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1.  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
2.  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
3.  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
4.  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
5.  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
6.  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
7.  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
8.  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
9.  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
10.  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
11.  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
12.  Prioritisation of Clinical Research by the Example of Type 2 Diabetes: A Caregiver-Survey on Perceived Relevance and Need for Evidence 
PLoS ONE  2012;7(3):e32414.
Background
The Cochrane Collaboration aims at providing the best available evidence for interventions in health care. We wished to examine to which extent treatments considered relevant by caregivers in type 2 diabetes are covered by Cochrane systematic reviews.
Methodology/Principal Findings
130 different interventions in type 2 diabetes were identified based on a review of clinical practice guidelines and expert opinion (Table S1). 459 members of the German Diabetes Society (diabetologists, general practitioners, diabetic nurses, nutritionists, podologists, others) were surveyed via e-mail-list to rank a) the perceived clinical relevance and b) the perceived need for evidence of interventions, based on an internet survey. In the Cochrane Library, there were, at the time of this evaluation, 56 reviews on interventions in diabetes. Generally, coverage of topics by Cochrane reviews reflected the perceived clinical relevance and perceived need for evidence. As an example, highly ranked treatments such as lifestyle changes or oral antidiabetics were well covered, while low rank treatments such as complementary approaches were not covered. Discrepancies occurred with new treatments such as amylin-analogues (low relevance, high need for evidence, review not yet completed) and interventions with immediate and dramatic effects such as treating hypoglycemia (high relevance, low need for evidence, no review). Also, there was a relative scarcity of reviews concerning specific problems, in particular, treatment of late diabetic complications.
Conclusions/Significance
For most interventions, perceived relevance and perceived need for evidence are reflected by the evidence already available. Prioritizing should aim at improving immediacy and consideration of the treatment of complications.
doi:10.1371/journal.pone.0032414
PMCID: PMC3308957  PMID: 22448219
13.  Plasma Heme Oxygenase-1 Concentration in Relation to Impaired Glucose Regulation in a Non-Diabetic Chinese Population 
PLoS ONE  2012;7(3):e32223.
Background
Our previous study has recently shown that plasma heme oxygenase-1 (HO-1), a stress-responsive protein, is elevated in individuals with type 2 diabetes. The current study aimed to examine the association between plasma HO-1 concentration and impaired glucose regulation (IGR) in non-diabetic individuals.
Methods
We conducted a case-control study including a total of 865 subjects (262 IGR individuals and 603 healthy controls) in a Chinese population. Basic characteristics were collected by questionnaire and standardized anthropometric measurements. Plasma HO-1 concentration was determined by ELISA.
Results
Plasma HO-1 concentration was significantly increased in IGR individuals compared with healthy controls (1.34 (0.81–2.29) ng/ml vs 0.98 (0.56–1.55) ng/ml, P<0.001). After adjustment for age, sex, and BMI, the ORs for IGR in the highest quartile of plasma HO-1 concentrations, compared with the lowest, was 3.42 (95% CI 2.11–5.54; P for trend <0.001). The trend remained significant even after additional adjustment for smoking, alcohol drinking, hypertension, family history of diabetes, lipid profiles and C-reactive protein. In the receiver-operating characteristic curve analysis, addition of plasma HO-1 concentration to a model with known risk factors yielded significantly improved discriminative value for IGR (area under the curves 0.75 (95% CI 0.71–0.78) vs. 0.72 (95% CI 0.69–0.76); P for difference = 0.026).
Conclusions
Elevated plasma HO-1 concentration is significantly associated with increased ORs for IGR. However, its clinical utility should be validated in further studies, especially in prospective cohort studies.
doi:10.1371/journal.pone.0032223
PMCID: PMC3299661  PMID: 22427825
14.  Medication Adherence in Type 2 Diabetes: The ENTRED Study 2007, a French Population-Based Study 
PLoS ONE  2012;7(3):e32412.
Background
Adherence to prescribed medications is a key dimension of healthcare quality. The aim of this large population-based study was to evaluate self-reported medication adherence and to identify factors linked with poor adherence in patients with type 2 diabetes in France.
