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1.  Aspirin and clonidine in non-cardiac surgery: acute kidney injury substudy protocol of the Perioperative Ischaemic Evaluation (POISE) 2 randomised controlled trial 
BMJ Open  2014;4(2):e004886.
Introduction
Perioperative Ischaemic Evaluation-2 (POISE-2) is an international 2×2 factorial randomised controlled trial of low-dose aspirin versus placebo and low-dose clonidine versus placebo in patients who undergo non-cardiac surgery. Perioperative aspirin (and possibly clonidine) may reduce the risk of postoperative acute kidney injury (AKI).
Methods and analysis
After receipt of grant funding, serial postoperative serum creatinine measurements began to be recorded in consecutive patients enrolled at substudy participating centres. With respect to the study schedule, the last of over 6500 substudy patients from 82 centres in 21 countries were randomised in December 2013. The authors will use logistic regression to estimate the adjusted OR of AKI following surgery (compared with the preoperative serum creatinine value, a postoperative increase ≥26.5 μmol/L in the 2 days following surgery or an increase of ≥50% in the 7 days following surgery) comparing each intervention to placebo, and will report the adjusted relative risk reduction. Alternate definitions of AKI will also be considered, as will the outcome of AKI in subgroups defined by the presence of preoperative chronic kidney disease and preoperative chronic aspirin use. At the time of randomisation, a subpopulation agreed to a single measurement of serum creatinine between 3 and 12 months after surgery, and the authors will examine intervention effects on this outcome.
Ethics and dissemination
The authors were competitively awarded a grant from the Canadian Institutes of Health Research for this POISE-2 AKI substudy. Ethics approval was obtained for additional kidney data collection in consecutive patients enrolled at participating centres, which first began for patients enrolled after January 2011. In patients who provided consent, the remaining longer term serum creatinine data will be collected throughout 2014. The results of this study will be reported no later than 2015.
Clinical Trial Registration Number
NCT01082874.
doi:10.1136/bmjopen-2014-004886
PMCID: PMC3939660  PMID: 24568963
Surgery; Epidemiology
2.  Impact of Phone Call Intervention on Glycemic Control in Diabetes Patients: A Systematic Review and Meta-Analysis of Randomized, Controlled Trials 
PLoS ONE  2014;9(2):e89207.
Background
Telephone-delivered intervention can provide many supports in diabetes self-management to improve glycemic control. Several trials showed that telephone intervention was positively associated with glycemic outcomes in diabetes. The objective of this meta-analysis was to assess the impact of telephone contact intervention (intervention group) on glycemic control compared with standard clinical care (control group).
Methods
Randomized control studies of telephone intervention in diabetes were searched on Medline (Pubmed), the Cochrane Central Register of Controlled Trials, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Web of Science (ISI), and Scopus. Electronic search was done from inception to April 2013. The following MeSH terms were used: diabetes mellitus, randomized control trials and telemedicine, together with keywords including phone intervention, diabetes, and glycemic control. Historical search was also conducted on the references of relevant articles. The quality of the trials was assessed using Maastricht-Amsterdam scale. Treatment effect was estimated with mean difference in the change of hemoglobin A1c (HbA1c) from baseline between the intervention and control groups.
Results
A total of 203 articles were examined. Five trials involving 953 patients met the inclusion criteria and contributed to the meta-analysis. Telephone contact intervention was no more effective than standard clinical care in improving glycemic control (pooled mean difference in HbA1c −0.38%, 95%CI −0.91 to 0.16%).
Conclusions
This meta-analysis showed that the phone contact intervention was no more effective than standard clinical care in improving glycemic control in diabetes. However, telephone intervention may still have potential benefits especially for low-and middle-income countries; thus further large sample size and well-controlled studies are needed to evaluate the impact of the intervention.
doi:10.1371/journal.pone.0089207
PMCID: PMC3929650  PMID: 24586596
3.  SUrvey of Guideline Adherence for Treatment of Systolic Heart Failure in Real World (SUGAR): A Multi-Center, Retrospective, Observational Study 
PLoS ONE  2014;9(1):e86596.
Background
Clinical practice guidelines have been slowly and inconsistently applied in clinical practice, and certain evidence-based, guideline-driven therapies for heart failure (HF) have been significantly underused. The purpose of this study was to survey guideline compliance and its effect on clinical outcomes in the treatment of systolic HF in Korea.
Method and Results
The SUrvey of Guideline Adherence for Treatment of Systolic Heart Failure in Real World (SUGAR) trial was a multi-center, retrospective, observational study on subjects with systolic HF (ejection fraction <45%) admitted to 23 university hospitals. The guideline adherence indicator (GAI) was defined as a performance measure on the basis of 3 pharmacological classes: angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor II blocker (ARB), beta-blocker (BB), and aldosterone antagonist (AA). Based on the overall adherence percentage, subjects were divided into 2 groups: those with good guideline adherence (GAI ≥50%) and poor guideline adherence (GAI <50%). We included 1319 regional participants as representatives of the standard population from the Korean national census in 2008. Adherence to drugs at discharge was as follows: ACEI or ARB, 89.7%; BB, 69.2%; and AA, 65.9%. Overall, 82.7% of the patients had good guideline adherence. Overall mortality and re-hospitalization rates at 1 year were 6.2% and 37.4%, respectively. Survival analysis by log-rank test showed a significant difference in event-free survival rate of mortality (94.7% vs. 89.8%, p = 0.003) and re-hospitalization (62.3% vs. 56.4%, p = 0.041) between the good and poor guideline-adherence groups.
