MD, UC San Diego School of Medicine (2018)
Use of robotic surgery has increased in urological practice over the last decade. However, the use, outcomes, and costs of robotic nephrectomy are unknown.To examine the trend in use of robotic-assisted operations for radical nephrectomy in the United States and to compare the perioperative outcomes and costs with laparoscopic radical nephrectomy.This retrospective cohort study used the Premier Healthcare database to evaluate outcomes of patients who had undergone robotic-assisted or laparoscopic radical nephrectomy for renal mass at 416 US hospitals between January 2003 and September 2015. Multivariable regression modeling was used to assess outcomes.Robotic-assisted vs laparoscopic radical nephrectomy.The primary outcome of the study was the trend in use of robotic-assisted radical nephrectomy. The secondary outcomes were perioperative complications, based on the Clavien classification system, and defined as any complication (Clavien grades 1-5) or major complications (Clavien grades 3-5, for which grade 5 results in death); resource use (operating time, blood transfusion, length of hospital stay); and direct hospital cost.Among 23?753 patients included in the study (mean age, 61.4 years; men, 13?792 [58.1%]), 18?573 underwent laparoscopic radical nephrectomy and 5180 underwent robotic-assisted radical nephrectomy. Use of robotic-assisted surgery increased from 1.5% (39 of 2676 radical nephrectomy procedures in 2003) to 27.0% (862 of 3194 radical nephrectomy procedures) in 2015 (P for trend <.001). In the weighted-adjusted analysis, there were no significant differences between robotic-assisted and laparoscopic radical nephrectomy in the incidence of any (Clavien grades 1-5) postoperative complications (adjusted rates, 22.2% vs 23.4%, difference, -1.2%; 95% CI, -5.4 to 3.0%) or major (Clavien grades 3-5) complications (adjusted rates, 3.5% vs 3.8%, difference, -0.3%; 95% CI, -1.0% to 0.5%). The rate of prolonged operating time (>4 hours) for patients undergoing the robotic-assisted procedure was higher than for patients receiving the laparoscopic procedure in the adjusted analysis (46.3% vs 25.8%; risk difference, 20.5%; 95% CI, 14.2% to 26.8%). Robotic-assisted radical nephrectomy was associated with higher mean 90-day direct hospital costs ($19?530 vs $16?851; difference, $2678; 95% CI, $838 to $4519), mainly accounted for operating room ($7217 vs $5378; difference, $1839; 95% CI, $1050 to $2628) and supply costs ($4876 vs $3891; difference, $985; 95% CI, $473 to $1498).Among patients undergoing radical nephrectomy for renal mass between 2003 and 2015, the use of robotic-assisted surgery increased substantially. The use of robotic-assistance was not associated with increased risk of any or major complications but was associated with prolonged operating time and higher hospital costs compared with laparoscopic surgery.
View details for PubMedID 29067427
How has the mean paternal age in the USA changed over the past 4 decades?The age at which men are fathering children in the USA has been increasing over time, although it varies by race, geographic region and paternal education level.While the rise in mean maternal age and its implications for fertility, birth outcomes and public health have been well documented, little is known about paternal characteristics of births within the USA.A retrospective data analysis of paternal age and reporting patterns for 168 867 480 live births within the USA since 1972 was conducted.All live births within the USA collected through the National Vital Statistics System (NVSS) of the Centers for Disease Control and Prevention (CDC) were evaluated. Inverse probability weighting (IPW) was used to reduce bias due to missing paternal records.Mean paternal age has increased over the past 44 years from 27.4 to 30.9 years. College education and Northeastern birth states were associated with higher paternal age. Racial/ethnic differences were also identified, whereby Asian fathers were the oldest and Black fathers were the youngest. The parental age difference (paternal age minus maternal age) has decreased over the past 44 years. Births to Black and Native American mothers were most often lacking paternal data, implying low paternal reporting. Paternal reporting was higher for older and more educated women.Although we utilized IPW to reduce the impact of paternal reporting bias, our estimates may still be influenced by the missing data in the NVSS.Paternal age is rising within the USA among all regions, races and education levels. Given the implications for offspring health and demographic patterns, further research on this trend is warranted.No funding was received for this study and there are no competing interests.N/A.
