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1.  Gynecomastia – evaluation and current treatment options 
Clinical question:
What is the best management approach for gynecomastia?
In most patients, surgical correction usually leads to immediate cosmetic and symptomatic improvement and is considered the best approach. In men who are being treated with antiandrogen therapies, pharmacological intervention with tamoxifen is the most effective approach, followed by radiotherapy.
Pitfalls to avoid when treating gynecomastia Failure to detect the very rare male breast cancerOverly aggressive early intervention or evaluationAppropriate medical interventionWhen to refer to specialist treatment
PMCID: PMC3071351  PMID: 21479145
gynecomastia; testosterone; estrogen
2.  Gynecomastia: Pathophysiology, Evaluation, and Management 
Mayo Clinic Proceedings  2009;84(11):1010-1015.
Gynecomastia, defined as benign proliferation of male breast glandular tissue, is usually caused by increased estrogen activity, decreased testosterone activity, or the use of numerous medications. Although a fairly common presentation in the primary care setting and mostly of benign etiology, it can cause patients considerable anxiety. The initial step is to rule out pseudogynecomastia by careful history taking and physical examination. A stepwise approach that includes imaging and laboratory testing to exclude neoplasms and endocrinopathies may facilitate cost-effective diagnosis. If results of all studies are normal, idiopathic gynecomastia is diagnosed. The evidence in this area is mainly of observational nature and lower quality.
PMCID: PMC2770912  PMID: 19880691
3.  Midodrine for Orthostatic Hypotension: A Systematic Review and Meta-Analysis of Clinical Trials 
Journal of General Internal Medicine  2013;28(11):1496-1503.
To perform a systematic review and meta-analysis of clinical trials evaluating the efficacy and safety of midodrine in orthostatic hypotension (OH).
We searched major databases and related conference proceedings through June 30, 2012. Two reviewers independently selected studies and extracted data. Random-effects meta-analysis was used to pool the outcome measures across studies.
Seven trials were included in the efficacy analysis (enrolling 325 patients, mean age 53 years) and two additional trials were included in the safety analysis. Compared to placebo, the mean change in systolic blood pressure was 4.9 mmHg (p = 0.65) and the mean change in mean arterial pressure from supine to standing was −1.7 mmHg (p = 0.45). The change in standing systolic blood pressure before and after giving midodrine was 21.5 mmHg (p < 0.001). A significant improvement was seen in patients’ and investigators’ global assessment symptoms scale (a mean difference of 0.70 [95 % CI 0.30–1.09; p < 0.001] and 0.80 [95 % CI 0.76–0.85; p < 0.001], respectively). There was a significant increase in risk of piloerection, scalp pruritis, urinary hesitancy/retention, supine hypertension and scalp paresthesia after giving midodrine. The quality of evidence was limited by imprecision, heterogeneity and increased risk of bias.
There is insufficient and low quality evidence to support the use of midodrine for OH.
Electronic supplementary material
The online version of this article (doi:10.1007/s11606-013-2520-3) contains supplementary material, which is available to authorized users.
PMCID: PMC3797331  PMID: 23775146
orthostatic hypotension; midodrine; systematic review; meta-analysis; efficacy; safety
4.  Use of Sirolimus in Liver Transplant Recipients with Renal Insufficiency: Systematic Review and Meta-Analysis 
Hepatology (Baltimore, Md.)  2010;52(4):1360-1370.
Sirolimus is used in patients with renal insufficiency following liver transplantation (LT), especially in those with calcineurin inhibitor (CNI) associated nephrotoxicity.
We conducted a systematic review of all randomized controlled trials (RCTs) and observational studies to test the hypothesis that use of sirolimus is associated with an improvement in renal function at 1 year in LT recipients with renal insufficiency (GFR<60ml/min or creatinine≥1.5mg/dL).
We performed a search of all major databases, conference proceedings and relevant journals through December 2009 and contacted content experts, corresponding authors, and the pharmaceutical manufacturer. A random effects model was utilized to determine the pooled estimate of the change in renal function and pooled risk estimates of adverse events that may be associated with sirolimus based therapy at 1 year.