Conclusions
Among patients with systolic HF in Korea, adherence to pharmacologic treatment guidelines as determined by performance measures, including prescription of ACEI/ARB and BB at discharge, was associated with improved clinical outcomes.
doi:10.1371/journal.pone.0086596
PMCID: PMC3903552  PMID: 24475154
4.  The External Validity of Randomized Controlled Trials of Hypertension within China: from the Perspective of Sample Representation 
PLoS ONE  2013;8(12):e82324.
Objective
To explore external validity of randomized controlled trials (RCTs) of hypertension within China from the view of sample representation.
Methods
Comprehensive literature searches were performed in Medline, Embase, Cochrane Central Register of Controlled Trials (CCTR) et al and advanced search strategies were used to locate hypertension RCTs as well as observational studies conducted in China during 1996 to 2009 synchronously. The risk of bias in RCTs and observational studies was assessed by two modified scales respectively, and then both types of studies with 3 or more grading scores were included for the purpose of evaluating of external validity. Following that the study characteristics relative to sample representation were extracted from RCTs and observational studies synchronously, and the later were taken as external references for validating sample representation of RCTs.
Results
226 hypertension RCTs and 21 observational studies were included for final analysis. Comparing samples with observational studies, the mean age of samples within RCTs was 54.46 years, significantly lower than that of observational studies (66.35 years) (P=0.002). The average disease course in patients of RCTs was 3.89 years and grade III hypertensive patients accounted for 17%; both were lower than that of the observational studies (12.96 years, P<0.001; 34%, P=0.026 respectively). In addition, the proportions of patients with complications due to heart failure, stroke, diabetes, or coronary heart disease in RCTs were 8%, 5%, 12% and 11% correspondingly, all of which were significantly less than that of observational studies (11%, 18%, 17% and 29%).
Conclusion
Sample characteristics within hypertension RCTs were significantly different from those in observational studies. The samples in most RCTs were under-represented. It’s feasible to take samples of observational studies as a mirror of the actual composition of hypertension patients in the real world, if the reporting of observational studies is abundant and available.
doi:10.1371/journal.pone.0082324
PMCID: PMC3855762  PMID: 24324771
5.  Is “Appearing Chronically Ill” a Sign of Poor Health? A Study of Diagnostic Accuracy 
PLoS ONE  2013;8(11):e79934.
Objective
To determine the sensitivity and specificity of a physician’s assessment that a patient “appears chronically ill” for the detection of poor health status.
Methods
The health status of 126 adult outpatients was determined using the 12-Item Short Form Health Survey (SF-12). Physician participants (n = 111 residents and faculty) viewed photographs of each patient participant and assessed whether or not the patient appeared chronically ill. For the entire group of physicians, the median sensitivity and specificity of “appearing chronically ill” for the detection of poor health status (defined as SF-12 physical health score below age group norms by at least 1 SD) were calculated. The study took place from February 2009 to January 2011.
Results
Forty-two participants (33%) had an SF-12 physical health score ≥1 SD below age group norms, and 22 (18%) had a score ≥2 SD below age group norms. When poor health status was defined as an SF-12 physical score ≥1 SD below age group norms, the median sensitivity was 38.1% (IQR 28.6–47.6%), specificity 78.6% (IQR 69.0–84.0%), positive likelihood ratio 1.64 (IQR 1.42–2.15), and negative likelihood ratio 0.82 (IQR 0.74–0.87). For an SF-12 physical score ≥2 SD below age group norms, the median sensitivity was 45.5% (IQR 36.4–54.5%), specificity 76.9% (IQR 66.3–83.7%), positive likelihood ratio 1.77 (IQR 1.49–2.25), and negative likelihood ratio 0.75 (IQR 0.66–0.86).
Conclusions
Our study suggests that a physician’s assessment that a patient “appears chronically ill” has poor sensitivity and modest specificity for the detection of poor health status in adult outpatients. The associated likelihood ratios indicate that this assessment may have limited diagnostic value.
doi:10.1371/journal.pone.0079934
PMCID: PMC3842283  PMID: 24312192
6.  The Association between Diabetes Mellitus and Nonarteritic Anterior Ischemic Optic Neuropathy: A Systematic Review and Meta-Analysis 
PLoS ONE  2013;8(9):e76653.
Background
The association of diabetes mellitus (DM) with nonarteritic anterior ischemic optic neuropathy (NAION) has been inconclusive.
Purpose
To determine whether DM is associated with an increased risk of NAION.
Methods
A comprehensive literature search was performed for published studies reporting both DM and NAION based on PubMed and EMBASE. After reviewing characteristics of all the included studies systematically, meta-analytical method was employed to calculate the pooled odds ratio (OR) and associated 95% confidence interval (CI) from random-effects models. Heterogeneity was assessed by Q-statistic test. Funnel Plot, Begg's and Egger's linear regression test were applied to evaluate publication bias. A sensitivity analysis and meta-regression analysis were also performed to assess the robustness of results.
Results
2,096 participants from 12 case-control studies were pooled for a meta-analysis. The result of meta-analysis of these studies indicated that DM is associated with increased risk of NAION (pooled OR = 1.64, 95% CI = 1.17–2.30; P = 0.004). Sensitivity analysis indicated our findings are robust, and meta-regression analysis revealed no significant effect in terms of geographical area, gender, age of patients with NAION, the year of the publication, source of the controls, and sample size (all p>0.05). Evidence of publication bias was not observed in our study.
Conclusion
Meta-analysis suggests that DM might be associated with increased risk of NAION.
doi:10.1371/journal.pone.0076653
PMCID: PMC3786911  PMID: 24098798
7.  Vitamin D Supplementation and Breast Cancer Prevention: A Systematic Review and Meta-Analysis of Randomized Clinical Trials 
PLoS ONE  2013;8(7):e69269.
