Outcomes over 20 years performing robot-assisted laparoscopic prostatectomy: a single-surgeon experience.

OBJECTIVE: To evaluate a single surgeon's 20-year experience with robotic radical prostatectomy. METHODS: Patients who had undergone robot-assisted laparoscopic prostatectomy by a single surgeon were identified via an IRB approved prospectively maintained prostate cancer database. Patients were divided into 5-year cohorts (cohort A 2001-2005; cohort B 2006-2010; cohort C 2011-2015; cohort D 2016-2021) for analysis. Oncologic and quality of life outcomes were recorded at the time of follow-up visits. Continence was defined as 0-1 pad with occasional dribbling. Potency was defined as intercourse or an erection sufficient for intercourse within the last 4 weeks. RESULTS: Three thousand one hundred fifty-two patients met criteria for inclusion. Clavien ≥ 3 complication rates decreased from 5.9% to 3.2%, p = 0.021. There was considerable Gleason grade group (GG) and stage migration to more advanced disease between cohort A (6.4% GG4 or GG5, 16.2% pT3 or pT4, 1.2% N1) and cohort D (17% GG4 or GG5, 45.5% pT3 or pT4, 14.4% N1; p < 0.001). Consistent with this, an increasing proportion of patients required salvage treatments over time (14.6% of cohort A vs 22.5% of cohort D, p < 0.001). 1-year continence rates improved from 74.8% to greater than 92.4%, p < 0.001. While baseline potency and use of intraoperative nerve spare decreased, for patients potent at baseline, there were no significant differences for potency at one year (p = 0.065). CONCLUSIONS: In this 20-year review of our experience with robotic prostatectomy, complication rates and continence outcomes improved over time, and there was a migration to more advanced disease at the time of surgery.

Rabbits use both spectral and temporal cues to discriminate the fundamental frequency of harmonic complexes with missing fundamentals.

The pitch of harmonic complex tones (HCTs) common in speech, music, and animal vocalizations plays a key role in the perceptual organization of sound. Unraveling the neural mechanisms of pitch perception requires animal models, but little is known about complex pitch perception by animals, and some species appear to use different pitch mechanisms than humans. Here, we tested rabbits' ability to discriminate the fundamental frequency (F0) of HCTs with missing fundamentals, using a behavioral paradigm inspired by foraging behavior in which rabbits learned to harness a spatial gradient in F0 to find the location of a virtual target within a room for a food reward. Rabbits were initially trained to discriminate HCTs with F0s in the range 400-800 Hz and with harmonics covering a wide frequency range (800-16,000 Hz) and then tested with stimuli differing in spectral composition to test the role of harmonic resolvability (experiment 1) or in F0 range (experiment 2) or in both F0 and spectral content (experiment 3). Together, these experiments show that rabbits can discriminate HCTs over a wide F0 range (200-1,600 Hz) encompassing the range of conspecific vocalizations and can use either the spectral pattern of harmonics resolved by the cochlea for higher F0s or temporal envelope cues resulting from interaction between unresolved harmonics for lower F0s. The qualitative similarity of these results to human performance supports the use of rabbits as an animal model for studies of pitch mechanisms, providing species differences in cochlear frequency selectivity and F0 range of vocalizations are taken into account.NEW & NOTEWORTHY Understanding the neural mechanisms of pitch perception requires experiments in animal models, but little is known about pitch perception by animals. Here we show that rabbits, a popular animal in auditory neuroscience, can discriminate complex sounds differing in pitch using either spectral cues or temporal cues. The results suggest that the role of spectral cues in pitch perception by animals may have been underestimated by predominantly testing low frequencies in the range of human voice.

Do commonly used prostate medications alter prostate MRI and fusion biopsy performance?

