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1.  Epidermal Growth Factor Receptor–Targeted Therapy in Locally Advanced or Metastatic Squamous Cell Carcinoma of the Penis 
BJU international  2014;113(6):871-877.
To evaluate the safety and efficacy of epidermal growth factor receptor (EGFR)–targeted therapy in patients with advanced penile or scrotal cancer.
Patients and Methods
We retrospectively reviewed charts of patients with penile or scrotal squamous cell carcinoma who had visited our tertiary cancer center from 2002 through 2009, including their subsequent treatment and follow-up. We collected details of EGFR-targeted therapy and clinical outcomes. Treatment-associated time to disease progression (TTP), overall survival (OS), responses to therapy, and toxicity were evaluated.
Twenty-four patients had received EGFR-targeted therapies, including cetuximab, erlotinib, and gefitinib. The most common treatment given (67% of patients) was cetuximab combined with one or more cytotoxic drugs. The most common adverse effect was skin rash (71%); median TTP and OS were 11.3 weeks (1–40 weeks) and 29.6 weeks (2–205 weeks), respectively. OS for patients with visceral or bone metastases was significantly less than it was for those without (24.7 weeks vs. 49.9 weeks, P = .013). Among 17 patients treated with cetuximab alone or in combination with cisplatin, there were four partial responses (23.5%) including two patients with seemingly chemo-resistant tumor.
Our results suggest that cetuximab has antitumor activity in metastatic penile cancer, and may enhance the effect of cisplatin-based chemotherapy. Prospective studies of EGFR-targeted therapies in men with these tumors are warranted.
PMCID: PMC4321685  PMID: 24053151
Anti-epidermal growth factor monoclonal antibody; Penile Neoplasms; Squamous Cell Carcinoma; Survival
2.  Effect of standardized training on the reliability of the Cochrane risk of bias assessment tool: a study protocol 
Systematic Reviews  2014;3(1):144.
The Cochrane risk of bias (RoB) tool has been widely embraced by the systematic review community, but several studies have reported that its reliability is low. We aim to investigate whether training of raters, including objective and standardized instructions on how to assess risk of bias, can improve the reliability of this tool. We describe the methods that will be used in this investigation and present an intensive standardized training package for risk of bias assessment that could be used by contributors to the Cochrane Collaboration and other reviewers.
This is a pilot study. We will first perform a systematic literature review to identify randomized clinical trials (RCTs) that will be used for risk of bias assessment. Using the identified RCTs, we will then do a randomized experiment, where raters will be allocated to two different training schemes: minimal training and intensive standardized training. We will calculate the chance-corrected weighted Kappa with 95% confidence intervals to quantify within- and between-group Kappa agreement for each of the domains of the risk of bias tool. To calculate between-group Kappa agreement, we will use risk of bias assessments from pairs of raters after resolution of disagreements. Between-group Kappa agreement will quantify the agreement between the risk of bias assessment of raters in the training groups and the risk of bias assessment of experienced raters. To compare agreement of raters under different training conditions, we will calculate differences between Kappa values with 95% confidence intervals.
This study will investigate whether the reliability of the risk of bias tool can be improved by training raters using standardized instructions for risk of bias assessment. One group of inexperienced raters will receive intensive training on risk of bias assessment and the other will receive minimal training. By including a control group with minimal training, we will attempt to mimic what many review authors commonly have to do, that is—conduct risk of bias assessment in RCTs without much formal training or standardized instructions. If our results indicate that an intense standardized training does improve the reliability of the RoB tool, our study is likely to help improve the quality of risk of bias assessments, which is a central component of evidence synthesis.
Electronic supplementary material
The online version of this article (doi:10.1186/2046-4053-3-144) contains supplementary material, which is available to authorized users.
PMCID: PMC4273317  PMID: 25495124
Systematic review; Meta-analysis; Risk of bias; RCT; Cochrane
3.  Global Neural Pattern Similarity as a Common Basis for Categorization and Recognition Memory 
The Journal of Neuroscience  2014;34(22):7472-7484.
Familiarity, or memory strength, is a central construct in models of cognition. In previous categorization and long-term memory research, correlations have been found between psychological measures of memory strength and activation in the medial temporal lobes (MTLs), which suggests a common neural locus for memory strength. However, activation alone is insufficient for determining whether the same mechanisms underlie neural function across domains. Guided by mathematical models of categorization and long-term memory, we develop a theory and a method to test whether memory strength arises from the global similarity among neural representations. In human subjects, we find significant correlations between global similarity among activation patterns in the MTLs and both subsequent memory confidence in a recognition memory task and model-based measures of memory strength in a category learning task. Our work bridges formal cognitive theories and neuroscientific models by illustrating that the same global similarity computations underlie processing in multiple cognitive domains. Moreover, by establishing a link between neural similarity and psychological memory strength, our findings suggest that there may be an isomorphism between psychological and neural representational spaces that can be exploited to test cognitive theories at both the neural and behavioral levels.