Eleven studies (3 RCTs and 8 observational) met final inclusion criteria. A non significant improvement of 3.38 ml/min (95% CI -2.93 to 9.69) was observed among methodologically sound observational studies and controlled trials reporting the primary outcome. Among controlled trials, sirolimus use was associated with a 10.35 ml/min (95% CI 3.98 - 16.77) improvement in GFR or creatinine clearance. Sirolimus was not significantly associated with death, RR=1.12 (95% CI 0.66-1.88) or graft failure, RR=0.80 (95% CI 0.45-1.41), though reporting was incomplete. It was associated with a statistically significant risk of infection (RR=2.47, 95% CI 1.14-5.36), rash (RR=7.57, 95% CI 1.75-32.70), ulcers (RR=7.44, 95% CI 2.03-27.28) and discontinuation of therapy (RR=3.61, 95% CI 1.32-9.89).
Conversion to sirolimus from CNI is associated with a non significant improvement in renal function in LT recipients with renal insufficiency, though results are limited by heterogeneity, risk of bias, and lack of standardized reporting.
PMCID: PMC4130484  PMID: 20815021
side effects; rapamycin; mTOR Inhibitor; calcineurin inhibitors
5.  Erlotinib in wild type epidermal growth factor receptor non-small cell lung cancer: A systematic review 
Annals of Thoracic Medicine  2013;8(4):204-208.
Targeting epidermal growth factor receptors (EGFR) is an innovative approach to managing non-small cell lung cancer (NSCLC) which harbors EGFR mutation. However, the efficacy of these agents like erlotinib in patients without the mutation is not known.
This systematic review included Phase III randomized clinical trials that compared single agent erlotinib to other management options in the setting of NSCLC with reported outcome data on patients with EGFR wild type (EGFRWT) tumors. Outcome data include overall survival (OS), progression free survival (PFS) and response rate (RR). Random effects meta-analysis was used to pool outcomes across studies.
Three studies met the inclusion criteria. These studies included a total of 2044 patients with outcome data on 674 patients with EGFRWT tumors (33%). Meta-analysis revealed a statistically significant improvement in OS with erlotinib (hazard ratio of 0.780; 95% confidence interval: 0.654-0.930, P = 0.006). Data were not available to perform PFS or RR analysis. The quality of this evidence is considered to be moderate to high.
Our study revealed a significant benefit of erlotinib in patient with EGFRWT tumors compared with other approaches. These findings add another therapeutic option to patients generally considered difficult to treat.
PMCID: PMC3821279  PMID: 24250733
Epidermal growth factor; erlotinib; non-small cell lung cancer
6.  Improving understanding in the research informed consent process: a systematic review of 54 interventions tested in randomized control trials 
BMC Medical Ethics  2013;14:28.
Obtaining informed consent is a cornerstone of biomedical research, yet participants comprehension of presented information is often low. The most effective interventions to improve understanding rates have not been identified.
To systematically analyze the random controlled trials testing interventions to research informed consent process. The primary outcome of interest was quantitative rates of participant understanding; secondary outcomes were rates of information retention, satisfaction, and accrual. Interventional categories included multimedia, enhanced consent documents, extended discussions, test/feedback quizzes, and miscellaneous methods.
The search spanned from database inception through September 2010. It was run on Ovid MEDLINE, Ovid EMBASE, Ovid CINAHL, Ovid PsycInfo and Cochrane CENTRAL, ISI Web of Science and Scopus. Five reviewers working independently and in duplicate screened full abstract text to determine eligibility. We included only RCTs. 39 out of 1523 articles fulfilled review criteria (2.6%), with a total of 54 interventions. A data extraction form was created in Distiller, an online reference management system, through an iterative process. One author collected data on study design, population, demographics, intervention, and analytical technique.