Methodology
The ENTRED study 2007, a French national survey of people treated for diabetes, was based on a representative sample of patients who claimed reimbursement for oral hypoglycaemic agents and/or insulin at least three times between August 2006 and July 2007, and who were randomly selected from the database of the two main National Health Insurance Systems. Medication adherence was determined using a six-item self-administered questionnaire. A multinomial polychotomous logistic regression model was used to identify factors associated with medication adherence in the 3,637 persons with type 2 diabetes.
Principal Findings
Thirty nine percent of patients reported good medication adherence, 49% medium adherence and 12% poor adherence. The factors significantly associated with poor adherence in multivariate analysis were socio-demographic factors: age <45 years, non-European geographical origin, financial difficulties and being professionally active; disease and therapy-related factors: HbA1c>8% and existing diabetes complications; and health care-related factors: difficulties for taking medication alone, decision making by the patient only, poor acceptability of medical recommendations, lack of family or social support, need for information on treatment, reporting no confidence in the future, need for medical support and follow-up by a specialist physician.
Conclusions
In a country with a high level of access to healthcare, our study demonstrated a substantial low level of medication adherence in type 2 diabetic patients. Better identification of those with poor adherence and individualised suitable recommendations remain essential for better healthcare management.
doi:10.1371/journal.pone.0032412
PMCID: PMC3293796  PMID: 22403654
15.  An Updated Review of the Efficacy of Cupping Therapy 
PLoS ONE  2012;7(2):e31793.
Background
Since 1950, traditional Chinese medicine (TCM) cupping therapy has been applied as a formal modality in hospitals throughout China and elsewhere in the world. Based on a previous systematic literature review of clinical studies on cupping therapy, this study presents a thorough review of randomized controlled trials (RCTs) to evaluate the therapeutic effect of cupping therapy.
Method
Six databases were searched for articles published through 2010. RCTs on cupping therapy for various diseases were included. Studies on cupping therapy combined with other TCM treatments versus non-TCM therapies were excluded.
Results
135 RCTs published from 1992 through 2010 were identified. The studies were generally of low methodological quality. Diseases for which cupping therapy was commonly applied were herpes zoster, facial paralysis (Bell palsy), cough and dyspnea, acne, lumbar disc herniation, and cervical spondylosis. Wet cupping was used in most trials, followed by retained cupping, moving cupping, and flash cupping. Meta-analysis showed cupping therapy combined with other TCM treatments was significantly superior to other treatments alone in increasing the number of cured patients with herpes zoster, facial paralysis, acne, and cervical spondylosis. No serious adverse effects were reported in the trials.
Conclusions
Numerous RCTs on cupping therapy have been conducted and published during the past decades. This review showed that cupping has potential effect in the treatment of herpes zoster and other specific conditions. However, further rigorously designed trials on its use for other conditions are warranted.
doi:10.1371/journal.pone.0031793
PMCID: PMC3289625  PMID: 22389674
16.  Sources of Dietary Protein in Relation to Blood Pressure in a General Dutch Population 
PLoS ONE  2012;7(2):e30582.
Background
Little is known about the relation of different dietary protein types with blood pressure (BP). We examined whether intake of total, plant, animal, dairy, meat, and grain protein was related to BP in a cross sectional cohort of 20,820 Dutch adults, aged 20–65 y and not using antihypertensive medication.
Design
Mean BP levels were calculated in quintiles of energy-adjusted protein with adjustment for age, sex, BMI, education, smoking, and intake of energy, alcohol, and other nutrients including protein from other sources. In addition, mean BP difference after substitution of 3 en% carbohydrates or MUFA with protein was calculated.
Results
Total protein and animal protein were not associated with BP (ptrend = 0.62 and 0.71 respectively), both at the expense of carbohydrates and MUFA. Systolic BP was 1.8 mmHg lower (ptrend<0.01) in the highest (>36 g/d) than in the lowest (<27 g/d) quintile of plant protein. This inverse association was present both at the expense of carbohydrates and MUFA and more pronounced in individuals with untreated hypertension (−3.6 mmHg) than in those with normal (+0.1 mmHg) or prehypertensive BP (−0.3 mmHg; pinteraction<0.01). Meat and grain protein were not related to BP. Dairy protein was directly associated with systolic BP (+1.6 mmHg, ptrend<0.01), but not with diastolic BP (ptrend = 0.24).