PMCID: PMC4035513  PMID: 24872552
Evidence-based healthcare decisions are best informed by comparisons of all relevant interventions used to treat conditions in specific patient populations. Observational studies are being performed to help fill evidence gaps. However, widespread adoption of evidence from observational studies has been limited due to a variety of factors, including the lack of consensus regarding accepted principles for their evaluation and interpretation. Two Task Forces were formed to develop questionnaires to assist decision makers in evaluating observational studies, with one Task Force addressing retrospective research and the other prospective research. The intent was to promote a structured approach to reduce the potential for subjective interpretation of evidence and drive consistency in decision-making. Separately developed questionnaires were combined into a single questionnaire consisting of 33 items. These were divided into two domains: relevance and credibility. Relevance addresses the extent to which findings, if accurate, apply to the setting of interest to the decision maker. Credibility addresses the extent to which the study findings accurately answer the study question. The questionnaire provides a guide for assessing the degree of confidence that should be placed from observational studies and promotes awareness of the subtleties involved in evaluating those.
PMCID: PMC4217656  PMID: 24636373
bias; checklist; comparative effectiveness research; confounding; consensus; credibility; decision-making; epidemiologic research design; observational study methods; prospective observational study; publishing standards; quality; questionnaire; relevance; retrospective observational study; validity
5.  Decoding the Brain’s Algorithm for Categorization from its Neural Implementation 
Current biology : CB  2013;23(20):10.1016/j.cub.2013.08.035.
Acts of cognition can be described at different levels of analysis: what behavior should characterize the act, what algorithms and representations underlie the behavior, and how the algorithms are physically realized in neural activity [1]. Theories that bridge levels of analysis offer more complete explanations by leveraging the constraints present at each level [2–4]. Despite the great potential for theoretical advances, few studies of cognition bridge levels of analysis. For example, formal cognitive models of category decisions accurately predict human decision making [5, 6], but whether model algorithms and representations supporting category decisions are consistent with underlying neural implementation remains unknown. This uncertainty is largely due to the hurdle of forging links between theory and brain [7–9]. Here, we tackle this critical problem by using brain response to characterize the nature of mental computations that support category decisions to evaluate two dominant, and opposing, models of categorization. We found that brain states during category decisions were significantly more consistent with latent model representations from exemplar [5] rather than prototype theory [10, 11]. Representations of individual experiences, not the abstraction of experiences, are critical for category decision making. Holding models accountable for behavior and neural implementation provides a means for advancing more complete descriptions of the algorithms of cognition.
PMCID: PMC3874407  PMID: 24094852
6.  Hospitalization for partial nephrectomy was not associated with intrathecal opioid analgesia: Retrospective analysis 
Saudi Journal of Anaesthesia  2014;8(4):517-522.
The aim of this retrospective study is to test the hypothesis that the use of spinal analgesia shortens the length of hospital stay after partial nephrectomy.
Materials and Methods:
We reviewed all patients undergoing partial nephrectomy for malignancy through flank incision between January 1, 2008, and June 30, 2011. We excluded patients who underwent tumor thrombectomy, used sustained-release opioids, or had general anesthesia supplemented by epidural analgesia. Patients were grouped into “spinal” (intrathecal opioid injection for postoperative analgesia) versus “general anesthetic” group, and “early” discharge group (within 3 postoperative days) versus “late” group. Association between demographics, patient physical status, anesthetic techniques, and surgical complexity and hospital stay were analyzed using multivariable logistic regression analysis.
Of 380 patients, 158 (41.6%) were discharged “early” and 151 (39.7%) were “spinal” cases. Both spinal and early discharge groups had better postoperative pain control and used less postoperative systemic opioids. Spinal analgesia was associated with early hospital discharge, odds ratio 1.52, (95% confidence interval 1.00-2.30), P = 0.05, but in adjusted analysis was no longer associated with early discharge, 1.16 (0.73-1.86), P = 0.52. Early discharge was associated with calendar year, with more recent years being associated with early discharge.
Spinal analgesia combined with general anesthesia was associated with improved postoperative pain control during the 1st postoperative day, but not with shorter hospital stay following partial nephrectomy. Therefore, unaccounted practice changes that occurred during more recent times affected hospital stay.
PMCID: PMC4236940  PMID: 25422611
Hospital length of stay; neuroaxial anesthesia; radical nephrectomy
The Journal of urology  2009;182(6):2601-2606.
Recent observations suggest that partial nephrectomy for small renal tumors may be associated with improved survival compared with radical nephrectomy. We evaluated survival in patients with renal tumors 4-7cm using a bi-institutional collaboration.