In recent years, the scientific evidence linking vitamin D status or supplementation to breast cancer has grown notably. To investigate the role of vitamin D supplementation on breast cancer incidence, we conducted a systematic review and meta-analysis of randomized controlled trials comparing vitamin D with placebo or no treatment. We used OVID to search MEDLINE (R), EMBASE and CENTRAL until April 2012. We screened the reference lists of included studies and used the “Related Article” feature in PubMed to identify additional articles. No language restrictions were applied. Two reviewers independently extracted data on methodological quality, participants, intervention, comparison and outcomes. Risk Ratios and 95% Confident Intervals for breast cancer were pooled using a random-effects model. Heterogeneity was assessed using the I2 test. In sensitivity analysis, we assessed the impact of vitamin D dosage and mode of administration on treatment effects. Only two randomized controlled trials fulfilled the pre-set inclusion criteria. The pooled analysis included 5372 postmenopausal women. Overall, Risk Ratios and 95% Confident Intervals were 1.11 and 0.74–1.68. We found no evidence of heterogeneity. Neither vitamin D dosage nor mode of administration significantly affected breast cancer risk. However, treatment efficacy was somewhat greater when vitamin D was administered at the highest dosage and in combination with calcium (Risk Ratio 0.58, 95% Confident Interval 0.23–1.47 and Risk Ratio 0.93, 95% Confident Interval 0.54–1.60, respectively). In conclusions, vitamin D use seems not to be associated with a reduced risk of breast cancer development in postmenopausal women. However, the available evidence is still limited and inadequate to draw firm conclusions. Study protocol code: FARM8L2B5L.
doi:10.1371/journal.pone.0069269
PMCID: PMC3718745  PMID: 23894438
8.  Patients’ Insight of Interpreting Prescriptions and Drug Labels - A Cross Sectional Study 
PLoS ONE  2013;8(6):e65019.
Background
Errors in consuming drugs are associated with significant morbidity and mortality, besides an impact on the already overburdened health-care system. Misunderstanding drug labels and prescriptions plays an important role in contributing to adverse drug events.
Objective
To evaluate abilities to understand prescriptions and drug labels among patients attending tertiary care hospital in Karachi.
Methods
A cross sectional study was conducted at the Aga Khan University Hospital (AKUH), from January to March 2009. After informed consent, 181 adult patients and their healthy attendants were interviewed at AKUH using a standardized questionnaire, which ascertained patient demographics, factors that might increase exposure to health-care personnel as well as the basic knowledge and understanding of prescriptions and drug labels.
Results
Out of 181, majority 137(76%) had received graduate or post-graduate degrees. 16 (9%) had received no formal education; of which all were females and 89(84%) of the total females were housewives. Overall, 130(72%) followed only a single doctor’s prescription. Majority failed to understand various medical terminologies related to dosage. In the high literacy group, 45(33%) understood once daily OD (p = 0.003), 27(20%) thrice daily TID (p = 0.05), 29(21%) twice daily BD (p = 0.01), 31(23%) thrice daily TDS (p = 0.002) and 43(31%) as needed SOS (p = 0.003) as compared to the group with no formal education, who were unable to comprehend the terms. The most common reason for using more than one prescription was decreased satisfaction with the doctor in 19(39%) and multiple co-morbids as responded by 17(35%) of patients. Knowledge regarding various medical terminologies used for dosage and routes of drug administration were also understood more frequently among the English medium respondents. The elderly identified medicine through color (47%, p<0.001), and were less likely to understand drug indications (p = 0.05) compared to younger subjects.
Conclusion
Understanding of drug prescriptions is alarmingly low in the community, even amongst the educated. Care givers need to revisit this often ignored aspect of patient care.
doi:10.1371/journal.pone.0065019
PMCID: PMC3670850  PMID: 23755168
9.  Education in Health Research Methodology: Use of a Wiki for Knowledge Translation 
PLoS ONE  2013;8(5):e64922.
Introduction
A research-practice gap exists between what is known about conducting methodologically rigorous randomized controlled trials (RCTs) and what is done. Evidence consistently shows that pediatric RCTs are susceptible to high risk of bias; therefore novel methods of influencing the design and conduct of trials are required. The objective of this study was to develop and pilot test a wiki designed to educate pediatric trialists and trainees in the principles involved in minimizing risk of bias in RCTs. The focus was on preliminary usability testing of the wiki.
Methods
The wiki was developed through adaptation of existing knowledge translation strategies and through tailoring the site to the identified needs of the end-users. The wiki was evaluated for usability and user preferences regarding the content and formatting. Semi-structured interviews were conducted with 15 trialists and systematic reviewers, representing varying levels of experience with risk of bias or the conduct of trials. Data were analyzed using content analysis.
Results
Participants found the wiki to be well organized, easy to use, and straightforward to navigate. Suggestions for improvement tended to focus on clarification of the text or on esthetics, rather than on the content or format. Participants liked the additional features of the site that were supplementary to the text, such as the interactive examples, and the components that focused on practical applications, adding relevance to the theory presented. While the site could be used by both trialists and systematic reviewers, the lack of a clearly defined target audience caused some confusion among participants.
Conclusions
Participants were supportive of using a wiki as a novel educational tool. The results of this pilot test will be used to refine the risk of bias wiki, which holds promise as a knowledge translation intervention for education in medical research methodology.
doi:10.1371/journal.pone.0064922
PMCID: PMC3669055  PMID: 23741424
10.  Consultant Input in Acute Medical Admissions and Patient Outcomes in Hospitals in England: A Multivariate Analysis 
PLoS ONE  2013;8(4):e61476.