Conclusions
Total protein and animal protein were not associated with BP in this general untreated Dutch population. Plant protein may be beneficial to BP, especially in people with elevated BP. However, because high intake of plant protein may be a marker of a healthy diet and lifestyle in general, confirmation from randomized controlled trials is warranted.
doi:10.1371/journal.pone.0030582
PMCID: PMC3274530  PMID: 22347387
17.  Is There Any Association between Use of Smokeless Tobacco Products and Coronary Heart Disease in Bangladesh? 
PLoS ONE  2012;7(1):e30584.
Background
Most epidemiological studies exploring the association between smokeless tobacco (SLT) use and coronary heart disease (CHD) have been in Western populations, and have focused on SLT products used in those countries. Few studies come from South Asian countries. Our objective was to determine the association between SLT use and CHD among non-smoking adults in Bangladesh.
Methods
A matched case-control study of non-smoking Bangladeshi adults aged 40–75 years was conducted in 2010. Incident cases of CHD were selected from two cardiac hospitals. Community controls, matched to CHD cases, were selected from neighbourhoods, and hospital controls were selected from outpatient departments of the same hospitals. The Rose Angina Questionnaire (RAQ) was also used to re-classify cases and controls.
Results
The study enrolled 302 cases, 1,208 community controls and 302 hospital controls. Current use was higher among community controls (38%) compared to cases (33%) and hospital controls (32%). Current use of SLT was not significantly associated with an increased risk of CHD when community controls were used (adjusted OR 0.87, 95% CI 0.63–1.19), or when hospital controls were used (adjusted OR 1.00, 95% CI 0.63–1.60), or when both control groups were combined (adjusted OR 1.00, 95% CI 0.74–1.34). Risk of CHD did not increase with use of individual types except gul, frequency, duration, past use of SLT products, or using the RAQ to re-classify cases and controls. There was a significant association between gul use and CHD when both controls were combined (adjusted OR 2.93, 95% CI 1.28–6.70).
Conclusions
There was no statistically significant association between SLT use in general and CHD among non-smoking adults in Bangladesh. Further research on the association between gul use and CHD in Bangladesh along with SLT use and CHD in other parts of the subcontinent will guide public health policy and interventions that focus on SLT-related diseases.
doi:10.1371/journal.pone.0030584
PMCID: PMC3262837  PMID: 22276217
18.  Risk of Death and Cardiovascular Outcomes with Thiazolidinediones: A Study with the General Practice Research Database and Secondary Care Data 
PLoS ONE  2011;6(12):e28157.
Objective
To describe the likely extent of confounding in evaluating the risks of cardiovascular (CV) events and mortality in patients using diabetes medication.
Methods
The General Practice Research Database was used to identify inception cohorts of insulin and different oral antidiabetics. An analysis of bias and incidence of mortality, acute coronary syndrome, stroke and heart failure were analysed in GPRD, Hospital Episode Statistics and death certificates.
Results
206,940 patients were identified. The bias analysis showed that past thiazolidinedione users had a lower mortality risk compared to past metformin users. There were no differences between past users of rosiglitazone and pioglitazone (adjusted RR of 1.04; 95% CI 0.93–1.18). Current rosiglitazone users had an increased risk of death (adjusted RR 1.20; 95% CI 1.08–1.34) and of hospitalisation for heart failure (adjusted RR of 1.73; 95% CI 1.19–2.51) compared to current pioglitazone users. Risk of mortality was increased two-fold shortly after starting rosiglitazone. Excess risk of death over 3 years with rosiglitazone was 0.3 per 100 in those aged 50–64 years, 2.0 aged 65–74, 3.0 aged 75–84, and 7.0 aged 85+. The cause of death with rosiglitazone was more likely to be due to a disease of the circulatory system.
Conclusions
Higher risks for death (overall and due to cardiovascular disease) and heart failure were found for rosiglitazone compared to pioglitazone. These excess risks were largest in patients aged 65 years or older. The European regulatory decision to suspend rosiglitazone is supported by this study.
doi:10.1371/journal.pone.0028157
PMCID: PMC3229530  PMID: 22164237
19.  Frequency and Associated Factors for Care Giving among Elderly Patients Visiting a Teaching Hospital in Karachi, Pakistan 
PLoS ONE  2011;6(11):e25873.