Combining institutional databases from Mayo Clinic and Memorial Sloan-Kettering, we identified 1,159 patients with sporadic, unilateral, solitary and localized renal masses 4.1–7.0 cm who underwent radical or partial nephrectomy between 1989 and 2006. Patient outcome was compared using Cox proportional hazards regression models.
Among the 1,159 patients, 873 (75%) and 286 (25%) were treated with radical and partial nephrectomy, respectively. Patients treated with partial (vs radical) nephrectomy were significantly more likely to have a solitary kidney (10% vs 0.2%, p<0.001) and chronic kidney disease (15% vs 7%, p<0.001). Median duration of follow-up for survivors was 4.8 years (range 0-19). There was not a significant difference in overall survival when comparing patients treated with radical and partial nephrectomy (p=0.8). Interestingly, in a subset of 943 patients with RCC, those treated with radical nephrectomy were significantly more likely to die from RCC compared with those treated with partial nephrectomy (hazard ratio 2.16; 95% CI 1.04–4.50; p=0.039) although this association only approached statistical significance in a multivariable analysis (hazard ratio 1.97; 95% CI 0.92–4.20; p=0.079).
Our results suggest that overall and cancer-specific survival is not compromised when partial nephrectomy is utilized for patients with 4-7cm renal cortical tumors. With the benefit of preserving renal function, our results support the use of partial nephrectomy whenever technically feasible for renal tumors up to 7cm.
PMCID: PMC4171846  PMID: 19836797
Kidney neoplasms; Nephrectomy; Carcinoma; renal cell; Survival; Treatment outcome
8.  Stress Incontinence in the Era of Regenerative Medicine: Reviewing the Importance of the Pudendal Nerve 
The Journal of urology  2013;190(1):22-28.
Regenerative medicine will likely facilitate improved stress urinary incontinence (SUI) treatment via restoration of its neurogenic, myogenic, and structural etiologies. Understanding these pathophysiologies and how each can optimally benefit from cellular, molecular, and minimally invasive therapies will become necessary. While stem cells in sphincteric deficiency dominate the regenerative urology literature, little is published on pudendal nerve (PN) regeneration or other regenerative targets. The purpose of this review is to discuss regenerative therapies for PN injury in SUI.
Materials and Methods
A PubMed® search for pudendal nerve combined individually with regeneration, injury, electrophysiology, measurement, and activity produced a combined but non-independent 621 results. English language articles were reviewed by title for relevance, identifying a combined but non-independent 68 articles. A subsequent Google Scholar® searchand review of references in articles obtained aided in broadening discussion.
Electrophysiological studies associate PN dysfunction with SUI clinically and assess PN regeneration functionally while animal models provide physiological insight. Stem cell treatment has improved continence clinically while ex vivo sphincteric bulk and muscle function gains have been noted in the laboratory. Stem cells, neurotrophic factors, and electrical stimulation each benefit PN regeneration in animal models.
Most regenerative work to date focuses on stem cells restoring sphincteric function and bulk, but whether a sphincter denervated by PN injury will benefit is unclear. Regeneration of the PN appears possible through minimally invasive therapies that exhibit significant clinical potential. Treating poor central control and coordination of the neuromuscular continence mechanism remains another challenge.
PMCID: PMC4158918  PMID: 23376143
Urethral Sphincter; Neurotrophin; Stem Cell; Neuromuscular Continence; Electrophysiology
9.  Recent advances in patient and proxy-reported quality of life research 
A number of articles addressing various aspects of health-related quality of life (HRQoL) were published in the Health and Quality of Life Outcomes (HQLO) journal in 2012 and 2013. This review provides a summary of studies describing recent methodological advances and innovations in HRQoL felt to be of relevance to clinicians and researchers.
Scoping review of original research articles, reviews and short reports published in the HQLO journal in 2012 and 2013. Publications describing methodological advances and innovations in HRQoL were reviewed in detail, summarized and grouped into thematic categories.
358 titles and abstracts were screened initially, and 16 were considered relevant and incorporated in this review. Two studies discussed development and interpretation of HRQoL outcomes; two described pediatric HRQoL measurement; four involved incorporation of HRQoL in economic evaluations; and eight described methodological issues and innovations in HRQoL measures.
Several studies describing important advancements and innovations in HRQoL, such as the development of the PROMIS pediatric proxy-item bank and guidelines for constructing patient-reported outcome (PRO) instruments, were published in the HQLO journal in 2012 and 2013. Proposed future directions for the majority of these studies include extension and further validation of the research across a diverse range of health conditions.