AIMS: To determine whether phosphodiesterase inhibitors (PDEi) or α-antagonists (AA) were associated with differences in region of interest (ROI) characteristics or prostate cancer detection on fusion biopsy (FB). MATERIALS AND METHODS: Records from 847 consecutive patients undergoing FB at three separate institutions over a period of 2 years were retrospectively reviewed. Associations between medication use, Prostate Imaging Reporting & Data System (PIRADS) scores, and ROI locations were assessed with ordinal logistic regression. Associations with lesion size and International Society of Urologic Pathology (ISUP) grade group (GG) on biopsy were tested using multivariate regression. RESULTS: Medication use included PDEi in 14.2% and AA in 23.0%. PDEi use was associated with 19.3% smaller lesion diameter (-2.8 mm; CI from -4.8 to -0.7; p < 0.01) and lower PIRADS scores on MRI (OR 0.60; CI 0.40 - 1.00; p = 0.05). AA use was associated with higher PIRADS scores (OR 1.43; CI 0.97 - 2.11; p = 0.06), fewer positive fusion-directed biopsy cores (-28.6%, CI from -57.9 to 0.01%, p = 0.05), and downgrading on final pathology (-19%; CI from -40 to 2%; p = 0.06). CONCLUSION: For PIRADS scores ≥ 3, PDEi use is associated with smaller ROI and lower PIRADS scores, while AA use is associated with higher PIRADS scores. Neither medication was associated with differences in biopsy GG. Prospective studies are needed to investigate the discordance between multi-parametric magnetic resonance imaging (mpMRI) results and oncologic outcomes associated with PDEi and AA use.

Outcomes of MRI fusion-guided versus systematic standard prostate biopsies.

INTRODUCTION: The current utility of MRI-fusion targeted biopsy as either an adjunct to or replacement for systematic template biopsy for the detection of clinically significant prostate cancer is disputed. The purpose of this study is to assess the current effectiveness of MRI-targeted versus systematic template prostate biopsies at two institutions and to consider possible underlying factors that could impact variability between detection rates in our patient population compared to others. MATERIALS AND METHODS: A retrospective review from our prospectively maintained prostate cancer databases was conducted. Patients with prostate MRI lesions (PI-RADSv2) receiving concurrent systematic 12-core and MRI-fusion targeted biopsies were reviewed. Clinically significant cancer was considered to be Grade Group ≥ 2. RESULTS: A total of 457 patients were included in the analysis; 255 patients received their biopsy at Institution A and 202 at Institution B. Overall cancer detection rate was 68%; the clinically significant cancer detection rate was 34%. Both MRI-targeted and systematic biopsies identified unique cases of clinically significant prostate cancer that the other modality missed. Out of 157 cases of clinically significant prostate cancer, MRI-targeted biopsy identified 29/157 cases (18%) missed by systematic biopsy, while systematic biopsy identified 37/157 cases (24%) missed by MRI-targeted biopsy (p = .39). Individual biopsy performance was similar when stratified by active surveillance or prior biopsy status, PI-RADSv2 score, and institution. CONCLUSIONS: MRI-fusion targeted and systematic biopsy each identified unique cases of clinically significant prostate cancer. Both biopsy modalities should be utilized in order to provide the greatest sensitivity for the detection of clinically significant prostate cancer.

Identification of a five gene signature to predict time to biochemical recurrence after radical prostatectomy.

BACKGROUND: Identification of novel biomarkers associated with high-risk prostate cancer or biochemical recurrence can drive improvement in detection, prognosis, and treatment. However, studies can be limited by small sample sizes and sparse clinical follow-up data. We utilized a large sample of prostate specimens to identify a predictive model of biochemical recurrence following radical prostatectomy and we validated this model in two external data sets. METHODS: We analyzed prostate specimens from patients undergoing radical prostatectomy at Hartford Hospital between 2008 and 2011. RNA isolated from formalin-fixed paraffin-embedded prostates was hybridized to a custom Affymetrix microarray. Regularized (least absolute shrinkage and selection operator [Lasso]) Cox regression was performed with cross-validation to identify a model that incorporated gene expression and clinical factors to predict biochemical recurrence, defined as postoperative prostate-specific antigen (PSA) > 0.2 ng/ml or receipt of triggered salvage treatment. Model performance was assessed using time-dependent receiver operating curve (ROC) curves and survival plots. RESULTS: A total of 606 prostate specimens with gene expression and both pre- and postoperative PSA data were available for analysis. We identified a model that included Gleason grade and stage as well as five genes (CNRIP1, endoplasmic reticulum protein 44 [ERP44], metaxin-2 [MTX2], Ras homolog family member U [RHOU], and OXR1). Using the Lasso method, we determined that the five gene model independently predicted biochemical recurrence better than a model that included Gleason grade and tumor stage alone. The time-dependent ROCAUC for the five gene signature including Gleason grade and tumor stage was 0.868 compared to an AUC of 0.767 when Gleason grade and tumor stage were included alone. Low and high-risk groups displayed significant differences in their recurrence-free survival curves. The predictive model was subsequently validated on two independent data sets identified through the Gene Expression Omnibus. The model included genes (RHOU, MTX2, and ERP44) that have previously been implicated in prostate cancer biology. CONCLUSIONS: Expression of a small number of genes is associated with an increased risk of biochemical recurrence independent of classical pathological hallmarks.