Objective
To study frequency and associated factors for care giving among elderly patients visiting a teaching hospital in Karachi, Pakistan.
Methodology
A cross sectional questionnaire-based study was conducted at the Community Health Centre (CHC), Aga Khan University Hospital (AKUH) Karachi, Pakistan from September to November 2009. All individuals, visiting the CHC and aged 65 years or above were interviewed after taking written informed consent.
Results
A total of 400 elderly completed the interview. Majority were females, 65–69 years age, More than half of the individuals ie: 227 (85%) had received Care Giver experience for assistance and among these 195(72%) had care provided by an immediate family member. A large proportion of them stated that their Care Givers managed to provide less than four hours in a day for care giving. Around 37% showed substantial improvement in their relationship with the care givers. About 70% of the respondents stated that the care provided by the Care Giver improved their quality of life.
Conclusion
Elderly care is provided by majority of the family members resulting in increased satisfaction level, however small number still not satisfied due to unfulfilled need of these older people. This demands that efforts should be made to strengthen the family support by increasing awareness regarding elderly care and arranging support system by the government.
doi:10.1371/journal.pone.0025873
PMCID: PMC3208547  PMID: 22073142
20.  Status of B-Vitamins and Homocysteine in Diabetic Retinopathy: Association with Vitamin-B12 Deficiency and Hyperhomocysteinemia 
PLoS ONE  2011;6(11):e26747.
Diabetic retinopathy (DR) is a common cause of blindness. Although many studies have indicated an association between homocysteine and DR, the results so far have been equivocal. Amongst the many determinants of homocysteine, B-vitamin status was shown to be a major confounding factor, yet very little is known about its relationship to DR. In the present study, we, therefore, investigated the status of B-vitamins and homocysteine in DR. A cross-sectional case–control study was conducted with 100 normal control (CN) subjects and 300 subjects with type-2 diabetes (T2D). Of the 300 subjects with T2D, 200 had retinopathy (DR) and 100 did not (DNR). After a complete ophthalmic examination including fundus fluorescein angiography, the clinical profile and the blood levels of all B-vitamins and homocysteine were analyzed. While mean plasma homocysteine levels were found to be higher in T2D patients compared with CN subjects, homocysteine levels were particularly high in the DR group. There were no group differences in the blood levels of vitamins B1 and B2. Although the plasma vitamin-B6 and folic acid levels were significantly lower in the DNR and DR groups compared with the CN group, there were no significant differences between the diabetes groups. Interestingly, plasma vitamin-B12 levels were found to be significantly lower in the diabetes groups compared with the CN group; further, the levels were significantly lower in the DR group compared with the DNR group. Higher homocysteine levels were significantly associated with lower vitamin-B12 and folic acid but not with other B-vitamins. Additionally, hyperhomocysteinemia and vitamin-B12 deficiency did not seem to be related to subjects' age, body mass index, or duration of diabetes. These results thus suggest a possible association between vitamin-B12 deficiency and hyperhomocysteinemia in DR. Further, the data indicate that vitamin-B12 deficiency could be an independent risk factor for DR.
doi:10.1371/journal.pone.0026747
PMCID: PMC3206053  PMID: 22069468
21.  Diabetes Mellitus and Its Correlates in an Iranian Adult Population 
PLoS ONE  2011;6(10):e26725.
The rising epidemic of diabetes imposes a substantial economic burden on the Middle East. Using baseline data from a population based cohort study, we aimed to identify the correlates of diabetes mellitus (DM) in a mainly rural population from Iran. Between 2004 and 2007, 50044 adults between 30 and 87 years old from Golestan Province located in Northeast Iran were enrolled in the Golestan Cohort Study. Demographic and health-related information was collected using questionnaires. Individuals' body sizes at ages 15 and 30 were assessed by validated pictograms ranging from 1 (very lean) to 7 in men and 9 in women. DM diagnosis was based on the self-report of a physician's diagnosis. The accuracy of self-reported DM was evaluated in a subcohort of 3811 individuals using fasting plasma glucose level and medical records. Poisson regression with robust variance estimator was used to estimate prevalence ratios (PR's). The prevalence of self-reported DM standardized to the national and world population was 5.7% and 6.2%, respectively. Self-reported DM had 61.5% sensitivity and 97.6% specificity. Socioeconomic status was inversely associated with DM prevalence. Green tea and opium consumption increased the prevalence of DM. Obesity at all ages and extreme leanness in childhood increased diabetes prevalence. Being obese throughout life doubled DM prevalence in women (PR: 2.1; 95% CI: 1.8, 2.4). These findings emphasize the importance of improving DM awareness, improving general living conditions, and early lifestyle modifications in diabetes prevention.