Recent recommendations for physicians in the UK outline key aspects of care that should improve patient outcomes and experience in acute hospital care. Included in these recommendations are Consultant patterns of work to improve timeliness of clinical review and improve continuity of care. This study used a contemporaneous validated survey compared with clinical outcomes derived from Hospital Episode Statistics, between April 2009 and March 2010 from 91 acute hospital sites in England to evaluate systems of consultant cover for acute medical admissions. Clinical outcomes studied included adjusted case fatality rates (aCFR), including the ratio of weekend to weekday mortality, length of stay and readmission rates. Hospitals that had an admitting Consultant presence within the Acute Medicine Unit (AMU, or equivalent) for a minimum of 4 hours per day (65% of study group) had a lower aCFR compared with hospitals that had Consultant presence for less than 4 hours per day (p<0.01) and also had a lower 28 day re-admission rate (p<0.01). An ‘all inclusive’ pattern of Consultant working, incorporating all the guideline recommendations and which included the minimum Consultant presence of 4 hours per day (29%) was associated with reduced excess weekend mortality (p<0.05). Hospitals with >40 acute medical admissions per day had a lower aCFR compared to hospitals with fewer than 40 admissions per day (p<0.03) and had a lower 7 day re-admission rate (p<0.02). This study is the first large study to explore the potential relationships between systems of providing acute medical care and clinical outcomes. The results show an association between well-designed systems of Consultant working practices, which promote increased patient contact, and improved patient outcomes in the acute hospital setting.
doi:10.1371/journal.pone.0061476
PMCID: PMC3629209  PMID: 23613858
11.  How are Treatment Decisions Made about Artificial Nutrition for Individuals at Risk of Lacking Capacity? A Systematic Literature Review 
PLoS ONE  2013;8(4):e61475.
Background
Worldwide, the number of individuals lacking the mental capacity to participate in decisions about their own healthcare is increasing. Due to the ageing global population and advancing medical treatments, there are now many more people living longer with neurological disorders, such as dementia, acquired brain injuries, and intellectual disabilities. Many of these individuals have feeding difficulties and may require artificial nutrition. However, little is known about the decision-making process; the evidence base is uncertain and often ethically complex. Using the exemplar of artificial nutrition, the objective of this review is to examine how treatment decisions are made when patients are at risk of lacking capacity.
Methods and Findings
We undertook a systematic review according to PRISMA guidelines to determine who was involved in decisions, and what factors were considered. We searched PubMed, AMED, CINAHL, EMBASE, PsychINFO, and OpenSigle for quantitative and qualitative studies (1990–2011). Citation, reference, hand searches and expert consultation were also undertaken. Data extraction and quality assessment were undertaken independently and in duplicate. We utilised Thomas and Harden’s ‘Thematic Synthesis’ for analysis. Sixty-six studies met inclusion criteria, comprising data from 40 countries and 34,649 patients, carers and clinicians. Six themes emerged: clinical indications were similar across countries but were insufficient alone for determining outcomes; quality of life was the main decision-making factor but its meaning varied; prolonging life was the second most cited factor; patient’s wishes were influential but not determinative; families had some influence but were infrequently involved in final recommendations; clinicians often felt conflicted about their roles.
Conclusions
When individuals lack mental capacity, decisions must be made on their behalf. Dynamic interactive factors, such as protecting right to life, not unnecessarily prolonging suffering, and individual preferences, need to be addressed and balanced. These findings provide an outline to aid clinical practice and develop decision-making guidelines.
doi:10.1371/journal.pone.0061475
PMCID: PMC3628879  PMID: 23613857
12.  Contemporary Management and Attainment of Cholesterol Targets for Patients with Dyslipidemia in China 
PLoS ONE  2013;8(4):e47681.
Aims
It is well-established that lipid disorder is an important cardiovascular risk factor, and failure to reach optimal lipid levels significantly contributes to the residual cardiovascular risks. However, limited information is available on the management and the attainment of recommended cholesterol targets in real-world practice in China.
Methods and Results
A nationally representative sample of 12,040 patients with dyslipidemia from 19 provinces and 84 hospitals across China were consecutively enrolled in this survey. Risk stratification and individual cholesterol target was established for all participants. This survey identified a high-risk cohort, with over 50% of patients had hypertension, 37.5% had coronary artery disease, and more than 30% had peripheral artery disease. Thirty-nine percent of all participants received lipid lowering medications. And the majority of them (94.5%) had statins (42.5% with atorvastatin, 29.0% with simvastatin, and 15.2% with rosuvastatin). However, the overall attainment for low-density lipoprotein cholesterol (LDL-C) target is low (25.8%), especially, in female (22.2%), and in patients with increased body mass index (BMI) (38.3% for BMI<18.5, 28.1% for BMI 18.5–24.9, 26.0% for BMI 25.0–29.9, and 17.4% for BMI≥30, P<0.0001). Subgroup analysis also showed the attainment is significantly lower in patients who were stratified into high (19.9%) and very high (21.1%) risk category. In logistic regression analysis, eight factors (BMI, gender, coronary artery disease, systolic and diastolic blood pressure, hypertension, family history of premature coronary artery disease and current smoking) were identified as independent predictors of LDL-C attainment.
Conclusions
Despite the proven benefits of lipid-lowering therapies, current management of dyslipidemia continues to be unsatisfied. A considerable proportion of patients failed to achieve guideline-recommended targets in China, and this apparent treatment gap was more pronounced among patients with increased BMI, higher risk stratification and women.
doi:10.1371/journal.pone.0047681
PMCID: PMC3621908  PMID: 23593110
13.  The Role of Systematic Reviews in Pharmacovigilance Planning and Clinical Trials Authorisation Application: Example from the SLEEPS Trial 
PLoS ONE  2013;8(3):e51787.
Background
Adequate sedation is crucial to the management of children requiring assisted ventilation on Paediatric Intensive Care Units (PICU). The evidence-base of randomised controlled trials (RCTs) in this area is small and a trial was planned to compare midazolam and clonidine, two sedatives widely used within PICUs neither of which being licensed for that use. The application to obtain a Clinical Trials Authorisation from the Medicines and Healthcare products Regulatory Agency (MHRA) required a dossier summarising the safety profiles of each drug and the pharmacovigilance plan for the trial needed to be determined by this information. A systematic review was undertaken to identify reports relating to the safety of each drug.
