic interventions. The Supportive Care Guidelines Group conducted a systematic review of the evidence for the effectiveness of those therapies in patients with depression and cancer and developed the present clinical practice guideline based on that review and on expert consensus.
Outcomes
Outcomes of interest included symptomatic response to treatment, discontinuation rate of treatment, adverse effects, and quality of life.
Methodology
Clinical recommendations were developed by the Supportive Care Guidelines Group based on a systematic review of the published literature through June 2005, feedback obtained from Ontario health care providers on the draft recommendations, the Report Approval Panel (rap) of Cancer Care Ontario’s Program in Evidence-Based Care, and expert consensus.
Results
The systematic review of the literature included eleven trials (seven of pharmacologic agents and four of non-pharmacologic interventions). Feedback received from 44 responding health care providers and the rap on the draft recommendations was addressed and documented in the guideline.
Among providers, 82% agreed with the draft recommendations as stated, 68% agreed that the report should be approved as a practice guideline, and 73% indicated that they would be likely to use the guideline in their own practice.
Practice Guideline
These recommendations apply to adult cancer patients with a diagnosis of major depression or other non-bipolar depressive disorders. They do not address the treatment of non-syndromal depressive symptoms, for which specific antidepressant treatment is not usually indicated. The guideline is intended both for oncology health professionals and for mental health professionals engaged in the treatment of cancer patients. Expert consensus was central to the development of the guideline recommendations because of limited evidence in cancer patients.
Recommendations
Treatment of pain and other reversible physical symptoms should be instituted before or with initiation of specific antidepressant treatment.
Antidepressant medications should be considered for the treatment of moderate-to-severe major depression in cancer patients. Current evidence does not support the relative superiority of one pharmacologic treatment over another, nor the superiority of pharmacologic treatment over psychosocial interventions. The choice of an antidepressant should be informed by individual medication and patient factors: the side effect profiles of the medication, tolerability of treatment (including the potential for interaction with other current medications), response to prior treatment, and patient preference.
Cancer patients diagnosed with major depression may benefit from a combined modality approach that includes both psychosocial and pharmacologic interventions. Psychosocial treatment approaches that may be of value include those that provide information and support and those that address any combination of emotional, cognitive, and behavioural factors.
Qualifying Statements
Referral to a mental health specialist is appropriate when the diagnosis of depression is unclear, when the syndrome is severe, when patients do not respond to treatment, or when other complicating factors that may affect the choice of treatment are present.
Although care has been taken in the preparation of the information contained in this guideline, any person seeking to apply or to consult the guideline is expected to use independent medical judgment in the context of individual clinical circumstances or to seek out the supervision of a qualified clinician.
PMCID: PMC2002483  PMID: 17938701
Practice guideline; depression; treatment; cancer
22.  Canadian guidelines for acute bacterial rhinosinusitis 
Canadian Family Physician  2014;60(3):227-234.
Objective
To provide a clinical summary of the Canadian clinical practice guidelines for acute bacterial rhinosinusitis (ABRS) that includes relevant considerations for family physicians.
Quality of evidence
Guideline authors performed a systematic literature search and drafted recommendations. Recommendations received both strength of evidence and strength of recommendation ratings. Input from external content experts was sought, as was endorsement from Canadian medical societies (Association of Medical Microbiology and Infectious Disease Canada, Canadian Society of Allergy and Clinical Immunology, Canadian Society of Otolaryngology—Head and Neck Surgery, Canadian Association of Emergency Physicians, and the Family Physicians Airways Group of Canada).
Main message
Diagnosis of ABRS is based on the presence of specific symptoms and their duration; imaging or culture are not needed in uncomplicated cases. Treatment is dependent on symptom severity, with intranasal corticosteroids (INCSs) recommended as monotherapy for mild and moderate cases, although the benefit might be modest. Use of INCSs plus antibiotics is reserved for patients who fail to respond to INCSs after 72 hours, and for initial treatment of patients with severe symptoms. Antibiotic selection must account for the suspected pathogen, the risk of resistance, comorbid conditions, and local antimicrobial resistance trends. Adjunct therapies such as nasal saline irrigation are recommended. Failure to respond to treatment, recurrent episodes, and signs of complications should prompt referral to an otolaryngologist. The guidelines address situations unique to the Canadian health care environment, including actions to take during prolonged wait periods for specialist referral or imaging.
Conclusion
The Canadian guidelines provide up-to-date recommendations for diagnosis and treatment of ABRS that reflect an evolving understanding of the disease. In addition, the guidelines offer useful tools to help clinicians discern viral from bacterial episodes, as well as optimally manage their patients with ABRS.
PMCID: PMC3952756  PMID: 24627376
23.  Monitoring diabetes in patients with and without rheumatoid arthritis: a Medicare study 
Arthritis Research & Therapy  2012;14(4):R166.