doi:10.1371/journal.pone.0026725
PMCID: PMC3203882  PMID: 22053206
22.  Association between Several Clinical and Radiological Determinants with Long-Term Clinical Progression and Good Prognosis of Lower Limb Osteoarthritis 
PLoS ONE  2011;6(10):e25426.
Objective
To investigate the factors associated with clinical progression and good prognosis in patients with lower limb osteoarthritis (OA).
Methods
Cohort study of 145 patients with OA in either knee, hip or both. Progression was defined as 1) new joint prosthesis or 2) increase in WOMAC pain or function score during 6-years follow-up above pre-defined thresholds. Patients without progression with decrease in WOMAC pain or function score lower than pre-defined thresholds were categorized as good prognosis. Relative risks (RRs) for progression and good prognosis with 95% confidence interval (95% CI) were calculated by comparing the highest tertile or category to the lowest tertile, for baseline determinants (age, sex, BMI, WOMAC pain and function scores, pain on physical examination, total range of motion (tROM), osteophytes and joint space narrowing (JSN) scores), and for worsening in WOMAC pain and function score in 1-year. Adjustments were performed for age, sex, and BMI.
Results
Follow-up was completed by 117 patients (81%, median age 60 years, 84% female); 62 (53%) and 31 patients (26%) showed progression and good prognosis, respectively. These following determinants were associated with progression: pain on physical examination (RR 1.2 (1.0 to 1.5)); tROM (1.4 (1.1 to 1.6); worsening in WOMAC pain (1.9 (1.2 to 2.3)); worsening in WOMAC function (2.4 (1.7 to 2.6)); osteophytes 1.5 (1.0 to 1.8); and JSN scores (2.3 (1.5 to 2.7)). Worsening in WOMAC pain (0.1 (0.1 to 0.8)) and function score (0.1 (0.1 to 0.7)), were negatively associated with good prognosis.
Conclusion
Worsening of self-reported pain and function in one year, limited tROM and higher osteophytes and JSN scores were associated with clinical progression. Worsening in WOMAC pain and function score in 1- year were associated with lower risk to have good prognosis. These findings help to inform patients with regard to their OA prognosis.
doi:10.1371/journal.pone.0025426
PMCID: PMC3198737  PMID: 22031816
23.  Age at Menarche and Its Association with the Metabolic Syndrome and Its Components: Results from the KORA F4 Study 
PLoS ONE  2011;6(10):e26076.
Objective
The metabolic syndrome is a major public health challenge and identifies persons at risk for diabetes and cardiovascular disease. The aim of this study was to examine the association between age at menarche and the metabolic syndrome (IDF and NCEP ATP III classification) and its components.
Design
1536 women aged 32 to 81 years of the German population based KORA F4 study were investigated. Data was collected by standardized interviews, physical examinations, and whole blood and serum measurements.
Results
Young age at menarche was significantly associated with elevated body mass index (BMI), greater waist circumference, higher fasting glucose levels, and 2 hour glucose (oral glucose tolerance test), even after adjusting for the difference between current BMI and BMI at age 25. The significant effect on elevated triglycerides and systolic blood pressure was attenuated after adjustment for the BMI change. Age at menarche was inversely associated with the metabolic syndrome adjusting for age (p-values: <0.001 IDF, 0.003 NCEP classification) and additional potential confounders including lifestyle and reproductive history factors (p-values: 0.001, 0.005). Associations remain significant when additionally controlling for recollected BMI at age 25 (p-values: 0.008, 0.033) or the BMI change since age 25 (p-values: 0.005, 0.022).