Methodology/Principal Findings
The Summary of Product Characteristics (SmPC) were obtained for each sedative. The MHRA were requested to provide reports relating to the use of each drug as a sedative in children under the age of 16. Medline was searched to identify RCTs, controlled clinical trials, observational studies, case reports and series. 288 abstracts were identified for midazolam and 16 for clonidine with full texts obtained for 80 and 6 articles respectively. Thirty-three studies provided data for midazolam and two for clonidine. The majority of data has come from observational studies and case reports. The MHRA provided details of 10 and 3 reports of suspected adverse drug reactions.
Conclusions/Significance
No adverse reactions were identified in addition to those specified within the SmPC for the licensed use of the drugs. Based on this information and the wide spread use of both sedatives in routine practice the pharmacovigilance plan was restricted to adverse reactions. The Clinical Trials Authorisation was granted based on the data presented in the SmPC and the pharmacovigilance plan within the clinical trial protocol restricting collection and reporting to adverse reactions.
doi:10.1371/journal.pone.0051787
PMCID: PMC3598865  PMID: 23554852
14.  Magnesium and the Risk of Cardiovascular Events: A Meta-Analysis of Prospective Cohort Studies 
PLoS ONE  2013;8(3):e57720.
Background
Prospective studies that have examined the association between dietary magnesium intake and serum magnesium concentrations and the risk of cardiovascular disease (CVD) events have reported conflicting findings. We undertook a meta-analysis to evaluate the association between dietary magnesium intake and serum magnesium concentrations and the risk of total CVD events.
Methodology/Principal Findings
We performed systematic searches on MEDLINE, EMBASE, and OVID up to February 1, 2012 without limits. Categorical, linear, and nonlinear, dose-response, heterogeneity, publication bias, subgroup, and meta-regression analysis were performed. The analysis included 532,979 participants from 19 studies (11 studies on dietary magnesium intake, 6 studies on serum magnesium concentrations, and 2 studies on both) with 19,926 CVD events. The pooled relative risks of total CVD events for the highest vs. lowest category of dietary magnesium intake and serum magnesium concentrations were 0.85 (95% confidence interval 0.78 to 0.92) and 0.77 (0.66 to 0.87), respectively. In linear dose-response analysis, only serum magnesium concentrations ranging from 1.44 to 1.8 mEq/L were significantly associated with total CVD events risk (0.91, 0.85 to 0.97) per 0.1 mEq/L (Pnonlinearity = 0.465). However, significant inverse associations emerged in nonlinear models for dietary magnesium intake (Pnonlinearity = 0.024). The greatest risk reduction occurred when intake increased from 150 to 400 mg/d. There was no evidence of publication bias.
Conclusions/Significance
There is a statistically significant nonlinear inverse association between dietary magnesium intake and total CVD events risk. Serum magnesium concentrations are linearly and inversely associated with the risk of total CVD events.
doi:10.1371/journal.pone.0057720
PMCID: PMC3592895  PMID: 23520480
15.  Efficacy of Intensive Control of Glucose in Stroke Prevention: A Meta-Analysis of Data from 59197 Participants in 9 Randomized Controlled Trials 
PLoS ONE  2013;8(1):e54465.
Background
The efficacy of treatments that lower glucose in reducing the risk of incident stroke remains unclear. We therefore did a systematic review and meta-analysis to evaluate the efficacy of intensive control of glucose in the prevention of stroke.
Methodology/Principal Findings
We systematically searched Medline, EmBase, and the Cochrane Library for trials published between 1950 and June, 2012. We included randomized controlled trials that reported on the effects of intensive control of glucose on incident stroke compared with standard care. Summary estimates of relative risk (RR) reductions were calculated with a random effects model, and the analysis was further stratified by factors that could affect the treatment effects. Of 649 identified studies, we included nine relevant trials, which provided data for 59197 patients and 2037 events of stroke. Overall, intensive control of glucose as compared to standard care had no effect on incident stroke (RR, 0.96; 95%CI 0.88–1.06; P = 0.445). In the stratified analyses, a beneficial effect was seen in those trials when body mass index (BMI) more than 30 (RR, 0.86; 95%CI: 0.75–0.99; P = 0.041). No other significant differences were detected between the effect of intensive control of glucose and standard care when based on other subset factors.
Conclusions/Significance
Our study indicated intensive control of glucose can effectively reduce the risk of incident stroke when patients with BMI more than 30.
doi:10.1371/journal.pone.0054465
PMCID: PMC3553082  PMID: 23372729
16.  Prognostic Value of Malondialdehyde Serum Levels in Severe Sepsis: A Multicenter Study 
PLoS ONE  2013;8(1):e53741.
Objective
The oxidant/antioxidant state in septic patients has only been studied in small series. We wished to determine whether malondialdehyde (MDA) serum levels were associated with severity and 30-day mortality in a large series of patients with sepsis.
Methods
We performed an observational, prospective, multicenter study in six Spanish Intensive Care Units. Serum levels of MDA were measured in a total of 228 patients (145 survivors and 83 non-survivors) with severe sepsis and 100 healthy controls.
Results
Serum levels of MDA were higher in severe septic patients than in healthy controls. Non-surviving septic patients had higher MDA values than survivors. MDA serum levels were associated with severity markers (lactic acid, SOFA, APACHE-II) and coagulation indices. Regression analysis showed that MDA serum levels were associated with 30-day survival (Hazard ratio = 1.05; 95% confidence interval = 1.009–1.091; p = 0.016). Receiver operating characteristic analysis showed that the area under curve of MDA serum levels to predict 30-day survival was 0.62 (95% CI = 0.56–0.69; P = 0.002). The risk of death in septic patients with MDA serum levels above 4.11 nmol/mL was higher than in patients with lower values (Hazard Ratio = 2.43; 95% CI = 1.49–3.94; p<0.001).