Meta-analysis was possible on 22 interventions: multimedia, enhanced form, and extended discussion categories; all 54 interventions were assessed by review. Meta-analysis of multimedia approaches was associated with a non-significant increase in understanding scores (SMD 0.30, 95% CI, -0.23 to 0.84); enhanced consent form, with significant increase (SMD 1.73, 95% CI, 0.99 to 2.47); and extended discussion, with significant increase (SMD 0.53, 95% CI, 0.21 to 0.84). By review, 31% of multimedia interventions showed significant improvement in understanding; 41% for enhanced consent form; 50% for extended discussion; 33% for test/feedback; and 29% for miscellaneous.Multiple sources of variation existed between included studies: control processes, the presence of a human proctor, real vs. simulated protocol, and assessment formats.
Enhanced consent forms and extended discussions were most effective in improving participant understanding. Interventions of all categories had no negative impact on participant satisfaction or study accrual. Identification of best practices for studies of informed consent interventions would aid future systematic comparisons.
PMCID: PMC3733934  PMID: 23879694
Informed consent; Comprehension; Systematic review
7.  Examining health promotion interventions for patients with chronic conditions using a novel patient-centered complexity model: protocol for a systematic review and meta-analysis 
Systematic Reviews  2013;2:29.
Successful chronic care self-management requires adherence to healthy lifestyle behaviors, but many healthcare-based health promotion interventions have resulted in small and unsustainable changes in patient behavior. Patients with chronic conditions may already be overwhelmed by burdensome illnesses and treatments, and not have the capacity to respond well to the additional work required of behavior modifications. To explore this phenomenon, we will apply the cumulative complexity model (CCM), a patient-centered model of patient complexity, to a systematic review and meta-analysis of healthcare-based health behavior interventions.
This systematic review will include randomized trials published between 2002 and 2012 that compared healthcare-based interventions aimed at improving healthy diet and physical activity in community dwelling adult patients with chronic conditions. After extracting study and risk of bias features from each trial, we will classify the interventions according to the conceptual model. We will then use meta-analysis and subgroup analysis to test hypotheses based on the conceptual model.
Healthcare providers need evidence of successful health promoting interventions for patients with chronic conditions who display common behavioral risk factors. To better understand how patients respond to interventions, we will apply the CCM, which accounts for both the capacity of patients with chronic conditions and their treatment-related workload, and posits that a balance between capacity and workload predicts successful enactment of self-care. Analysis will also include whether patients with multiple chronic conditions respond differently to interventions compared to those with single chronic conditions. The results of this review will provide insights as to how patients with chronic conditions respond to health-promoting interventions.
Review registration
PROSPERO registration number: CRD42012003428
PMCID: PMC3655854  PMID: 23663259
Health behavior; Comorbidities; Multimorbidity; Chronic conditions; Patient complexity; Cumulative complexity model; Physical activity; Diet
8.  Pharmacologic interventions for painful diabetic neuropathy: an umbrella systematic review and comparative effectiveness network meta-analysis (Protocol) 
Systematic Reviews  2012;1:61.
Neuropathic pain can reduce the quality of life and independence of 30% to 50% of patients with diabetes. The comparative effectiveness of analgesics for patients with diabetic neuropathy remains unclear. The aim of the current work, therefore, was to summarize the evidence about the analgesic effectiveness of the most common oral and topical agents used for the treatment of peripheral diabetic neuropathy.
We will use an umbrella approach (systematic review of systematic reviews) to identify eligible randomized controlled trials (RCTs) for the most common oral or topical analgesics for painful diabetic neuropathy. Two reviewers will independently determine RCT eligibility. Disagreement will be solved by consensus and arbitrated by a third reviewer. We will extract descriptive, methodological and efficacy data in duplicate. Results will be pooled and analyzed using classic random-effects meta-analyses and network meta-analyses to compute the absolute and relative efficacy of therapeutic options. We will use the I2 statistic and Cochran’s Q test to assess heterogeneity. Risk of bias and publication bias, if appropriate, will be evaluated, as well as overall strength of the evidence.