Conclusion
Young age at menarche might play a role in the development of the metabolic syndrome. This association is only partially mediated by weight gain and increased BMI. A history of early menarche may help to identify women at risk for the metabolic syndrome.
doi:10.1371/journal.pone.0026076
PMCID: PMC3196515  PMID: 22028807
24.  Prospective Validation of American Diabetes Association Risk Tool for Predicting Pre-Diabetes and Diabetes in Taiwan–Taichung Community Health Study 
PLoS ONE  2011;6(10):e25906.
Background
A simple diabetes risk tool that does not require laboratory tests would be beneficial in screening individuals at higher risk. Few studies have evaluated the ability of these tools to identify new cases of pre-diabetes. This study aimed to assess the ability of the American Diabetes Association Risk Tool (ADART) to predict the 3-year incidence of pre-diabetes and diabetes in Taiwanese.
Methods
This was a 3-year prospective study of 1021 residents with normoglycemia at baseline, gathered from a random sample of residents aged 40–88 years in a metropolitan city in Taiwan. The areas under the curve (AUCs) of three models were compared: ADART only, ADART plus lifestyle behaviors at baseline, and ADART plus lifestyle behaviors and biomarkers at baseline. The performance of ADART was compared with that of 16 tools that had been reported in the literature.
Results
The AUCs and their 95% confidence intervals (CIs) were 0.60 (0.54–0.66) for men and 0.72 (0.66–0.77) for women in model 1; 0.62 (0.56–0.68) for men and 0.74 (0.68–0.80) for women in model 2; and 0.64 (0.58–0.71) for men and 0.75 (0.69–0.80) for women in model 3. The AUCs of these three models were all above 0.7 in women, but not in men. No significant difference in either women or men (p = 0.268 and 0.156, respectively) was observed in the AUC of these three models. Compared to 16 tools published in the literature, ADART had the second largest AUC in both men and women.
Conclusions
ADART is a good screening tool for predicting the three-year incidence of pre-diabetes and diabetes in females of a Taiwanese population. The performance of ADART in men was similar to the results with other tools published in the literature. Its performance was one of the best among the tools reported in the literature.
doi:10.1371/journal.pone.0025906
PMCID: PMC3187817  PMID: 21998718
25.  Adult Patients with Congenital Adrenal Hyperplasia Have Elevated Blood Pressure but Otherwise a Normal Cardiovascular Risk Profile 
PLoS ONE  2011;6(9):e24204.
Objective
Treatment with glucocorticoids and mineralocorticoids has changed congenital adrenal hyperplasia (CAH) from a fatal to a chronic lifelong disease. Long-term treatment, in particular the chronic (over-)treatment with glucocorticoids, may have an adverse effect on the cardiovascular risk profile in adult CAH patients. The objective of this study was to evaluate the cardiovascular risk profile of adult CAH patients.
Design
Case-control study.
Patients and Measurements
In this case-control study the cardiovascular risk profile of 27 adult CAH patients and 27 controls, matched for age, sex and body mass index was evaluated by measuring ambulatory 24-hour blood pressure, insulin sensitivity (HOMA-IR), lipid profiles, albuminuria and circulating cardiovascular risk markers (PAI-1, tPA, uPA, tPA/PAI-1 complex, hsCRP, adiponectin, IL-6, IL-18 and leptin).
Results
24-Hour systolic (126.3 mmHg±15.5 vs 124.8 mmHg±15.1 in controls, P = 0.019) and diastolic (76.4 mmHg±12.7 vs 73.5 mmHg±12.4 in controls, P<0.001) blood pressure was significantly elevated in CAH patients compared to the control population. CAH patients had higher HDL cholesterol levels (P<0.01), lower hsCRP levels (P = 0.03) and there was a trend toward elevated adiponectin levels compared to controls. Other cardiovascular risk factors were similar in both groups.
Conclusion
Adult CAH patients have higher ambulatory blood pressure compared to healthy matched controls. Other cardiovascular risk markers did not differ, while HDL-cholesterol, hsCRP and adiponectin levels tended to be more favorable.
doi:10.1371/journal.pone.0024204
PMCID: PMC3164719  PMID: 21909422

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