Use of EPIC 26 to identify men likely to benefit from surgical interventions for urinary incontinence after radical prostatectomy.

PURPOSE: To examine outcomes of surgical procedures for urinary incontinence after radical prostatectomy (post-RP UI) and to identify patients who may benefit from a surgical intervention to treat post-RP UI. METHODS: A retrospective chart review identified men who underwent radical prostatectomy (RP) from July 2004 through July 2016 at our institution. Cases underwent surgical interventions for UI following RP. Controls had RP during the study period but did not have an intervention for UI following RP. We used the UI scale of the Expanded Prostate Index Composite (EPIC) 26 to: (1) quantify post-RP UI before and after UI intervention overall and for specific surgical procedures; (2) evaluate the significance of improvement in post-RP UI before and after UI intervention and (3) identify controls with levels of post-RP UI that were comparable to the cases. RESULTS: Two thousand nine hundred and sixty-eight RPs were performed; 48 patients underwent further surgical intervention (39 slings, 9 artificial urinary sphincter, AUS). For 20 cases with complete EPIC UI data (15 slings, 5 AUS), the median (IQR) pre-UI intervention score was 27.00 (IQR 22.75-42.75). Improvement was significant overall (p < 0.001) and for slings (p = 0.001). 71/2085 controls had post-prostatectomy UI scores ≤ 27.0, suggesting that they may have benefited from a post-RP surgical intervention for UI. CONCLUSION: Data support the effectiveness of surgery to treat post-RP UI. A sizeable population of unidentified men may benefit from a surgical intervention to treat urinary incontinence after RP.

Does post prostatectomy decipher score predict biochemical recurrence and impact care?

PURPOSE: To examine the ability of the Decipher test to predict early biochemical recurrence after radical prostatectomy and to impact clinical decisions in advance of metastasis and death. METHODS: We identified Decipher tests ordered after radical prostatectomy for adverse pathology in men treated for prostate cancer between 1/1/14 and 8/31/18. Biochemical recurrence was defined as prostate-specific antigen > 0.02 ng/mL. Decipher score is reported as lower risk (< 0.6) and higher risk ≥ 0.60). Kaplan-Meier analysis was used to examine the relationship between Decipher score and time to biochemical recurrence (months). Cox regression was used to analyze the relationship between Decipher score and time to biochemical recurrence while controlling for a number of clinical characteristics. Secondary analyses focused on a subset of men with prostate-specific antigen > 0.02 and < 0.20 ng/mL to determine if high-risk Decipher scores were associated with receipt of salvage treatment. RESULTS: A total of 203 cases were analyzed: 37.9% and 62.1% had lower and higher risk Decipher scores respectively, and 56.2% had a biochemical recurrence. Median (inter-quartile range) follow-up was 20 (13.5, 25.3) months. Decipher score was significantly associated with time to biochemical recurrence (p = 0.027) while in the secondary analyses, high-risk Decipher scores (≥ 0.60) were associated with salvage treatment (p = 0.018). Stage category and Decipher score were significant predictors of time from elevated PSA to salvage treatment in the secondary analyses. CONCLUSION: While it might not contribute statistically, Decipher score can be clinically useful in helping patients reach treatment decisions.

Use of the Urethral Sling to Treat Symptoms of Climacturia in Men After Radical Prostatectomy.