This network meta-analysis aims to synthesize available direct and indirect evidence of effectiveness of analgesics in the treatment of painful diabetic neuropathy. The network approach will offer the opportunity to generate a ranking based on efficacy and along with known side effects, costs, and administration burdens will enable patients and clinicians to make choices that best reflect their preferences for treatment of painful diabetic neuropathy.
PMCID: PMC3534585  PMID: 23198755
Comparative effectiveness research; Diabetic neuropathy; Network meta-analysis; Systematic review
9.  Enhancing Teamwork Between Chief Residents and Residency Program Directors: Description and Outcomes of an Experiential Workshop 
An effective working relationship between chief residents and residency program directors is critical to a residency program's success. Despite the importance of this relationship, few studies have explored the characteristics of an effective program director-chief resident partnership or how to facilitate collaboration between the 2 roles, which collectively are important to program quality and resident satisfaction. We describe the development and impact of a novel workshop that paired program directors with their incoming chief residents to facilitate improved partnerships.
The Accreditation Council for Graduate Medical Education sponsored a full-day workshop for residency program directors and their incoming chief residents. Sessions focused on increased understanding of personality styles, using experiential learning, and open communication between chief residents and program directors, related to feedback and expectations of each other. Participants completed an anonymous survey immediately after the workshop and again 8 months later to assess its long-term impact.
Participants found the workshop to be a valuable experience, with comments revealing common themes. Program directors and chief residents expect each other to act as a role model for the residents, be approachable and available, and to be transparent and fair in their decision-making processes; both groups wanted feedback on performance and clear expectations from each other for roles and responsibilities; and both groups identified the need to be innovative and supportive of changes in the program. Respondents to the follow-up survey reported that workshop participation improved their relationships with their co-chiefs and program directors.
Participation in this experiential workshop improved the working relationships between chief residents and program directors. The themes that were identified can be used to foster communication between incoming chief residents and residency directors and to develop a curriculum for chief resident development.
PMCID: PMC3244337  PMID: 23205220
10.  Efficacy of Continuous Glucose Monitoring in Improving Glycemic Control and Reducing Hypoglycemia: A Systematic Review and Meta-Analysis of Randomized Trials 
We conducted a systematic review and meta-analysis to assess the efficacy of continuous glucose monitoring (CGM) in improving glycemic control and reducing hypoglycemia compared to self-monitored blood glucose (SMBG).
We searched MEDLINE, EMBASE, Cochrane Central, Web of Science, and Scopus for randomized trials of adults and children with type 1 or type 2 diabetes mellitus (T1DM or T2DM). Pairs of reviewers independently selected studies, assessed methodological quality, and extracted data. Meta-analytic estimates of treatment effects were generated using a random-effects model.
Nineteen trials were eligible and provided data for meta-analysis. Overall, CGM was associated with a significant reduction in mean hemoglobin A1c [HbA1c; weighted mean difference (WMD) of -0.27% (95% confidence interval [CI] -0.44 to -0.10)]. This was true for adults with T1DM as well as T2DM [WMD -0.50% (95% CI -0.69 to -0.30) and -0.70 (95% CI, -1.14 to -0.27), respectively]. No significant effect was noted in children and adolescents. There was no significant difference in HbA1c reduction between studies of real-time versus non-realtime devices (WMD -0.22%, 95% CI, -0.59 to 0.15 versus -0.30%, 95% CI, -0.49 to -0.10; p for interaction 0.71). The quality of evidence was moderate due to imprecision, suggesting increased risk for bias. Data for the incidence of severe or nocturnal hypoglycemia were sparse and imprecise. In studies that reported patient satisfaction, users felt confident about the device and gave positive reviews.
Continuous glucose monitoring seems to help improve glycemic control in adults with T1DM and T2DM. The effect on hypoglycemia incidence is imprecise and unclear. Larger trials with longer follow-up are needed to assess the efficacy of CGM in reducing patient-important complications without significantly increasing the burden of care for patients with diabetes.