PMCID: PMC4159521  PMID: 25169205
10.  A Modern Cohort of Duodenal Obstruction Patients: Predictors of Delayed Transition to Full Enteral Nutrition 
Background. A common site for neonatal intestinal obstruction is the duodenum. Delayed establishment of enteral nutritional autonomy continues to challenge surgeons and, since early institution of nutritional support is critical in postoperative newborns, identification of patients likely to require alternative nutritional support may improve their outcomes. Therefore, we aimed to investigate risk factors leading to delayed establishment of full enteral nutrition in these patients. Methods. 87 patients who were surgically treated for intrinsic duodenal obstructions from 1998 to 2012 were reviewed. Variables were tested as potential risk factors. Median time to full enteral nutrition was estimated using the Kaplan-Meier method. Independent risk factors of delayed transition were identified using the multivariate Cox proportional hazards regression model. Results. Median time to transition to full enteral nutrition was 12 days (interquartile range: 9–17 days). Multivariate Cox analysis identified three significant risk factors for delayed enteral nutrition: gestational age (GA) ≤ 35 weeks (P < .001), congenital heart disease (CHD) (P = .02), and malrotation (P = .03). Conclusions. CHD and Prematurity are most commonly associated with delayed transition to full enteral nutrition. Thus, in these patients, supportive nutrition should strongly be considered pending enteral nutritional autonomy.
PMCID: PMC4150512  PMID: 25210625
Urology  2013;82(1):136-141.
To evaluate the impact of tumor histology on clinicopathologic outcomes for patients with renal cell carcinoma (RCC) and venous tumor thrombus (VTT).
We identified 807 patients with RCC and VTT who underwent nephrectomy at our institution between 1970–2008. All pathologic specimens were re-reviewed by a single urologic pathologist. Patients with non-clear cell RCC (non-ccRCC) (n=56) were matched 1:2 to patients with clear cell RCC (ccRCC) VTT based onsymptoms at presentation, regional lymph node involvement, distant metastases, tumor thrombus level, nuclear grade and sarcomatoid differentiation. Survival was estimated using the Kaplan-Meier method and compared with the log-rank test.
The 56 patients with non-ccRCC VTT included 26 papillary, 11 chromophobe, 5 collecting duct tumors, and 14 RCC not otherwise specified. Compared to unmatched patients with ccRCC VTT (n=751), patients with non-ccRCC VTT presented with larger tumor size (p=0.02), higher nuclear grade (p=0.04), and more frequent sarcomatoid differentiation (p<0.001) and lymph node invasion (p<0.001). However, when patients with non-ccRCC were matched to patients with cc-RCC, no significant differences were noted with regard to 5-year metastases-free survival (41% versus 34%; p=0.24) or cancer-specific survival (25% versus 27%; p=0.97).
Non-ccRCC VTT is associated with a high rate of adverse pathologic features. Nevertheless, when matched to patients with ccRCC, patients with non-ccRCC VTT did not have increased rates of recurrence or adverse survival. Aggressive surgical resection represents the mainstay of treatment in these cases, while continued efforts to optimize a multimodal management approach to such patients remain necessary.
PMCID: PMC3710713  PMID: 23642851
renal cell carcinoma; tumor thrombus; kidney cancer; histology
13.  The Effect of Benign Lower Urinary Tract Symptoms on Subsequent Prostate Cancer Testing and Diagnosis 
European urology  2013;63(6):1021-1027.
Lower urinary tract symptoms (LUTS) are common and have been associated with the subsequent diagnosis of prostate cancer (PCa) in population cohorts.
To determine whether the association between LUTS and PCa is due to the intensity of PCa testing after LUTS diagnosis.
Design, setting, and participants
We prospectively followed a representative, population-based cohort of 1922 men, aged 40–79 yr, from 1990 until 2010 with interviews, questionnaires, and abstracting of medical records for prostate outcomes. Men were excluded if they had a previous prostate biopsy or PCa diagnosis. Self-reported LUTS was defined as an American Urological Association symptom index score >7 (n = 621). Men treated for LUTS (n = 168) were identified from review of medical records and/or self report. Median follow-up was 11.8 yr (interquartile range: 10.7–12.3).
Outcome measurements and statistical analysis
Associations between self-reported LUTS, or treatment for LUTS, and risk of subsequent prostate biopsy and PCa were estimated using Cox proportional hazard models.
Results and limitations
Fifty-five percent of eligible men enrolled in the study. Men treated for LUTS were more likely to undergo a prostate biopsy (hazard ratio [HR]: 2.4; 95% confidence interval [CI], 1.7–3.3). Men younger than 65 yr who were treated for LUTS were more likely to be diagnosed with PCa (HR: 2.3, 95% CI, 1.5–3.5), while men aged >65 yr were not (HR: 0.89, 95% CI, 0.35–1.9). Men with self-reported LUTS were not more likely to be biopsied or diagnosed with PCa. Neither definition of LUTS was associated with subsequent intermediate to high-risk cancer. The study is limited by lack of histologic or prostate-specific antigen level data for the cohort.
These results indicate that a possible cause of the association between LUTS and PCa is increased diagnostic intensity among men whose LUTS come to the attention of physicians. Increased symptoms themselves were not associated with intensity of testing or diagnosis.