BACKGROUND: Climacturia affects up to 45% of men after radical prostatectomy (RP). Although urethral slings decrease the severity and frequency of stress incontinence after RP, their efficacy as a treatment for climacturia after RP has not been well studied. AIM: The aim of this study was to assess patient-reported changes in climacturia symptoms after implantation of a urethral sling as a treatment for stress incontinence after RP. METHODS: After Institutional Review Board approval, a retrospective chart review identified males aged 18-80 years who received urethral slings for stress incontinence after RP at our institution from 2012 to 2017. These patients were mailed an 11-item questionnaire asking them about climacturia symptoms before and after implantation of a urethral sling. Written informed consent was obtained from patients participating in the mailed questionnaire. OUTCOMES: Respondents were asked to report on climacturia frequency and severity, bother, partner bother, and incontinence before and after implantation of urethral slings. RESULTS: A total of 42 questionnaires were mailed; 17 were available for analysis. The median age (and interquartile range, IQR) of the sample at RP was 64 (59.5, 68.0). Almost all (94.1%) of the men were sexually active at the time of the study and 64.7% reported experiencing urinary leakage during sexual arousal. Most (58.8%) underwent the urethral sling procedure to treat general incontinence; 35.3% underwent the procedure to treat both general incontinence and incontinence during sexual activity and 1 (5.9%) underwent it for other reasons. A median of 28.1 months elapsed between RP and sling procedure (IQR: 18.36, 53.88; minimum: 8.00; maximum: 108.36). Statistically significant shifts toward improvement from presling to postsling were noted for frequency of leakage during sexual arousal or orgasm (P = .041) and for the degree to which leakage of urine during sexual arousal or orgasm was a "bother" (P = .027). While almost all (94%) of the men were incontinent before sling, this percentage dropped to 53% after sling (P = .031). CLINICAL IMPLICATIONS: Urethral slings should be discussed as a treatment strategy for climacturia during clinical consultations with patients. STRENGTHS & LIMITATIONS: Strengths include consistent surgical technique. Limitations include retrospective design, lack of a nonsling comparison group, subjective nature of outcome measures, possible response bias, and variability in time interval between RP and sling procedure. CONCLUSION: Use of urethral slings after RP is associated with improvements in climacturia symptoms, bother, and incontinence. Nolan J, Kershen R, Staff I, et al. Use of the Urethral Sling to Treat Symptoms of Climacturia in Men After Radical Prostatectomy. J Sex Med 2020;17:1203-1206.

Primed mesenchymal stem cells package exosomes with metabolites associated with immunomodulation.

Mesenchymal stem cell (MSC) based therapies are currently being evaluated as a putative therapeutic in numerous human clinical trials. Recent reports have established that exosomes mediate much of the therapeutic properties of MSCs. Exosomes are nanovesicles which mediate intercellular communication, transmitting signals between cells which regulate a diverse range of biological processes. MSC-derived exosomes are packaged with numerous types of proteins and RNAs, however, their metabolomic and lipidomic profiles to date have not been well characterized. We previously reported that MSCs, in response to priming culture conditions that mimic the in vivo microenvironmental niche, substantially modulate cellular signaling and significantly increase the secretion of exosomes. Here we report that MSCs exposed to such priming conditions undergo glycolytic reprogramming, which homogenizes MSCs' metabolomic profile. In addition, we establish that exosomes derive from primed MSCs are packaged with numerous metabolites that have been directly associated with immunomodulation, including M2 macrophage polarization and regulatory T lymphocyte induction.

Prostate cancer genomics: comparing results from three molecular assays.

INTRODUCTION: OncotypeDx, Prolaris, and Decipher have each been validated to predict outcomes and guide treatment for patients with clinically localized prostate cancer, but they have yet to be compared to one another. Here we assess the correspondence between the results of each. MATERIALS AND METHODS: We performed a retrospective chart review to identify patients who underwent at least two of the three genomic tests at Hartford Hospital between 2014 and 2017. We used test-specific definitions of a favorable prediction for each to compare the percent agreement between each pair. Results were also compared to treatment recommendations based on current National Comprehensive Cancer Network (NCCN) guidelines. We compared pair-wise agreement using Cohen's kappa (K). RESULTS: Twenty-two patients received at least two different genomic tests. For 12 patients who received both the Decipher and Prolaris, % agreement and K were 66.7 and 0.31 (p = .276), respectively. For 8 patients who received both Prolaris and Oncotype DX, % agreement and K were 75 and 0.39 (p = .168), respectively. Two patients received both Decipher and Oncotype DX, yielding 50% agreement and an incalculable K. For Prolaris versus NCCN, % agreement and K were 75 and .21, respectively (p = .117; n = 20). For Decipher versus NCCN, % agreement and K were 60 and .15, respectively (p = .268; n = 15). For Oncotype DX versus NCCN (n = 10), agreement was 50%, K was incalculable. CONCLUSIONS: Notable differences exist in prognostic outcomes obtained from OncotypeDx, Prolaris, and Decipher.

Return to work after robot-assisted laparoscopic prostatectomy versus radical retro-pubic prostatectomy.