Conclusions
The novel findings of our study on severe septic patients, to our knowledge the largest series providing data on the oxidative state, are that elevated MDA serum levels probably represent an unbalanced oxidant state and are related with poor prognosis in patients with severe sepsis.
doi:10.1371/journal.pone.0053741
PMCID: PMC3544841  PMID: 23341989
17.  Understanding of Statistical Terms Routinely Used in Meta-Analyses: An International Survey among Researchers 
PLoS ONE  2013;8(1):e47229.
Objective
Biomedical literature is increasingly enriched with literature reviews and meta-analyses. We sought to assess the understanding of statistical terms routinely used in such studies, among researchers.
Methods
An online survey posing 4 clinically-oriented multiple-choice questions was conducted in an international sample of randomly selected corresponding authors of articles indexed by PubMed.
Results
A total of 315 unique complete forms were analyzed (participation rate 39.4%), mostly from Europe (48%), North America (31%), and Asia/Pacific (17%). Only 10.5% of the participants answered correctly all 4 “interpretation” questions while 9.2% answered all questions incorrectly. Regarding each question, 51.1%, 71.4%, and 40.6% of the participants correctly interpreted statistical significance of a given odds ratio, risk ratio, and weighted mean difference with 95% confidence intervals respectively, while 43.5% correctly replied that no statistical model can adjust for clinical heterogeneity. Clinicians had more correct answers than non-clinicians (mean score ± standard deviation: 2.27±1.06 versus 1.83±1.14, p<0.001); among clinicians, there was a trend towards a higher score in medical specialists (2.37±1.07 versus 2.04±1.04, p = 0.06) and a lower score in clinical laboratory specialists (1.7±0.95 versus 2.3±1.06, p = 0.08). No association was observed between the respondents' region or questionnaire completion time and participants' score.
Conclusion
A considerable proportion of researchers, randomly selected from a diverse international sample of biomedical scientists, misinterpreted statistical terms commonly reported in meta-analyses. Authors could be prompted to explicitly interpret their findings to prevent misunderstandings and readers are encouraged to keep up with basic biostatistics.
doi:10.1371/journal.pone.0047229
PMCID: PMC3543405  PMID: 23326299
18.  Does Adhesive Capsulitis of the Shoulder Increase the Risk of Stroke? A Population-Based Propensity Score-Matched Follow-Up Study 
PLoS ONE  2012;7(11):e49343.
Objectives
A previous population-based study reported an increased risk of stroke after the occurrence of adhesive capsulitis of the shoulder (ACS), but there were substantial imbalances in the distribution of age and pre-existing vascular risk factors between subjects with ACS and without ACS, which might lead to a confounded association between ACS and stroke. The purpose of the present large-scale propensity score-matched population-based follow-up study was to clarify whether there is an increased stroke risk after ACS.
Methods
We used a logistic regression model that includes age, sex, pre-existing comorbidities and socioeconomic status as covariates to compute the propensity score. A total of 22025 subjects with at least two ambulatory visits with the principal diagnosis of ACS in 2001 was enrolled in the ACS group. The non-ACS group consisted of 22025, propensity score-matched subjects without ACS. The stroke-free survival curves for these 2 groups were compared using the Kaplan-Meier method. Stratified Cox proportional hazard regression with patients matched on propensity score was used to estimate the effect of ACS on the occurrence of stroke.
Results
During the two-year follow-up period, 657 subjects in the ACS group (2.98%) and 687 in the non-ACS group (3.12%) developed stroke. The hazard ratio (HR) of stroke for the ACS group was 0.93 compared to the non-ACS group (95% confidence interval [CI], 0.83–1.04, P = 0.1778). There was no statistically significant difference in stroke subtype distribution between the two groups (P = 0.2114).
Conclusions
These findings indicate that ACS itself is not associated with an increased risk of subsequent stroke.
doi:10.1371/journal.pone.0049343
PMCID: PMC3501521  PMID: 23185317
19.  Variable Lengths of Stay among Ischemic Stroke Subtypes in Chinese General Teaching Hospitals 
PLoS ONE  2012;7(9):e45101.
Background
Length of stay (LOS) is one of the most important quantitative indexes that measures health service utilization within a hospital. Many studies have examined the association of three major stroke categories with LOS. Our aim is to investigate the differences of LOS among ischemic stroke subtypes, results from which are helpful to healthcare providers and government agencies to improve health care delivery efficiency.
Methodology/Principal Findings
Using the Beijing Municipal Health Bureau’s hospitalization summary reports, we performed a retrospective study among first-ever in-hospital patients with ischemic stroke (ICD-10 I63) in three general teaching hospitals in Beijing, China, from 2006 to 2010 with generalized linear model. In our study, 5,559 patients (female, 36.0%; age, 64.4±12.9 years) were included. The estimated mean LOS of ischemic stroke was 17.4±1.8 days. After adjusting for confounders, LOS of lacunar infarction (14.7 days; p<0.001) and LOS of small cerebral infarction (17.0 days; p = 0.393) were shorter than that of single cerebral infarction (17.9 days, p<0.001). LOS of multi-infarct (19.0 days; p = 0.028), brainstem infarction (19.3 days; p = 0.045), basal ganglia infarction (18.5 days; p = 0.452) and other subtypes of ischemic stroke (18.9 days; p = 0.327) were longer than that of single cerebral infarction.