View details for PubMedID 28938735
Partial nephrectomy (PN) remains underutilized within the United States and few reports have attempted to explain this trend. The aim of this study is to evaluate the nationwide incidence of unsuccessful PN and factors that predict its occurrence.Using the Premier Healthcare Database, we retrospectively analyzed a weighted sample of 66,432 patients undergoing curative surgery for renal mass between 2003 and 2015. PN intent was denoted by presence of insurance claims for the administration of mannitol. Unsuccessful PN was defined as an event in which patients were administered mannitol but received radical nephrectomy. A multivariate logistic regression model was generated to identify factors predicting unsuccessful PN.Overall rates of unsuccessful PN declined from 33.5% to 14.5% since 2003. Conversion to radical nephrectomy occurred most frequently during laparoscopic (34.7%) and least frequently during robotic approach (13.6%). There was significant difference in the rate of unsuccessful PN between very high and very low volume surgeons (open: 39.4% vs. 13.3%, laparoscopic: 51.2% vs. 32.2%, and robot assisted: 27.1% vs. 9.4%, all P<0.001). After adjustment for patient- and hospital-related factors, surgical approach (laparoscopic vs. open, odds ratio = 1.74, 95% CI: 1.31-2.30, P<0.001) and annual surgeon volume (very high vs. very low, odds ratio = 0.27, 95% CI: 0.21-0.34 P<0.001) were associated with unsuccessful PN.Although the rate of unsuccessful PN appears to be declining, it still remains common for low volume surgeons and with the laparoscopic surgical approach. Further evaluation of its effect on health care outcomes is necessary.
View details for PubMedID 28889920
BACKGROUND: Pediatric cancer survivors suffer indirect long-term effects of their disease; however, there is a paucity of data regarding the effect of pediatric cancer survivorship on sexual function.AIM: To assess the prevalence and risk factors associated with sexual dysfunction among pediatric cancer survivors.METHODS: Pediatric cancer survivors were recruited to complete an online survey using the Female Sexual Function Index (FSFI) or the International Index of Erectile Function (IIEF-5), both validated questionnaires to assess female sexual dysfunction (FSD) and erectile dysfunction (ED). Patient demographics, oncologic history, prior treatment, and sexual habits were also queried. Logistic regression was used to evaluate risk factors for sexual dysfunction, and Mann-Whitney U test was used to identify factors associated with individual domains of the FSFI.OUTCOMES: The main outcome measures were FSFI and IIEF-5 score, which are used to diagnose FSD (FSFI<26.55) and ED (IIEF-5<22).RESULTS: A total of 21 (72.4%) female respondents and 20 (71.4%) male respondents were sexually active and completed the survey and FSFI or IIEF-5 questionnaire, respectively. Mean (±SD) age was 23.7 (4.1) years, andaverage age at diagnosis was 9.1 (5.0), with no difference between genders. Overall, 25.0% (5/20) of male and 52.4% (11/21) of female pediatric cancer survivors reported sexual dysfunction (P=.11). Oncologic history and prior treatment were not associated with sexual function. Females who reported difficulty relaxing during intercourse in the last 6months had higher odds of reporting sexual dysfunction (odds ratio: 13.6, 95% confidence interval: 1.2-151.2, P=.03). Subgroup analysis of FSFI domains found that previous radiation therapy was correlated with decreased lubrication and satisfaction during intercourse, whereas previous treatment to the pelvic region significantly reduced satisfaction and increased pain during intercourse.CLINICAL IMPLICATIONS: Female pediatric cancer survivors have higher odds of reporting sexual dysfunction after treatment and should be screened appropriately to provide early intervention and to mitigate risk.STRENGTH & LIMITATIONS: Our study includes validated questionnaires to assess FSD and ED and queries specific characteristics to assess their association with sexual dysfunction. However, the study is limited by sample size and its cross-sectional survey design.CONCLUSIONS: The prevalence of female sexual dysfunction in this cohort is higher than that in the general population of equivalent-aged individuals, and clinicians should be aware of these potential long-term sequelae. Greenberg DR, Khandwala YS, Bhambhvani HP, et-al. Male and Female Sexual Dysfunction in Pediatric Cancer Survivors. J Sex Med;XX:XXX-XXX.