INTRODUCTION: We compared the return-to-work interval (RTWI) after radical retro-pubic prostatectomy (RRP) and robot-assisted laparoscopic prostatectomy (RALP) in men being treated for early-stage prostate cancer. MATERIALS AND METHODS: We mailed a 28-item questionnaire to a random sample of 2,696 patients who either had RRP from 1995 to 2004 or RALP from 2004 to 2011. RESULTS: We received analyzable questionnaires from 315 patients; 178 had RALP and 137 had RPP. The median RTWI was shorter in the RALP group than in the RRP group (3 versus 4 weeks, p = .016). The percent of subjects who had not returned to work 4 weeks after surgery was 23.6% for RALP and 38.2% for RRP (p = .010). In multivariate regression analysis, surgical approach was a significant predictor of RTWI independent of other social/clinical variables that were associated with either surgical approach or RTWI (p = .014). CONCLUSION: Our data support a shortening of RTWI by RALP.

National Comprehensive Cancer Network® Favorable Intermediate Risk Prostate Cancer-Is Active Surveillance Appropriate?

PURPOSE: We compared pathological and biochemical outcomes after radical prostatectomy in patients at favorable intermediate risk who fulfilled current NCCN® (National Comprehensive Cancer Network®) Guidelines® for active surveillance criteria to outcomes in patients who met more traditional criteria for active surveillance. MATERIALS AND METHODS: We queried our institutional review board approved prostate cancer database for patients who met NCCN criteria for very low risk (T1c, Grade Group 1, 3 or fewer of 12 cores, 50% or less core volume and prostate specific antigen density less than 0.15 ng/ml), low risk (T1-T2a, Grade Group 1 and prostate specific antigen less than 10 ng/ml) or favorable intermediate risk (major pattern grade 3 and less than 50% positive biopsy cores) and who had 1 intermediate risk factor, including T2b/c, Grade Group 2 or prostate specific antigen 10 to 20 ng/ml. Men at intermediate risk who did not meet favorable criteria were labeled as being at unfavorable intermediate risk. Patients at favorable intermediate risk were compared to those at very low and low risk, and those at unfavorable intermediate risk to identify differences in rates of adverse pathological findings at radical prostatectomy, including Gleason score Grade Group 3-5, nonorgan confined disease or nodal involvement. Time to biochemical recurrence was compared among the groups using Cox regression. RESULTS: A total of 3,686 patients underwent radical prostatectomy between January 1, 2014 and December 31, 2015. Of these men 1,454, 250 and 1,362 fulfilled the criteria for low, favorable intermediate and unfavorable intermediate risk, respectively. The rate of adverse pathological findings in favorable intermediate risk cases was significantly higher than in low risk cases and significantly lower than in unfavorable intermediate risk cases (27.4% vs 14.8% and 48.5%, respectively, each p <0.001). Time to biochemical recurrence differed significantly among the risk groups (p <0.001). CONCLUSIONS: Relative to men at low risk those at favorable intermediate risk represent a distinct group. Care should be taken when selecting these patients for active surveillance and monitoring them once they are in an active surveillance program.

Global burden of diseases, injuries, and risk factors for young people's health during 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013.

BACKGROUND: Young people's health has emerged as a neglected yet pressing issue in global development. Changing patterns of young people's health have the potential to undermine future population health as well as global economic development unless timely and effective strategies are put into place. We report the past, present, and anticipated burden of disease in young people aged 10-24 years from 1990 to 2013 using data on mortality, disability, injuries, and health risk factors. METHODS: The Global Burden of Disease Study 2013 (GBD 2013) includes annual assessments for 188 countries from 1990 to 2013, covering 306 diseases and injuries, 1233 sequelae, and 79 risk factors. We used the comparative risk assessment approach to assess how much of the burden of disease reported in a given year can be attributed to past exposure to a risk. We estimated attributable burden by comparing observed health outcomes with those that would have been observed if an alternative or counterfactual level of exposure had occurred in the past. We applied the same method to previous years to allow comparisons from 1990 to 2013. We cross-tabulated the quantiles of disability-adjusted life-years (DALYs) by quintiles of DALYs annual increase from 1990 to 2013 to show rates of DALYs increase by burden. We used the GBD 2013 hierarchy of causes that organises 306 diseases and injuries into four levels of classification. Level one distinguishes three broad categories: first, communicable, maternal, neonatal, and nutritional disorders; second, non-communicable diseases; and third, injuries. Level two has 21 mutually exclusive and collectively exhaustive categories, level three has 163 categories, and level four has 254 categories. FINDINGS: The leading causes of death in 2013 for young people aged 10-14 years were HIV/AIDS, road injuries, and drowning (25·2%), whereas transport injuries were the leading cause of death for ages 15-19 years (14·2%) and 20-24 years (15·6%). Maternal disorders were the highest cause of death for young women aged 20-24 years (17·1%) and the fourth highest for girls aged 15-19 years (11·5%) in 2013. Unsafe sex as a risk factor for DALYs increased from the 13th rank to the second for both sexes aged 15-19 years from 1990 to 2013. Alcohol misuse was the highest risk factor for DALYs (7·0% overall, 10·5% for males, and 2·7% for females) for young people aged 20-24 years, whereas drug use accounted for 2·7% (3·3% for males and 2·0% for females). The contribution of risk factors varied between and within countries. For example, for ages 20-24 years, drug use was highest in Qatar and accounted for 4·9% of DALYs, followed by 4·8% in the United Arab Emirates, whereas alcohol use was highest in Russia and accounted for 21·4%, followed by 21·0% in Belarus. Alcohol accounted for 9·0% (ranging from 4·2% in Hong Kong to 11·3% in Shandong) in China and 11·6% (ranging from 10·1% in Aguascalientes to 14·9% in Chihuahua) of DALYs in Mexico for young people aged 20-24 years. Alcohol and drug use in those aged 10-24 years had an annual rate of change of >1·0% from 1990 to 2013 and accounted for more than 3·1% of DALYs. INTERPRETATION: Our findings call for increased efforts to improve health and reduce the burden of disease and risks for diseases in later life in young people. Moreover, because of the large variations between countries in risks and burden, a global approach to improve health during this important period of life will fail unless the particularities of each country are taken into account. Finally, our results call for a strategy to overcome the financial and technical barriers to adequately capture young people's health risk factors and their determinants in health information systems. FUNDING: Bill & Melinda Gates Foundation.