Conclusions
LOS of ischemic stroke patient differes across single cerebral infarction, lacunar infarction, multi-infarct and brainstem infarction patients. The ascending order of LOS was lacunar infarction, small cerebral infarction, single cerebral infarction, basal ganglia infarction, other subtypes of ischemic stroke, multi-infarct and brainstem infarction.
doi:10.1371/journal.pone.0045101
PMCID: PMC3461000  PMID: 23028783
20.  Development and Evaluation of a Simple and Effective Prediction Approach for Identifying Those at High Risk of Dyslipidemia in Rural Adult Residents 
PLoS ONE  2012;7(8):e43834.
Background
Dyslipidemia is an extremely prevalent but preventable risk factor for cardiovascular disease. However, many dyslipidemia patients remain undetected in resource limited settings. The study was performed to develop and evaluate a simple and effective prediction approach without biochemical parameters to identify those at high risk of dyslipidemia in rural adult population.
Methods
Demographic, dietary and lifestyle, and anthropometric data were collected by a cross-sectional survey from 8,914 participants living in rural areas aged 35–78 years. There were 6,686 participants randomly selected into a training group for constructing the artificial neural network (ANN) and logistic regression (LR) prediction models. The remaining 2,228 participants were assigned to a validation group for performance comparisons of ANN and LR models. The predictors of dyslipidemia risk were identified from the training group using multivariate logistic regression analysis. Predictive performance was evaluated by receiver operating characteristic (ROC) curve.
Results
Some risk factors were significantly associated with dyslipidemia, including age, gender, educational level, smoking, high-fat diet, vegetable and fruit intake, family history, physical activity, and central obesity. For the ANN model, the sensitivity, specificity, positive and negative likelihood ratio, positive and negative predictive values were 90.41%, 76.66%, 3.87, 0.13, 76.33%, and 90.58%, respectively, while LR model were only 57.37%, 70.91%, 1.97, 0.60, 62.09%, and 66.73%, respectively. The area under the ROC cure (AUC) value of the ANN model was 0.86±0.01, showing more accurate overall performance than traditional LR model (AUC = 0.68±0.01, P<0.001).
Conclusion
The ANN model is a simple and effective prediction approach to identify those at high risk of dyslipidemia, and it can be used to screen undiagnosed dyslipidemia patients in rural adult population. Further work is planned to confirm these results by incorporating multi-center and longer follow-up data.
doi:10.1371/journal.pone.0043834
PMCID: PMC3429495  PMID: 22952780
21.  Outcomes in Registered, Ongoing Randomized Controlled Trials of Patient Education 
PLoS ONE  2012;7(8):e42934.
Background
With the increasing prevalence of chronic noncommunicable diseases, patient education is becoming important to strengthen disease prevention and control. We aimed to systematically determine the extent to which registered, ongoing randomized controlled trials (RCTs) evaluated an educational intervention focus on patient-important outcomes (i.e., outcomes measuring patient health status and quality of life).
Methods
On May 6, 2009, we searched for all ongoing RCTs registered in the World Health Organization International Clinical Trials Registry platform. We used a standardized data extraction form to collect data and determined whether the outcomes assessed were 1) patient-important outcomes such as clinical events, functional status, pain, or quality of life or 2) surrogate outcomes, such as biological outcome, treatment adherence, or patient knowledge.
Principal Findings
We selected 268 of the 642 potentially eligible studies and assessed a random sample of 150. Patient-important outcomes represented 54% (178 of 333) of all primary outcomes and 46% (286 of 623) of all secondary outcomes. Overall, 69% of trials (104 of 150) used at least one patient-important outcome as a primary outcome and 66% (99 of 150) as a secondary outcome. Finally, for 31% of trials (46 of 150), primary outcomes were only surrogate outcomes. The results varied by medical area. In neuropsychiatric disorders, patient important outcomes represented 84% (51 of 61) of primary outcomes, as compared with 54% (32 of 59) in malignant neoplasm and 18% (4 of 22) in diabetes mellitus trials.
In addition, only 35% assessed the long-term impact of interventions (i.e., >6 months).
Conclusions
There is a need to improve the relevance of outcomes and to assess the long term impact of educational interventions in RCTs.
doi:10.1371/journal.pone.0042934
PMCID: PMC3420885  PMID: 22916183
22.  Heart Failure and Preserved Left Ventricular Function: Long Term Clinical Outcome 
PLoS ONE  2012;7(7):e41022.
Background
Patients with heart failure (HF) have a poor prognosis. The proportion of patients with HF and preserved left ventricular function (LVF) is increasing. Long term prognosis of HF with preserved LVF may not be so benign.
Objectives
To evaluate the long term clinical outcome of patients with HF and preserved LVF and predictors of outcome.
Methods
We prospectively evaluated 309 patients hospitalized with a definite clinical diagnosis of HF. Patients were followed for a mean of 6.5 years for clinical outcome.
Results
More than a third (36%) of the patients had preserved systolic LVF based on echocardiography. The long term survival rate in this group was poor and not significantly different from patients with reduced LVF (28% vs 23% respectively, P = 0.2). The adjusted survival rate by Cox regression analysis was also not significantly different (hazard ratio 1.16, 95% confidence interval 0.87–1.55, P = 0.31). The event free survival from death or heart failure re-hospitalization was also low in both groups and not significantly different between patients with preserved vs. reduced LVF (12% vs. 10% respectively, P = 0.2). Predictors of mortality in patients with preserved LVF were age, functional capacity and serum urea levels.
Conclusions
The long term clinical outcome of patients with heart failure and preserved LVF is poor and not significantly different from patients with reduced LVF.
doi:10.1371/journal.pone.0041022
PMCID: PMC3400584  PMID: 22829907
23.  Influence of Birth Preparedness, Decision-Making on Location of Birth and Assistance by Skilled Birth Attendants among Women in South-Western Uganda 
PLoS ONE  2012;7(4):e35747.