View details for DOI 10.1016/j.jsxm.2020.05.014
View details for PubMedID 32622765
INTRODUCTION: Bicycle seat pressure on the perineum may impair arousal and clitoral erection, likely contributing to genital pain and numbness experienced by female cyclists.AIM: We aimed to identify the association between genital pain and numbness experienced by female cyclists and female sexual dysfunction (FSD).METHODS: Female cyclists were recruited to complete an online survey using the Female Sexual Function Index (FSFI), a validated questionnaire to assess FSD. Cyclist demographics, experience, preferred riding style, use of ergonomic cycle modifications, and genital discomfort while riding were also queried. Multivariate logistic regression analysis was used to evaluate risk factors of FSD.MAIN OUTCOME MEASURES: The main outcome was FSFI score, which is used to diagnose FSD when the FSFI score is <26.55.RESULTS: Of the survey respondents, 178 (53.1%) completed the survey and FSFI questionnaire. Mean age was 48.1 years (±0.8 standard error [SE]), and the average riding experience was 17.1 years (±0.9 SE). Overall, 53.9% of female cyclists had FSD, 58.1% reported genital numbness, and 69.1% reported genital pain. After adjusting for age, body mass index, relationship status, smoking history, comorbidities, and average time spent cycling per week, females who reported experiencing genital numbness half the time or more were more likely to have FSD (adjusted odds ratio [aOR], 6.0; 95% CI, 1.5-23.6; P= .01), especially if localized to the clitoris (aOR, 2.5; 95% CI, 1.2-5.5; P= .02). Females that reported genital pain half the time or more while cycling also were more likely to have FSD (aOR, 3.6; 95% CI, 1.2-11.1; P= .02). Cyclists experiencing genital pain within the first hour of their ride were more likely to have FSD (aOR, 12.6; 95% CI, 2.5-63.1; P= .002). Frequency and duration of cycling were not associated with FSD. Analysis of FSFI domains found that the frequency of numbness was correlated with decreased arousal, orgasm, and satisfaction during intercourse, whereas the frequency of pain significantly reduced arousal, orgasm, and genital lubrication.CLINICAL IMPLICATIONS: Female cyclists that experience numbness and/or pain have higher odds of reporting FSD.STRENGTHS & LIMITATIONS: Our study includes a validated questionnaire to assess FSD and queries specific characteristics and symptoms of genital pain and genital numbness; however, the study is limited by its cross-sectional survey design.CONCLUSION: This study highlights the need for cyclists to address genital pain and numbness experienced while cycling, and future studies are required to determine if alleviating these symptoms can reduce the impact of cycling on female sexual function. Greenberg GR, Khandwala YS, Breyer BN, etal. Genital Pain and Numbness and Female Sexual Dysfunction in Adult Bicyclists. J Sex Med 2019; XX:XXX-XXX.
View details for DOI 10.1016/j.jsxm.2019.06.017
View details for PubMedID 31402178
Although five-alpha reductase inhibitor (5-ARI) is one of standard treatment for benign prostatic hyperplasia (BPH) or alopecia, potential complications after 5-ARI have been issues recently. This study aimed to investigate the risk of depression after taking 5-ARI and to quantify the risk using meta-analysis.A total of 209,940 patients including 207,798 in 5-ARI treatment groups and 110,118 in control groups from five studies were included for final analysis. Inclusion criteria for finial analysis incudes clinical outcomes regarding depression risk in BPH or alopecia patients. Overall hazard ratio (HR) and odds ratio (OR) for depression were analyzed. Moderator analysis and sensitivity analysis were performed to determine whether HR or OR could be affected by any variables, including number of patients, age, study type, and control type.The pooled overall HRs for the 5-ARI medication was 1.23 (95% confidence interval [CI], 0.99-1.54) in a random effects model. The pooled overall ORs for the 5-ARI medication was 1.19 (95% CI, 0.95-1.49) in random effects model. The sub-group analysis showed that non-cohort studies had higher values of HR and OR than cohort studies. Moderator analysis using meta-regression showed that there were no variables that affect the significant difference in HR and OR outcomes. However, in sensitivity analysis, HR was significantly increased by age (p=0.040).Overall risk of depression after 5-ARI was significantly not high, however its clinical importance needs validation by further studies. These quantitative results could provide useful information for both clinicians and patients.