Elaborative encoding through self-generation enhances outcomes with errorless learning: Findings from the Skypekids memory study.

Errorless learning has demonstrated efficacy in the treatment of memory impairment in adults and older adults with acquired brain injury. In the same population, use of elaborative encoding through supported self-generation in errorless paradigms has been shown to further enhance memory performance. However, the evidence base relevant to application of both standard and self-generation forms of errorless learning in children is far weaker. We address this limitation in the present study to examine recall performance in children with brain injury (n = 16) who were taught novel age-appropriate science and social science facts through the medium of Skype. All participants were taught these facts under conditions of standard errorless learning, errorless learning with self-generation, and trial-and-error learning after which memory was tested at 5-minute, 30-minute, 1-hour and 24-hour delays. Analysis revealed no main effect of time, with participants retaining most information acquired over the 24-hour testing period, but a significant effect of condition. Notably, self-generation proved more effective than both standard errorless and trial-and-error learning. Further analysis of the data revealed that severity of attentional impairment was less detrimental to recall performance under errorless conditions. This study extends the literature to provide further evidence of the value of errorless learning methods in children with ABI and the first demonstration of the effectiveness of self-generation when delivered via the Internet.

Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks in 188 countries, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013.

BACKGROUND: The Global Burden of Disease, Injuries, and Risk Factor study 2013 (GBD 2013) is the first of a series of annual updates of the GBD. Risk factor quantification, particularly of modifiable risk factors, can help to identify emerging threats to population health and opportunities for prevention. The GBD 2013 provides a timely opportunity to update the comparative risk assessment with new data for exposure, relative risks, and evidence on the appropriate counterfactual risk distribution. METHODS: Attributable deaths, years of life lost, years lived with disability, and disability-adjusted life-years (DALYs) have been estimated for 79 risks or clusters of risks using the GBD 2010 methods. Risk-outcome pairs meeting explicit evidence criteria were assessed for 188 countries for the period 1990-2013 by age and sex using three inputs: risk exposure, relative risks, and the theoretical minimum risk exposure level (TMREL). Risks are organised into a hierarchy with blocks of behavioural, environmental and occupational, and metabolic risks at the first level of the hierarchy. The next level in the hierarchy includes nine clusters of related risks and two individual risks, with more detail provided at levels 3 and 4 of the hierarchy. Compared with GBD 2010, six new risk factors have been added: handwashing practices, occupational exposure to trichloroethylene, childhood wasting, childhood stunting, unsafe sex, and low glomerular filtration rate. For most risks, data for exposure were synthesised with a Bayesian meta-regression method, DisMod-MR 2.0, or spatial-temporal Gaussian process regression. Relative risks were based on meta-regressions of published cohort and intervention studies. Attributable burden for clusters of risks and all risks combined took into account evidence on the mediation of some risks such as high body-mass index (BMI) through other risks such as high systolic blood pressure and high cholesterol. FINDINGS: All risks combined account for 57·2% (95% uncertainty interval [UI] 55·8-58·5) of deaths and 41·6% (40·1-43·0) of DALYs. Risks quantified account for 87·9% (86·5-89·3) of cardiovascular disease DALYs, ranging to a low of 0% for neonatal disorders and neglected tropical diseases and malaria. In terms of global DALYs in 2013, six risks or clusters of risks each caused more than 5% of DALYs: dietary risks accounting for 11·3 million deaths and 241·4 million DALYs, high systolic blood pressure for 10·4 million deaths and 208·1 million DALYs, child and maternal malnutrition for 1·7 million deaths and 176·9 million DALYs, tobacco smoke for 6·1 million deaths and 143·5 million DALYs, air pollution for 5·5 million deaths and 141·5 million DALYs, and high BMI for 4·4 million deaths and 134·0 million DALYs. Risk factor patterns vary across regions and countries and with time. In sub-Saharan Africa, the leading risk factors are child and maternal malnutrition, unsafe sex, and unsafe water, sanitation, and handwashing. In women, in nearly all countries