Introduction
Diabetes mellitus is a key predictor of mortality in rheumatoid arthritis (RA) patients. Both RA and diabetes increase the risk of cardiovascular disease (CVD), yet understanding of how comorbid RA impacts the receipt of guideline-based diabetes care is limited. The purpose of this study was to examine how the presence of RA affected hemoglobin A1C (A1c) and lipid measurement in older adults with diabetes.
Methods
Using a retrospective cohort approach, we identified beneficiaries ≥65 years old with diabetes from a 5% random national sample of 2004 to 2005 Medicare patients (N = 256,331), then examined whether these patients had comorbid RA and whether they received guideline recommended A1c and lipid testing in 2006. Multivariate logistic regression was used to examine the effect of RA on receiving guideline recommended testing, adjusting for baseline sociodemographics, comorbidities and health care utilization.
Results
Two percent of diabetes patients had comorbid RA (N = 5,572). Diabetes patients with comorbid RA were more likely than those without RA to have baseline cardiovascular disease (such as 17% more congestive heart failure), diabetes-related complications including kidney disease (19% higher), lower extremity ulcers (77% higher) and peripheral vascular disease (32% higher). In adjusted models, diabetes patients with RA were less likely to receive recommended A1c testing (odds ratio (OR) 0.84, CI 0.80 to 0.89) than those without RA, but were slightly more likely to receive lipid testing (OR 1.08, CI 1.01 to 1.16).
Conclusions
In older adults with diabetes, the presence of comorbid RA predicted lower rates of A1c testing but slightly improved lipid testing. Future research should examine strategies to improve A1c testing in patients with diabetes and RA, in light of increased CVD and microvascular risks in patients with both conditions.
doi:10.1186/ar3915
PMCID: PMC3580560  PMID: 22809064
24.  Management of fibromyalgia syndrome – an interdisciplinary evidence-based guideline 
The prevalence of fibromyalgia syndrome (FMS) of 1–2% in the general population associated with high disease-related costs and the conflicting data on treatment effectiveness had led to the development of evidence-based guidelines designed to provide patients and physicians guidance in selecting among the alternatives. Until now no evidence-based interdisciplinary (including patients) guideline for the management of FMS was available in Europe.
Therefore a guideline for the management of fibromyalgia syndrome (FMS) was developed by 13 German medical and psychological associations and two patient self-help organisations. The task was coordinated by two German scientific umbrella organisations, the Association of the Scientific Medical Societies in Germany AWMF and the German Interdisciplinary Association of Pain Therapy DIVS. A systematic search of the literature including all controlled studies, systematic reviews and meta-analyses of pharmacological and non-pharmacological treatments of FMS was performed in the Cochrane Library (1993–12/2006), Medline (1980–12/2006), PsychInfo (1966–12/2006) and Scopus (1980–12/ 2006). Levels of evidence were assigned according to the classification system of the Oxford-Centre for Evidence Based Medicine. Grading of the strengths of recommendations was done according to the German program for disease management guidelines. Standardized procedures were used to reach a consensus on recommendations. The guideline was reviewed and finally approved by the boards of the societies involved and published online by the AWMF on april 25, 2008: http://www.uni-duesseldorf.de/AWMF/ll/041-004.htm. A short version of the guideline for patients is available as well: http://www.uni-duesseldorf.de/AWMF/ll/041-004p.htm.
The following procedures in the management of FMS were strongly recommended: information on diagnosis and therapeutic options and patient-centered communication, aerobic exercise, cognitive and operant behavioural therapy, multicomponent treatment and amitriptyline. Based on expert opinion, a stepwise FMS-management was proposed. Step 1 comprises confirming the diagnosis and patient education and treatment of physical or mental comorbidities or aerobic exercise or cognitive behavioural therapy or amitriptyline. Step 2 includes multicomponent treatment. Step 3 comprises no further treatment or self-management (aerobic exercise, stress management) and/or booster multicomponent therapy and/or pharmacological therapy (duloxetine or fluoxetine or paroxetine or pregabalin or tramadol/aminoacetophen) and/or psychotherapy (hypnotherapy or written emotional disclosure) and/or physical therapy (balneotherapy or whole body heat therapy) and/or complementary therapies (homoeopathy or vegetarian diet). The choice of treatment options should be based on informed decision-making and respect of the patients’ preferences.
PMCID: PMC2703259  PMID: 19675740
fibromyalgia syndrome; systematic review; guideline; management
25.  The 2010 Canadian Hypertension Education Program recommendations for the management of hypertension: Part 2 – therapy 
OBJECTIVE:
To update the evidence-based recommendations for the prevention and treatment of hypertension in adults for 2010.