PMCID: PMC3637922  PMID: 23313032
14.  Augmentation of Youth Cognitive Behavioral and Pharmacological Interventions with Attention Modification: A Preliminary Investigation 
Depression and anxiety  2013;30(9):822-828.
Recent research suggests the efficacy of attention modification programs (AMP) in treating adult anxiety [1]. Though some research supports the success of AMP treatment in anxious youths [2, 3], to date no study has examined the efficacy of AMP as an adjunctive treatment to other psychosocial and pharmacological interventions for anxious youths within the community.
In the current study we examined the efficacy of AMP as an adjunctive treatment to standard care at a residential anxiety treatment facility. Adolescents (N = 42) completed either an active (attention modification program, AMP; n = 21) or a control (attention control condition, ACC; n = 21) condition, in addition to the facility's standard treatment protocol, which included cognitive behavioral therapy with or without medication.
While anxiety symptoms decreased for participants across both groups, participants in the AMP group experienced a significantly greater decrease in anxiety symptoms from point of intake to point of discharge, in comparison to participants in the ACC group.
These results suggest that AMP is an effective adjunctive treatment to the standard treatments of choice for anxiety disorders, and may hold promise for improving treatment response in highly anxious youths.
PMCID: PMC4005412  PMID: 23658147
anxiety disorders; attention training; cognitive bias modification; dissemination; treatment; youth
15.  Acute and Chronic Acetaminophen Use and Renal Disease: A Case-Control Study Using Pharmacy and Medical Claims 
Studies have examined the association between acetaminophen (APAP) use and renal disease; however, their interpretation is limited by a number of methodological issues.
To study the association between acute and chronic prescription-acquired APAP use and renal disease.
This was a retrospective case-control study of medical and pharmacy claims of a 10% random sample of the enrollees from the IMS LifeLink Health Plans commercial claims dataset for dates of service from January 1, 1997, through December 31, 2009. Subjects were continuously enrolled and aged 18 years or older. Cases had at least 1 incident claim of renal disease defined by ICD-9-CM codes in the primary diagnosis field. Controls were randomly selected from individuals without evidence of renal disease, liver disease, or asthma in medical claims and matched to cases in a 3-to-1 ratio based on 3 variables (age, gender, and geographic region). APAP exposure, dose, and duration were measured in the 7 and 30 days (acute) and in the 1-year (chronic) look-back periods. Multivariable conditional logistic regression was used to estimate the risk of APAP exposure adjusted for comorbidities, use of other nephrotoxic drugs, and health system factors.
There were 4,724 cases and 14,172 controls with a mean (SD) age of 60.8 (17.8) years, and 52.6% were males; 10.9% of cases and 4.2% of controls had APAP exposure in the 30 days pre-index with mean potential maximum daily doses of 3,846.5 mg and 3,190.8 mg, respectively. Acute APAP exposure was significantly associated with renal disease, and the risk decreased with longer look-back periods (7 days: adjusted odds ratio [OR]=1.93, 95% CI=1.61-2.30); 30 days: OR=1.71, 95% CI=1.48-1.97). Cumulative APAP dose greater than 1 kg and APAP use for longer than 30 days in the pre-index year were not significantly associated with an increased risk of renal disease (both P values=0.900).
Acute prescription-acquired APAP use was associated with renal disease, while chronic use was not. Because this study assessed APAP use in pharmacy claims, further research accounting for OTC APAP use is warranted before the safety of chronic APAP consumption can be firmly established.
PMCID: PMC4000171  PMID: 22468732
16.  Pre-operative nomogram predicting 12-year probability of metastatic renal cancer 
The Journal of urology  2008;179(6):2146-2151.
For patients with renal masses localized to the kidney, there is currently no pre-operative tool to predict the likelihood of metastatic recurrence following surgical intervention. The primary goal of this study was to develop a predictive model that could be used in the pre-operative setting.
We pooled institutional databases from Memorial Sloan-Kettering and Mayo Clinic and identified 2,517 patients with renal masses and no concurrent evidence of metatases, who underwent radical or partial nephrectomy and with complete data. Cox proportional hazard regression analyses were used to model pre-operative clinical and radiographic characteristics as predictors for development of metastases following nephrectomy. Internal validation was performed with a statistical bootstrapping technique.
Metastatic recurrence developed in 340 of the 2517 patients. Median follow-up for patients without metastatic recurrence was 4.7 years. A nomogram was developed using pre-operative characteristics to predict the 12-year likelihood of post-operative metastatic recurrence, with a concordance index (CI) of 0.80. In contrast, the concordance index of pre-operative TNM staging was 0.71. Size of the primary renal mass, evidence of lymphadenopathy or necrosis on pre-operative imaging and the mode of presentation were important predictors for the subsequent development of metastases.