PMCID: PMC3192603  PMID: 21880239
biosensing techniques; blood glucose self-monitoring; diabetes mellitus
11.  The association of hypertriglyceridemia with cardiovascular events and pancreatitis: a systematic review and meta-analysis 
Hypertriglyceridemia may be associated with important complications. The aim of this study is to estimate the magnitude of association and quality of supporting evidence linking hypertriglyceridemia to cardiovascular events and pancreatitis.
We conducted a systematic review of multiple electronic bibliographic databases and subsequent meta-analysis using a random effects model. Studies eligible for this review followed patients longitudinally and evaluated quantitatively the association of fasting hypertriglyceridemia with the outcomes of interest. Reviewers working independently and in duplicate reviewed studies and extracted data.
35 studies provided data sufficient for meta-analysis. The quality of these observational studies was moderate to low with fair level of multivariable adjustments and adequate exposure and outcome ascertainment. Fasting hypertriglyceridemia was significantly associated with cardiovascular death (odds ratios (OR) 1.80; 95% confidence interval (CI) 1.31-2.49), cardiovascular events (OR, 1.37; 95% CI, 1.23-1.53), myocardial infarction (OR, 1.31; 95% CI, 1.15-1.49), and pancreatitis (OR, 3.96; 95% CI, 1.27-12.34, in one study only). The association with all-cause mortality was not statistically significant.
The current evidence suggests that fasting hypertriglyceridemia is associated with increased risk of cardiovascular death, MI, cardiovascular events, and possibly acute pancreatitis.
Précis: hypertriglyceridemia is associated with increased risk of cardiovascular death, MI, cardiovascular events, and possibly acute pancreatitis
PMCID: PMC3342117  PMID: 22463676
Hypertriglyceridemia; Cardiovascular disease; Pancreatitis; Systematic reviews and meta-analysis
12.  Sexual Abuse and Lifetime Diagnosis of Psychiatric Disorders: Systematic Review and Meta-analysis 
Mayo Clinic Proceedings  2010;85(7):618-629.
OBJECTIVE: To systematically assess the evidence for an association between sexual abuse and a lifetime diagnosis of psychiatric disorders.
PATIENTS AND METHODS: We performed a comprehensive search (from January 1980-December 2008, all age groups, any language, any population) of 9 databases: MEDLINE, EMBASE, CINAHL, Current Contents, PsycINFO, ACP Journal Club, CCTR, CDSR, and DARE. Controlled vocabulary supplemented with keywords was used to define the concept areas of sexual abuse and psychiatric disorders and was limited to epidemiological studies. Six independent reviewers extracted descriptive, quality, and outcome data from eligible longitudinal studies. Odds ratios (ORs) and 95% confidence intervals (CIs) were pooled across studies by using the random-effects model. The I2 statistic was used to assess heterogeneity.
RESULTS: The search yielded 37 eligible studies, 17 case-control and 20 cohort, with 3,162,318 participants. There was a statistically significant association between sexual abuse and a lifetime diagnosis of anxiety disorder (OR, 3.09; 95% CI, 2.43-3.94), depression (OR, 2.66; 95% CI, 2.14-3.30), eating disorders (OR, 2.72; 95% CI, 2.04-3.63), posttraumatic stress disorder (OR, 2.34; 95% CI, 1.59-3.43), sleep disorders (OR, 16.17; 95% CI, 2.06-126.76), and suicide attempts (OR, 4.14; 95% CI, 2.98-5.76). Associations persisted regardless of the victim's sex or the age at which abuse occurred. There was no statistically significant association between sexual abuse and a diagnosis of schizophrenia or somatoform disorders. No longitudinal studies that assessed bipolar disorder or obsessive-compulsive disorder were found. Associations between sexual abuse and depression, eating disorders, and posttraumatic stress disorder were strengthened by a history of rape.
CONCLUSION: A history of sexual abuse is associated with an increased risk of a lifetime diagnosis of multiple psychiatric disorders.
In this article of 37 eligible studies with 3,162,318 participants, a statistically significant association was found between sexual abuse and a lifetime diagnosis of anxiety disorder, depression, eating disorders, posttraumatic stress disorder, sleep disorders, and suicide attempts. Associations persisted regardless of the victim's sex or age at which time the abuse occurred.