in the Americas, north Africa, and the Middle East, and in many other high-income countries, high BMI is the leading risk factor, with high systolic blood pressure as the leading risk in most of Central and Eastern Europe and south and east Asia. For men, high systolic blood pressure or tobacco use are the leading risks in nearly all high-income countries, in north Africa and the Middle East, Europe, and Asia. For men and women, unsafe sex is the leading risk in a corridor from Kenya to South Africa. INTERPRETATION: Behavioural, environmental and occupational, and metabolic risks can explain half of global mortality and more than one-third of global DALYs providing many opportunities for prevention. Of the larger risks, the attributable burden of high BMI has increased in the past 23 years. In view of the prominence of behavioural risk factors, behavioural and social science research on interventions for these risks should be strengthened. Many prevention and primary care policy options are available now to act on key risks. FUNDING: Bill & Melinda Gates Foundation.

A comparison of preliminary oncologic outcome and postoperative complications between patients undergoing either open or robotic radical cystectomy.

PURPOSE: To compare complications and outcomes in patients undergoing either open radical cystectomy (ORC) or robotic-assisted radical cystectomy (RRC). MATERIALS AND METHODS: We retrospectively identified patients that underwent ORC or RRC between 2003- 2013. We statistically compared preliminary oncologic outcomes of patients for each surgical modality. RESULTS: 92 (43.2%) and 121 (56.8%) patients underwent ORC and RRC, respectively. While operative time was shorter for ORC patients (403 vs. 508 min; p<0.001), surgical blood loss and transfusion rates were significantly lower in RRC patients (p<0.001 and 0.006). Length of stay was not different between groups (p=0.221). There was no difference in the proportion of lymph node-positive patients between groups. However, RRC patients had a greater number of lymph nodes removed during surgery (18 vs. 11.5; p<0.001). There was no significant difference in the incidence of pre-existing comorbidities or in the Clavien distribution of complications between groups. ORC and RRC patients were followed for a median of 1.38 (0.55-2.7) and 1.40 (0.58-2.59) years, respectively (p=0.850). During this period, a lower proportion (22.3%) of RRC patients experienced disease recurrence vs. ORC patients (34.8%). However, there was no significant difference in time to recurrence between groups. While ORC was associated with a higher all-cause mortality rate (p=0.049), there was no significant difference in disease-free survival time between groups. CONCLUSIONS: ORC and RRC patients experience postoperative complications of similar rates and severity. However, RRC may offer indirect benefits via reduced surgical blood loss and need for transfusion.

Dopamine transporter genotype is associated with a lateralized resistance to distraction during attention selection.

Although lateral asymmetries in orienting behavior are evident across species and have been linked to interhemispheric asymmetries in dopamine signaling, the relative contribution of attentional versus motoric processes remains unclear. Here we took a cognitive genetic approach to adjudicate between roles for dopamine in attentional versus response selection. A sample of nonclinical adult humans (N = 518) performed three cognitive tasks (spatial attentional competition, spatial cueing, and flanker tasks) that varied in the degree to which they required participants to resolve attentional or response competition. All participants were genotyped for two putatively functional tandem repeat polymorphisms of the dopamine transporter gene (DAT1; SLC6A3), which are argued to influence the level of available synaptic dopamine and confer risk to disorders of inattention. DAT1 genotype modulated the task-specific effects of the various task-irrelevant stimuli across both the spatial competition and spatial cueing but not flanker tasks. Specifically, compared with individuals carrying one or two copies of the 10-repeat DAT1 allele, individuals without this allele demonstrated an immunity to distraction, such that response times were unaffected by increases in the number of distractor stimuli, particularly when these were presented predominantly in the left hemifield. All three genotype groups exhibited uniform costs of resolving leftward response selection in a standard flanker task. None of these significant effects could be explained by speed-accuracy trade-offs, suggesting that participants without the 10-repeat allele of the DAT1 tandem repeat polymorphism possess an enhanced attentional ability to suppress task-irrelevant stimuli in the left hemifield.