We present a pre-operative nomogram that accurately predicts the development of metastatic recurrence following nephrectomy. This nomogram may be potentially useful to identify high-risk patients for clinical trials in neoadjuvant setting.
PMCID: PMC3985125  PMID: 18423735
nomogram; renal masses; nephrectomy; metastasis
17.  Association of Single-Nucleotide Polymorphisms of the Tau Gene With Late-Onset Parkinson Disease 
The human tau gene, which promotes assembly of neuronal microtubules, has been associated with several rare neurologic diseases that clinically include parkinsonian features. We recently observed linkage in idiopathic Parkinson disease (PD) to a region on chromosome 17q21 that contains the tau gene. These factors make tau a good candidate for investigation as a susceptibility gene for idiopathic PD, the most common form of the disease.
To investigate whether the tau gene is involved in idiopathic PD.
Design, Setting, and Participants
Among a sample of 1056 individuals from 235 families selected from 13 clinical centers in the United States and Australia and from a family ascertainment core center, we tested 5 single-nucleotide polymorphisms (SNPs) within the tau gene for association with PD, using family-based tests of association. Both affected (n = 426) and unaffected (n = 579) family members were included; 51 individuals had unclear PD status. Analyses were conducted to test individual SNPs and SNP haplotypes within the tau gene.
Main Outcome Measure
Family-based tests of association, calculated using asymptotic distributions.
Analysis of association between the SNPs and PD yielded significant evidence of association for 3 of the 5 SNPs tested: SNP 3, P = .03; SNP 9i, P = .04; and SNP 11, P = .04. The 2 other SNPs did not show evidence of significant association (SNP 9ii, P = .11, and SNP 9iii, P = .87). Strong evidence of association was found with haplotype analysis, with a positive association with one haplotype (P = .009) and a negative association with another haplotype (P = .007). Substantial linkage disequilibrium (P<.001) was detected between 4 of the 5 SNPs (SNPs 3,9i, 9ii, and 11).
This integrated approach of genetic linkage and positional association analyses implicates tau as a susceptibility gene for idiopathic PD.
PMCID: PMC3973175  PMID: 11710889
18.  A Malachite Green-Based Assay to Assess Glucan Phosphatase Activity 
Analytical biochemistry  2012;435(1):54-56.
With the recent discovery of a unique class of dual-specificity phosphatases that dephosphorylate glucans, we report an in vitro assay tailored for the detection of phosphatase activity against phosphorylated glucans. We demonstrate that in contrast to a general phosphatase assay utilizing a synthetic substrate, only phosphatases that possess glucan phosphatase activity liberate phosphate from the phosphorylated glucan amylopectin using the described assay. This assay is simple and cost-effective, providing reproducible results that clearly establish the presence or absence of glucan phosphatase activity. The assay described will be a useful tool in characterizing emerging members of the glucan phosphatase family.
PMCID: PMC3577954  PMID: 23201267
Glucan; Phosphatase; Malachite green; Amylopectin; Glycogen; Starch
19.  Dynamic prediction of metastases after radical prostatectomy for prostate cancer 
BJU international  2011;108(11):1762-1768.
To develop a dynamic algorithm that predicts the risk of metastases from any time point after radical prostatectomy (RP).
Patients and methods
The study cohort consisted of 5741 RP patients who were treated from 1990–99.
Patients were grouped into one of four clinical states at follow-up: State1, prostate-specific antigen (PSA) undetectable; State2, PSA 0.15–0.39 ng/mL; State3, PSA ≥ 0.4 ng/mL; and State4, previous androgen deprivation or radiation therapy.
Follow-up epochs (alive and at risk of systemic progression) at 0, 2, 4 and 6 years post-RP, cumulative incidence curves and multistate Cox models were used to assess the risk of metastases over the ensuing 5-year interval.
Gleason score, seminal vesicle and surgical margin involvement, and PSA variables were evaluated as predictors.
Median follow-up was 11.7 years, with 4411, 4256 and 3983 patients followed with PSA at 2, 4 and 6 years, respectively.
In total, 287 metastatic events occurred and the 5-year risk of metastasis was 0.4%, 2.1%, 8.7% and 12.6% for men in States 1, 2, 3 and 4, respectively.
Independent predictors of metastasis by group included seminal vesicle involvement (all groups), Gleason score (groups 1, 3 and 4), current PSA (groups 3 and 4) and maximum past PSA (group 4).
We present a web-based prognostic tool for patients undergoing RP that is valid at many time points after surgery.
Our tool predicts the development of metastases.
PMCID: PMC3954129  PMID: 21615849
prostatectomy; prostate cancer; clinical prediction; metastases; outcome assessment
20.  Treatment of Obsessive-Compulsive Disorder Complicated by Comorbid Eating Disorders 
Cognitive behaviour therapy  2013;42(1):64-76.