PMCID: PMC2894717  PMID: 20458101
13.  Stopping randomized trials early for benefit: a protocol of the Study Of Trial Policy Of Interim Truncation-2 (STOPIT-2) 
Trials  2009;10:49.
Randomized clinical trials (RCTs) stopped early for benefit often receive great attention and affect clinical practice, but pose interpretational challenges for clinicians, researchers, and policy makers. Because the decision to stop the trial may arise from catching the treatment effect at a random high, truncated RCTs (tRCTs) may overestimate the true treatment effect. The Study Of Trial Policy Of Interim Truncation (STOPIT-1), which systematically reviewed the epidemiology and reporting quality of tRCTs, found that such trials are becoming more common, but that reporting of stopping rules and decisions were often deficient. Most importantly, treatment effects were often implausibly large and inversely related to the number of the events accrued. The aim of STOPIT-2 is to determine the magnitude and determinants of possible bias introduced by stopping RCTs early for benefit.
We will use sensitive strategies to search for systematic reviews addressing the same clinical question as each of the tRCTs identified in STOPIT-1 and in a subsequent literature search. We will check all RCTs included in each systematic review to determine their similarity to the index tRCT in terms of participants, interventions, and outcome definition, and conduct new meta-analyses addressing the outcome that led to early termination of the tRCT. For each pair of tRCT and systematic review of corresponding non-tRCTs we will estimate the ratio of relative risks, and hence estimate the degree of bias. We will use hierarchical multivariable regression to determine the factors associated with the magnitude of this ratio. Factors explored will include the presence and quality of a stopping rule, the methodological quality of the trials, and the number of total events that had occurred at the time of truncation.
Finally, we will evaluate whether Bayesian methods using conservative informative priors to "regress to the mean" overoptimistic tRCTs can correct observed biases.
A better understanding of the extent to which tRCTs exaggerate treatment effects and of the factors associated with the magnitude of this bias can optimize trial design and data monitoring charters, and may aid in the interpretation of the results from trials stopped early for benefit.
PMCID: PMC2723099  PMID: 19580665
14.  Off-hour presentation and outcomes in patients with acute myocardial infarction: systematic review and meta-analysis 
Objective To assess the association between off-hour (weekends and nights) presentation, door to balloon times, and mortality in patients with acute myocardial infarction.
Data sources Medline in-process and other non-indexed citations, Medline, Embase, Cochrane Database of Systematic Reviews, and Scopus through April 2013.
Study selection Any study that evaluated the association between time of presentation to a healthcare facility and mortality or door to balloon times among patients with acute myocardial infarction was included.
Data extraction Studies’ characteristics and outcomes data were extracted. Quality of studies was assessed with the Newcastle-Ottawa scale. A random effect meta-analysis model was applied. Heterogeneity was assessed using the Q statistic and I2.
Results 48 studies with fair quality, enrolling 1 896 859 patients, were included in the meta-analysis. 36 studies reported mortality outcomes for 1 892 424 patients with acute myocardial infarction, and 30 studies reported door to balloon times for 70 534 patients with ST elevation myocardial infarction (STEMI). Off-hour presentation for patients with acute myocardial infarction was associated with higher short term mortality (odds ratio 1.06, 95% confidence interval 1.04 to 1.09). Patients with STEMI presenting during off-hours were less likely to receive percutaneous coronary intervention within 90 minutes (odds ratio 0.40, 0.35 to 0.45) and had longer door to balloon time by 14.8 (95% confidence interval 10.7 to 19.0) minutes. A diagnosis of STEMI and countries outside North America were associated with larger increase in mortality during off-hours. Differences in mortality between off-hours and regular hours have increased in recent years. Analyses were associated with statistical heterogeneity.
Conclusion This systematic review suggests that patients with acute myocardial infarction presenting during off-hours have higher mortality, and patients with STEMI have longer door to balloon times. Clinical performance measures may need to account for differences arising from time of presentation to a healthcare facility.
PMCID: PMC3898160  PMID: 24452368

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