View details for DOI 10.5534/wjmh.190046
View details for PubMedID 31190484
View details for PubMedID 29558551
BACKGROUND: Although combination therapy with 5 alpha-reductase inhibitor (5ARI) and alpha-blocker is one of the standard interventions in symptomatic benign prostatic hyperplasia (BPH), 5ARI monotherapy is seldom the focus of attention. Adverse events associated with 5ARI include depression and suicidal attempts in addition to persistent erectile dysfunction. The aim of this study is to update our knowledge of clinical efficacy and incidence of adverse events associated with 5ARI treatment in symptomatic BPH.METHODS AND FINDINGS: A meta-analysis of randomized controlled clinical trials (RCTs) from 1966 until March, 2017 was performed using database from PubMed, Cochrane Collaboration and Embase. A total of 23395 patients were included in this study and the inclusion criteria were: RCTs with 5ARI and placebo in symptomatic BPH patients. Parameters included prostate specific antigen (PSA), prostate volume (PV), International Prostate Symptom Score (IPPS), post-void residual urine (PVR), voiding symptoms of IPSS (voiding IPSS), maximum urinary flow rate (Qmax), and adverse events (AEs). A meta-analysis with meta-regression was performed for each effect size and adverse events, sensitivity analysis, cumulative analysis along with the analysis of ratio of means (ROM) in the placebo group. A total of 42 studies were included in this study for review, and a total of 37 studies were included in the meta-analysis, including a total of 23395 patients (treatment group: 11392, placebo group: 12003). The effect size of all variables except PVR showed a significant improvement following 5ARI treatment compared with placebo. However, the effect size of differences showed declining trend in PV, IPSS and Qmax according to recent years of publication. In ROM analysis, PV showed no significant increase in the placebo group, with a ROM of 1.00 (95% CI, 0.88, 1.14). The 5ARI treatment resulted in a significantly higher incidence of decreased libido (OR = 1.7; 95% CI, 1.36, 2.13), ejaculatory disorder (OR = 2.94; 95% CI, 2.15, 4.03), gynecomastia (OR = 2.32; 95% CI, 1.41, 3.83), and impotence (OR = 1.74; 95% CI, 1.32, 2.29). Our study has the following limitations: included studies were heterogeneous and direct comparison of efficacy between alpha blocker and 5ARI was not performed. Adverse events including depression or suicidal attempt could not be analyzed in this meta-analysis setting.CONCLUSIONS: Although there was a significant clinical benefit of 5ARI monotherapy compared with placebo, the effective size was small. Moreover, the risk of adverse events including sexually related complications were high. Additional head-to-head studies are needed to re-evaluate the clinical efficacy of 5ARI compared with alpha-adrenergic receptor blockers.
View details for PubMedID 30281615
Chronic scrotal pain is a common yet poorly understood urologic disease. Current treatment paradigms are sub-optimal and include anti-inflammatory drugs and opioids as well as invasive surgical management such as microdenervation of the spermatic cord. In this study, the efficacy of external vibratory stimulation (EVS) was evaluated as an alternative treatment option for idiopathic scrotal pain.Ten consecutive patients presenting to an academic urology clinic between December 2016 and April 2017 with scrotal pain were prospectively enrolled. After a comprehensive history and physical exam, patients were presented with and oriented to a spherical vibratory device that they were instructed to use topically each day for four weeks. Average and maximum pain severity, frequency, and bother scores were tracked at 2-week intervals using a visual analog scale (0-10) via survey. Descriptive statistics facilitated interpretation of individual changes in pain.Nine men, with a median age of 46 years, completed at least 2 weeks of the study intervention. 78% (7/9) of men achieved some improvement in daily scrotal pain levels. Overall, average pain decreased from 4.9 to 2.7 (p=0.009) while maximum pain severity decreased from 6.3 to 4.0 (p=0.013). The frequency of pain also decreased for 55.6% (5/9) of men. No severe side effects were noted by any of the participants though several patients reported mild paresthesia only during application of the device. The majority of men expressed interest in continuing treatment after conclusion of the study.External vibratory stimulation has been suggested as a promising non-invasive tool to alleviate chronic pain. As a proof-of-concept, we implemented EVS to treat men with idiopathic orchialgia. The majority of patients noted benefit in both severity and frequency of pain. Given its low risk profile, EVS deserves further evaluation and inclusion in treatment guidelines as a promising experimental therapy for a disease with few conservative treatment options available to providers.In this longitudinal study, external vibratory stimulation was found to decrease chronic scrotal pain without any adverse effects. The use of this non-invasive, non-pharmaceutical therapy to treat chronic scrotal pain has the potential to decrease physician and patient dependence on surgical procedures and opioid prescriptions. Future randomized, double blind clinical trials with a placebo arm are required to corroborate these findings and establish the true efficacy of EVS.