Eating disorders and obsessive-compulsive disorder (OCD) commonly co-occur, but there is little data for how to treat these complex cases. To address this gap, we examined the naturalistic outcome of 56 patients with both disorders, who received a multimodal treatment program designed to address both problems simultaneously.
A residential treatment program developed a cognitive-behavioral approach for patients with both OCD and an eating disorder by integrating exposure and response prevention (ERP) treatment for OCD with ERP strategies targeting eating pathology. Patients also received a supervised eating plan, medication management, and social support. At admission and discharge, patients completed validated measures of OCD severity (the Yale-Brown Obsessive-Compulsive Scale—Self Report [Y-BOCS-SR]), eating disorder severity (the Eating Disorders Examination-Questionnaire), and depressive severity (the Beck Depression Inventory II [BDI-II]). Body mass index (BMI) was also measured. Paired-sample t-tests examined change on these measures.
Main Results
Between 2006 and 2011, 56 individuals completed all study measures at admission and discharge. Mean length of stay was 57 days (SD = 27). Most (89%) were on psychiatric medications. Significant decreases were observed in OCD severity, eating disorder severity, and depression. Those with bulimia nervosa showed more improvement than those with anorexia nervosa. BMI significantly increased, primarily among those underweight at admission.
Simultaneous treatment of OCD and eating disorders using a multimodal approach that emphasizes ERP techniques for both OCD and eating disorders can be an effective treatment strategy for these complex cases.
PMCID: PMC3947513  PMID: 23316878
anorexia nervosa; bulimia nervosa; cognitive-behavioral therapy; exposure therapy; OCD
21.  A Single Institution's Overweight Pediatric Population and Their Associated Comorbid Conditions 
ISRN Obesity  2014;2014:517694.
Background. Obesity studies are often performed on population data. We sought to examine the incidence of obesity and its associated comorbidities in a single freestanding children's hospital. Methods. We performed a retrospective analysis of all visits to Boston Children's Hospital from 2000 to 2012. This was conducted to determine the incidence of obesity, morbid obesity, and associated comorbidities. Each comorbidity was modeled independently. Incidence rate ratios were calculated, as well as odds ratios. Results. A retrospective review of 3,185,658 person-years in nonobese, 26,404 person-years in obese, and 25,819 person-years in the morbidly obese was conducted. Annual rates of all major comorbidities were increased in all patients, as well as in our obese and morbidly obese counterparts. Incidence rate ratios (IRR) and odds ratios (OR) were also significantly increased across all conditions for both our obese and morbidly obese patients. Conclusions. These data illustrate the substantial increases in obesity and associated comorbid conditions. Study limitations include (1) single institution data, (2) retrospective design, and (3) administrative undercoding. Future treatment options need to address these threats to longevity and quality of life.
PMCID: PMC3945184  PMID: 24693463
22.  Smartphone medication adherence apps: Potential benefits to patients and providers 
To provide an overview of medication adherence, discuss the potential for smartphone medication adherence applications (adherence apps) to improve medication nonadherence, evaluate features of adherence apps across operating systems (OSs), and identify future opportunities and barriers facing adherence apps.
Practice description
Medication nonadherence is a common, complex, and costly problem that contributes to poor treatment outcomes and consumes health care resources. Nonadherence is difficult to measure precisely, and interventions to mitigate it have been largely unsuccessful.
Practice innovation
Using smartphone adherence apps represents a novel approach to improving adherence. This readily available technology offers many features that can be designed to help patients and health care providers improve medication-taking behavior.
Main outcome measures
Currently available apps were identified from the three main smartphone OSs (Apple, Android, and Blackberry). In addition, desirable features for adherence apps were identified and ranked by perceived importance to user desirability using a three-point rating system: 1, modest; 2, moderate; or 3, high. The 10 highest-rated apps were installed and subjected to user testing to assess app attributes using a standard medication regimen.
160 adherence apps were identified and ranked. These apps were most prevalent for the Android OS. Adherence apps with advanced functionality were more prevalent on the Apple iPhone OS. Among all apps, MyMedSchedule, MyMeds, and RxmindMe rated the highest because of their basic medication reminder features coupled with their enhanced levels of functionality.
Despite being untested, medication apps represent a possible strategy that pharmacists can recommend to nonadherent patients and incorporate into their practice.
PMCID: PMC3919626  PMID: 23571625
Smartphones; nonadherence; applications
23.  Association of Microvascular and Capillary-Lymphatic Invasion with Outcome for Patients with Renal Cell Carcinoma 
The Journal of urology  2013;190(1):37-43.
We evaluated the association of microvascular invasion (MVI) and capillary-lymphatic invasion (CLI) with patient outcome following nephrectomy for renal cell carcinoma (RCC).