Introduction
Assistance by skilled birth attendants (SBAs) during childbirth is one of the strategies aimed at reducing maternal morbidity and mortality in low-income countries. However, the relationship between birth preparedness and decision-making on location of birth and assistance by skilled birth attendants in this context is not well studied. The aim of this study was to assess the influence of birth preparedness practices and decision-making and assistance by SBAs among women in south-western Uganda.
Methods
Community survey methods were used to identify 759 recently delivered women from 120 villages in rural Mbarara district. Interviewer-administered questionnaires were used to collect data. Logistic regression analyses were conducted to assess the relationship between birth preparedness, decision-making on location of birth and assistance by SBAs.
Results
35% of the women had been prepared for childbirth and the prevalence of assistance by SBAs in the sample was 68%. The final decision regarding location of birth was made by the woman herself (36%), the woman with spouse (56%) and the woman with relative/friend (8%). The relationships between birth preparedness and women decision-making on location of birth in consultation with spouse/friends/relatives and choosing assistance by SBAs showed statistical significance which persisted after adjusting for possible confounders (OR 1.5, 95% CI: 1.0–2.4) and (OR 4.4, 95% CI: 3.0–6.7) respectively. Education, household assets and birth preparedness showed clear synergistic effect on the relationship between decision-maker on location of birth and assistance by SBAs. Other factors which showed statistical significant relationships with assistance by SBAs were ANC attendance, parity and residence.
Conclusion
Women’s decision-making on location of birth in consultation with spouse/friends/relatives and birth preparedness showed significant effect on choosing assistance by SBAs at birth. Education and household assets ownership showed a synergistic effect on the relationship between the decision-maker and assistance by SBAs.
doi:10.1371/journal.pone.0035747
PMCID: PMC3338788  PMID: 22558214
24.  From the Trenches: A Cross-Sectional Study Applying the GRADE Tool in Systematic Reviews of Healthcare Interventions 
PLoS ONE  2012;7(4):e34697.
Background
GRADE was developed to address shortcomings of tools to rate the quality of a body of evidence. While much has been published about GRADE, there are few empirical and systematic evaluations.
Objective
To assess GRADE for systematic reviews (SRs) in terms of inter-rater agreement and identify areas of uncertainty.
Design
Cross-sectional, descriptive study.
Methods
We applied GRADE to three SRs (n = 48, 66, and 75 studies, respectively) with 29 comparisons and 12 outcomes overall. Two reviewers graded evidence independently for outcomes deemed clinically important a priori. Inter-rater reliability was assessed using kappas for four main domains (risk of bias, consistency, directness, and precision) and overall quality of evidence.
Results
For the first review, reliability was: κ = 0.41 for risk of bias; 0.84 consistency; 0.18 precision; and 0.44 overall quality. Kappa could not be calculated for directness as one rater assessed all items as direct; assessors agreed in 41% of cases. For the second review reliability was: 0.37 consistency and 0.19 precision. Kappa could not be assessed for other items; assessors agreed in 33% of cases for risk of bias; 100% directness; and 58% overall quality. For the third review, reliability was: 0.06 risk of bias; 0.79 consistency; 0.21 precision; and 0.18 overall quality. Assessors agreed in 100% of cases for directness. Precision created the most uncertainty due to difficulties in identifying “optimal” information size and “clinical decision threshold”, as well as making assessments when there was no meta-analysis. The risk of bias domain created uncertainty, particularly for nonrandomized studies.
Conclusions
As researchers with varied levels of training and experience use GRADE, there is risk for variability in interpretation and application. This study shows variable agreement across the GRADE domains, reflecting areas where further guidance is required.
doi:10.1371/journal.pone.0034697
PMCID: PMC3320617  PMID: 22496843
25.  Low Lipoprotein(a) Concentration Is Associated with Cancer and All-Cause Deaths: A Population-Based Cohort Study (The JMS Cohort Study) 
PLoS ONE  2012;7(4):e31954.
Background
Experimental studies support the anti-neoplastic effect of apo(a), but several clinical studies have reported contradictory results. The purpose of this study was to determine whether a low lipoprotein(a) [Lp(a)] concentration is related to mortality from major causes of death, especially cancer.
Methods
The subjects were 10,413 participants (4,005 men and 6,408 women) from a multi-center population-based cohort study in Japan (The Jichi Medical School cohort study). The average age at registration was 55.0 years, and the median observation period was 4,559 days. As the estimated hazard ratio was high for both the low and very high Lp(a) levels, we defined two Lp(a) groups: a low Lp(a) group [Lp(a)<80 mg/L] and an intermediate-to-high Lp(a) group [Lp(a)≥80]. Participants who died from malignant neoplasms (n = 316), cardiovascular disease (202), or other causes (312) during the observation period were examined.
Results
Cumulative incidence plots showed higher cumulative death rates for the low Lp(a) group than for the intermediate-to-high Lp(a) group for all-cause, cancer, and miscellaneous-cause deaths (p<0.001, p = 0.03, and p = 0.03, respectively). Cox proportional hazards analyses with the sex and age of the participants, body mass index, and smoking and drinking histories as covariates showed that a low Lp(a) level was a significant risk for all-cause, cancer, and miscellaneous-cause deaths (p<0.001, p = 0.003, and p = 0.01, respectively). The hazard ratio (95% CI) [1.48, 1.15–1.92] of a low Lp(a) level for cancer deaths was almost the same as that for a male sex (1.46, 1.00–2.13).
Conclusions
This is the first report to describe the association between a low Lp(a) level and all-cause or cancer death, supporting the anti-neoplastic effect of Lp(a). Further epidemiological studies are needed to confirm the present results.
doi:10.1371/journal.pone.0031954
PMCID: PMC3317664  PMID: 22485129

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