View details for PubMedID 29126848
We sought to determine whether infertile men can accurately be identified within a large insurance claims database to validate its use for reproductive health research.Prior literature suggests that men coded for infertility are at higher risk for chronic disease though it was previously unclear if these diagnostic codes correlated with true infertility. We found that the specificity of one International Classification of Disease (9th edition) code in predicting abnormal semen parameters was 92.4%, rising to 99.8% if a patient had three different codes for infertility. The positive predictive value was as high as 85%. The use of claims data for male infertility research has been rapidly progressing due to its high power and feasibility. The high specificity of ICD codes for men with abnormal semen parameters is reassuring and validates prior studies as well as future investigation into men's health.
View details for PubMedID 28718160
View details for PubMedID 28365161
Little is known about the impact of surgeon volume on the success of the robot-assisted partial nephrectomy (RAPN). The objective of this study was to compare the perioperative outcomes and cost related to RAPN by annual surgeon volumes.Using the Premier Hospital Database, we retrospectively analyzed 39,773 patients who underwent RAPN between 2003 and 2015 in the United States. Surgeons for each index case were grouped into quintiles for each respective year. Outcomes were 90-day postoperative complications, operating room time (ORT), blood transfusion, length of stay, and direct hospital costs. Logistic regression and generalized linear models were used to identify factors predicting complications and cost.After accounting for patient and hospital demographics, high- and very high-volume surgeons had 40% and 42% decreased odds of having major complications (p?=?0.045 and p?=?0.027, respectively). Surgeons with higher volumes were associated with fewer odds of prolonged ORT (0.68 for low, 0.72 for intermediate, 0.56 for high, 0.44 for very high volume, all p?0.05) and length of hospital stay (0.67 for intermediate, 0.51 for high, 0.45 for very high volume, all p?0.01) compared with very low-volume surgeons. The 90-day hospital cost was also significantly lower for the surgeons with higher volume, but the statistical significance diminished after consideration of hospital clustering.Surgeons with very high RAPN volumes were found to have superior perioperative outcomes. Although cost of care appeared to correlate with surgeon volume, there may be other more influential factors predicting cost.
View details for DOI 10.1089/end.2017.0207
View details for PubMedID 28537505
To identify racial differences in semen quality among men living in the same geographic area and seeking fertility evaluation.Men obtaining a semen analysis for infertility evaluation or treatment between 2012 and 2016 at a single center were identified, and demographic data including height, weight, body mass index (BMI), and age were described. Mean semen parameters and the proportions of men with suboptimal parameters based on the World Health Organization's fifth edition criteria were also compared based on race. Multivariable regression analysis was conducted incorporating age, BMI, and year of evaluation. Further subanalyses based on BMI were subsequently performed.White men produced greater volumes of semen on average; however, Asian men had higher sperm concentrations and total sperm count. A lower proportion of Asian men compared to white men had semen quality in the suboptimal range for most semen parameters, whereas a higher proportion of white men were found to have azoospermia. Stratification by BMI groups attenuated the observed differences between whites and Asians, yet Asian male semen quality remained higher.Among men evaluated for infertility at a single center, Asians had lower volume but higher sperm concentrations compared with whites, which was influenced by differences in azoospermia prevalence. Although anthropometric and demographic factors attenuated the differences, even after adjustment, the contrasts remained. Our study suggests that racial differences exist in semen quality at the time of infertility evaluation.