Material and Methods
We identified 1,433 patients surgically treated for sporadic, unilateral RCC between 2001 and 2008. All specimens were reviewed by a single uropathologist for MVI and CLI. Associations with time to metastases and death from RCC were evaluated using Cox proportional hazards models, controlling for established clinicopathologic prognostic variables.
MVI and CLI were identified in 11% (119/1,103) and 2% (17/1,103) with clear cell, 2% (5/219) and <1% (1/219) with papillary, and 1% (1/86) and 0 with chromophobe RCC, respectively. Median follow-up for patients still alive was 6.4 years (range 0-11). In clear cell RCC, MVI was univariately associated with an increased risk of metastases (HR 3.5,p<0.001) and cancer-specific death (HR 3.0,p<0.001). However, on multivariate analyses, these associations were no longer statistically significant (HR 1.2,p=0.4 and HR 1.3,p=0.1, respectively). CLI remained significantly associated with an increased risk of metastases and death both univariately (HR 15.9,p<0.001 and HR 11.6,p<0.001, respectively) and on multivariate analyses (HR 3.2,p<0.001 and HR 3.1,p<0.001, respectively).
MVI is associated with an increased risk of metastases and cancer death for patients with clear cell RCC, although this does not remain significant after controlling for established prognostic variables. Meanwhile, CLI appears to be independently associated with metastases and cancer death even after controlling for known prognostic risk factors; however, given its rarity, this feature may prove to be of limited clinical significance.
PMCID: PMC3918167  PMID: 23353044
Renal cell carcinoma; microvessels
24.  High-resolution single-molecule characterization of the enzymatic states in Escherichia coli F1-ATPase 
The rotary motor F1-ATPase from the thermophilic Bacillus PS3 (TF1) is one of the best-studied of all molecular machines. F1-ATPase is the part of the enzyme F1FO-ATP synthase that is responsible for generating most of the ATP in living cells. Single-molecule experiments have provided a detailed understanding of how ATP hydrolysis and synthesis are coupled to internal rotation within the motor. In this work, we present evidence that mesophilic F1-ATPase from Escherichia coli (EF1) is governed by the same mechanism as TF1 under laboratory conditions. Using optical microscopy to measure rotation of a variety of marker particles attached to the γ-subunit of single surface-bound EF1 molecules, we characterized the ATP-binding, catalytic and inhibited states of EF1. We also show that the ATP-binding and catalytic states are separated by 35±3°. At room temperature, chemical processes occur faster in EF1 than in TF1, and we present a methodology to compensate for artefacts that occur when the enzymatic rates are comparable to the experimental temporal resolution. Furthermore, we show that the molecule-to-molecule variation observed at high ATP concentration in our single-molecule assays can be accounted for by variation in the orientation of the rotating markers.
PMCID: PMC3538426  PMID: 23267177
F1-ATPase; single molecule; molecular motors
25.  Neurotrophin Therapy Improves Recovery of the Neuromuscular Continence Mechanism Following Simulated Birth Injury in Rats 
Neurourology and urodynamics  2012;32(1):82-87.
Stress Urinary Incontinence (SUI) affects women both acutely and chronically after vaginal delivery. Current SUI treatments assume the neuromuscular continence mechanism, comprised of the pudendal nerve (PN) and external urethral sphincter (EUS), is either intact or irreparable. This study investigated the ability of neurotrophin therapy to facilitate recovery of the neuromuscular continence mechanism.
Virgin, Sprague Dawley rats received simulated childbirth injury or sham injury and treatment with continuous infusion of brain derived neurotrophic factor (BDNF) or saline placebo to the site of PN injury. Continence was assessed by leak point pressure (LPP) and EUS electromyography (EMG) 14 and 21 days after injury. Structural recovery was assessed histologically. Molecular assessment of the muscular and neuroregenerative response was determined via measurement of EUS BDNF and PN βII-tubulin expression respectively, 4, 8, and 12 days after injury.
Following injury, LPP was significantly reduced with saline compared to either BDNF treatment or sham injury. Similarly, compared to sham injury, resting EUS EMG amplitude and firing rate, as well as amplitude during LPP were significantly reduced with saline but not BDNF treatment. Histology confirmed improved EUS recovery with BDNF treatment. EUS BDNF and PN βII-tubulin expression demonstrated that BDNF treatment improved the neurogenerative response and may facilitate sphincteric recovery.
Continuous targeted neurotrophin therapy accelerates continence recovery after simulated childbirth injury likely through stimulating neuroregeneration and facilitating EUS recovery and re-innervation. Neurotrophins or other therapies targeting neuromuscular regeneration may be useful for treating SUI related to failure of the neuromuscular continence mechanism.
PMCID: PMC3419785  PMID: 22581583
Urinary Incontinence; Stress; Vaginal Delivery; Childbirth Injury; Pudendal Nerve; Neurotrophin

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