OPTIONS AND OUTCOMES:
For lifestyle and pharmacological interventions, randomized trials and systematic reviews of trials were preferentially reviewed. Changes in cardiovascular morbidity and mortality were the primary outcomes of interest. However, for lifestyle interventions, blood pressure lowering was accepted as a primary outcome given the general lack of long-term morbidity and mortality data in this field. Progressive renal impairment was also accepted as a clinically relevant primary outcome among patients with chronic kidney disease.
EVIDENCE:
A Cochrane Collaboration librarian conducted an independent MEDLINE search from 2008 to August 2009 to update the 2009 recommendations. To identify additional studies, reference lists were reviewed and experts were contacted. All relevant articles were reviewed and appraised independently by both content and methodological experts using prespecified levels of evidence.
RECOMMENDATIONS:
For lifestyle modifications to prevent and treat hypertension, restrict dietary sodium to 1500 mg (65 mmol) per day in adults 50 years of age or younger, to 1300 mg (57 mmol) per day in adults 51 to 70 years of age, and to 1200 mg (52 mmol) per day in adults older than 70 years of age; perform 30 min to 60 min of moderate aerobic exercise four to seven days per week; maintain a healthy body weight (body mass index 18.5 kg/m2 to 24.9 kg/m2) and waist circumference (less than 102 cm for men and less than 88 cm for women); limit alcohol consumption to no more than 14 standard drinks per week for men or nine standard drinks per week for women; follow a diet that emphasizes fruits, vegetables and low-fat dairy products, dietary and soluble fibre, whole grains and protein from plant sources, and that is low in saturated fat and cholesterol; and consider stress management in selected individuals with hypertension.
For the pharmacological management of hypertension, treatment thresholds and targets should be predicated on the patient’s global atherosclerotic risk, target organ damage and comorbid conditions. Blood pressure should be decreased to less than 140/90 mmHg in all patients, and to less than 130/80 mmHg in patients with diabetes mellitus or chronic kidney disease. Most patients will require more than one agent to achieve these target blood pressures. Antihypertensive therapy should be considered in all adult patients regardless of age (caution should be exercised in elderly patients who are frail). For adults without compelling indications for other agents, considerations for initial therapy should include thiazide diuretics, angiotensin-converting enzyme (ACE) inhibitors (in patients who are not black), long-acting calcium channel blockers (CCBs), angiotensin receptor blockers (ARBs) or beta-blockers (in those younger than 60 years of age). A combination of two first-line agents may also be considered as initial treatment of hypertension if systolic blood pressure is 20 mmHg above target or if diastolic blood pressure is 10 mmHg above target. The combination of ACE inhibitors and ARBs should not be used, unless compelling indications are present to suggest consideration of dual therapy.
Agents appropriate for first-line therapy for isolated systolic hypertension include thiazide diuretics, long-acting dihydropyridine CCBs or ARBs. In patients with coronary artery disease, ACE inhibitors, ARBs or beta-blockers are recommended as first-line therapy; in patients with cerebrovascular disease, an ACE inhibitor/diuretic combination is preferred; in patients with proteinuric nondiabetic chronic kidney disease, ACE inhibitors or ARBs (if intolerant to ACE inhibitors) are recommended; and in patients with diabetes mellitus, ACE inhibitors or ARBs (or, in patients without albuminuria, thiazides or dihydropyridine CCBs) are appropriate first-line therapies. In selected high-risk patients in whom combination therapy is being considered, an ACE inhibitor plus a long-acting dihydropyridine CCB is preferable to an ACE inhibitor plus a thiazide diuretic. All hypertensive patients with dyslipidemia should be treated using the thresholds, targets and agents outlined in the Canadian lipid treatment guidelines. Selected patients with hypertension who do not achieve thresholds for statin therapy, but who are otherwise at high risk for cardiovascular events, should nonetheless receive statin therapy. Once blood pressure is controlled, low-dose acetylsalicylic acid therapy should be considered.
VALIDATION:
All recommendations were graded according to the strength of the evidence and voted on by the 63 members of the Canadian Hypertension Education Program Evidence-Based Recommendations Task Force. All recommendations reported here achieved at least 80% consensus. These guidelines will continue to be updated annually.
SPONSORS:
The Canadian Hypertension Education Program process is sponsored by the Canadian Hypertension Society, Blood Pressure Canada, the Public Health Agency of Canada, the College of Family Physicians of Canada, the Canadian Pharmacists Association, the Canadian Council of Cardiovascular Nurses, and the Heart and Stroke Foundation of Canada.
PMCID: PMC2886555  PMID: 20485689
Antihypertensive drugs; Blood pressure; Guidelines; High blood pressure; Hypertension; Lifestyle interventions

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