View details for DOI 10.1016/j.urology.2017.03.064
View details for PubMedID 28522219
To examine trends in utilization of open, laparoscopic and robot-assisted surgical approaches for treatment of patients with chronic kidney disease (CKD) undergoing partial nephrectomy (PN) within the USA.We analyzed a weighted sample of 112,117 patients from the Premier administrative dataset who underwent PN for renal mass between 2003 and 2015. Proportions of surgical approach utilization were evaluated by CKD status and further stratified by surgery year and surgeon volume. A multivariate logistic regression model was created to predict receipt of minimally invasive PN.Seven thousand five hundred and sixty-five (6.7%) patients with CKD were identified. The proportion of CKD patients receiving open PN decreased from 72.4% in 2003-2007 to 36.1% in 2012-2015 (p < 0.001). Although the robot-assisted PN was the dominant surgical approach for both patients with and without CKD in 2012-2015, the proportion receiving open PN was higher in patients with CKD compared to those without CKD (p = 0.018). Multivariate analysis showed that the presence of CKD was independently associated with lower odds of receiving a minimally invasive approach (OR 0.47 for the entire study cohort, OR 0.27 for high volume robot-assisted PN surgeons, and OR 0.51 for recent years, all p < 0.001). These trends remained when CKD stages were evaluated individually.Patients with CKD undergoing PN were preferentially treated with open surgery despite an overall increase in robot-assisted PN use over the past 13 years. Further studies evaluating surgical outcomes in this population are warranted for determination of optimal approach and construction of evidence-based guidelines.
View details for PubMedID 28852937
Urological surgeries have contributed to the increasing prevalence of minimally invasive robotic procedures. Although factors influencing the adoption of robot-assisted radical prostatectomy have previously been identified, the explanation for the rapid rise in robotic partial nephrectomies remains unknown. Using a retrospective population-based sample, we attempt to determine hospital and surgeon-specific factors influencing a surgeon's decision to utilize robotic assistance for partial nephrectomies.A nationally representative weighted sample of all men who underwent a partial nephrectomy in the United States between 2003 and 2014 was identified within the Premier Hospital Database. Hospital, surgeon, and patient characteristics for each operation were analyzed. Descriptive statistics and a multivariate regression model stratified according to the Law of Diffusion of Innovation were performed.A weighted sample of 14,890 nephrectomies was included in the study. Patient demographics were similar between the two groups. The adoption of robotic technology followed the Law of Diffusion of Innovation with the percentage of partial nephrectomies with robotic assistance increasing yearly, reaching 64.1% by 2013. Surgical volume was a significant factor driving the use of robotic assistance, with high volume surgeons (>5 partial nephrectomies/year) performing 23.2% more robotic partial nephrectomies per year than their low volume colleagues (=?5 partial nephrectomies/year) from 2009 to 2013 (p?0.001).This retrospective population-based study examines key factors influencing the diffusion of robotic technology for partial nephrectomies. Surgical volume and year of surgery were found to be the most significant factor in robotic adoption, with other patient and hospital-specific characteristics playing a minor role. Future studies are needed to correlate adoption rates with the clinical or cost-effectiveness of novel technologies within the medical field to determine whether rapid adoption is a patient-centered vs a clinician-centered decision point.
View details for PubMedID 28699357
We describe the availability of preventive health services in US emergency departments (EDs), as well as ED directors' preferred service and perceptions of barriers to offering preventive services.Using the 2007 National Emergency Department Inventory (NEDI)-USA, we randomly sampled 350 (7%) of 4,874 EDs. We surveyed directors of these EDs to determine the availability of (1) screening and referral programs for alcohol, tobacco, geriatric falls, intimate partner violence, HIV, diabetes, and hypertension; (2) vaccination programs for influenza and pneumococcus; and (3) linkage programs to primary care and health insurance. ED directors were asked to select the service they would most like to implement and to rate 5 potential barriers to offering preventive services.Two hundred seventy-seven EDs (80%) responded across 46 states. Availability of services ranged from 66% for intimate partner violence screening to 19% for HIV screening. ED directors wanted to implement primary care linkage most (17%) and HIV screening least (2%). ED directors "agreed/strongly agreed" that the following are barriers to ED preventive care: cost (74%), increased patient length of stay (64%), lack of follow-up (60%), resource shifting leading to worse patient outcomes (53%), and philosophical opposition (27%).Most US EDs offer preventive services, but availability and ED director preference for type of service vary greatly. The majority of EDs do not routinely offer Centers for Disease Control and Prevention-recommended HIV screening. Most ED directors are not philosophically opposed to offering preventive services but are concerned with added costs, effects on ED operations, and potential lack of follow-up.
View details for DOI 10.1016/j.annemergmed.2010.07.015
View details for Web of Science ID 000287464900007
View details for PubMedID 20889237
View details for PubMedCentralID PMC3538034