Prostate atypia: does repeat biopsy detect clinically significant prostate cancer?

BACKGROUND: While the treatment pathway in response to benign or malignant prostate biopsies is well established, there is uncertainty regarding the risk of subsequently diagnosing prostate cancer when an initial diagnosis of prostate atypia is made. As such, we investigated the likelihood of a repeat biopsy diagnosing prostate cancer (PCa) in patients in which an initial biopsy diagnosed prostate atypia. METHODS: We reviewed our prospectively maintained prostate biopsy database to identify patients who underwent a repeat prostate biopsy within one year of atypia (atypical small acinar proliferation; ASAP) diagnosis between November 1987 and March 2011. Patients with a history of PCa were excluded. Chart review identified patients who underwent radical prostatectomy (RP), radiotherapy (RT), or active surveillance (AS). For some analyses, patients were divided into two subgroups based on their date of service. RESULTS: Ten thousand seven hundred and twenty patients underwent 13,595 biopsies during November 1987-March 2011. Five hundred and sixty seven patients (5.3%) had ASAP on initial biopsy, and 287 (50.1%) of these patients underwent a repeat biopsy within one year. Of these, 122 (42.5%) were negative, 44 (15.3%) had atypia, 19 (6.6%) had prostatic intraepithelial neoplasia, and 102 (35.6%) contained PCa. Using modified Epstein's criteria, 27/53 (51%) patients with PCa on repeat biopsy were determined to have clinically significant tumors. 37 (36.3%) proceeded to RP, 25 (24.5%) underwent RT, and 40 (39.2%) received no immediate treatment. In patients who underwent surgery, Gleason grade on final pathology was upgraded in 11 (35.5%), and downgraded 1 (3.2%) patient. CONCLUSIONS: ASAP on initial biopsy was associated with a significant risk of PCa on repeat biopsy in patients who subsequently underwent definitive local therapy. Patients with ASAP should be counseled on the probability of harboring both clinically significant and insignificant prostate cancer.

Robotic-assisted laparoscopic catheterizable bladder augment: a novel approach to treat recurrent bladder neck contracture following radical prostatectomy.

INTRODUCTION: Bladder neck contractures (BNC) are an uncommon complication following radical prostatectomy. Occasionally, BNCs can be refractory to endoscopic approaches. We describe the effectiveness of a novel robotic-assisted laparoscopic catheterizable bladder augment in treating recalcitrant BNCs. MATERIALS AND METHODS: Patients undergoing robotic-assisted radical prostatectomy (RALP) between 2004-2014 who developed a postoperative BNC were identified. We documented our experience with robotic-assisted laparoscopic catheterizable bladder augment for recalcitrant BNCs. Total operative time, robotic time, estimated surgical blood, length of hospital stay, serum creatinine, complications, and postoperative course/upper tract imaging were recorded. RESULTS: Thirty-six of 2002 RALP patients (1.8%) experienced a post-surgical BNC at 182 days post-surgery. Twenty-two (61.1%) underwent a single dilation and/or transurethral incision. Eleven (30.6%) required = 1 procedure. Three patients (8.3%) had recalcitrant BNCs. One patient with normal bladder capacity elected open urethroplasty. The remaining two had reduced bladder capacity, detrusor over-activity and failed multiple incisions and self-catheterization. In one patient, the stricture was complete. The other patient experienced urethral leakage requiring bladder neck closure. In both patients, a robotic approach, utilizing an ileal-cecal segment as a catheterizable augment, was performed. At 16 and 89 months follow up, both are continent, with stable renal function and normal upper tracts. CONCLUSION: Robotic-assisted laparoscopic catheterizable bladder augment is a viable treatment for recurrent BNCs. This approach may be particularly well suited for patients with concurrent hyperreflexia or decreased bladder capacity.