Establishing Task-Relevant MVC Protocols for Modelling Sustained Isometric Force Variability: A Manual Control Study.

The present study examined how prevalent methods for determining maximal voluntary contraction (MVC) impact the experimentally derived functions of graded force-force variability. Thirty-two young healthy subjects performed continuous isometric force tracking (20 s trials) at 10 target percentages (5-95% MVC) normalized to a conventional discrete-point (n = 16), or sustained (n = 16) MVC calculation. Distinct rates and magnitudes of change were observed for absolute variability (standard deviation (SD), root mean squared error (RMSE)), tracking error (RMSE, constant error (CE)), and complexity (detrended fluctuation analysis (DFA)) (all p < 0.05) of graded force fluctuations between the MVC groups. Differential performance strategies were observed beyond ~65% MVC, with the discrete-point group minimizing their SD at force values below that of the criterion target (higher CE/RMSE). Moreover, the sustained group's capacity to minimize SD/RMSE/CE corresponded to a more complex structure in their force fluctuations. These findings reveal that the time component of MVC estimation has a direct influence on the corrective strategies supporting near-maximal manual force control. While discrete MVC protocols predominate in the study of manual strength/endurance/precision, a 1:1 MVC-task mapping appears more to be ecologically valid if visuo-motor precision outcomes are of central importance.

Patient Perpetrated Sexual Harassment of Urologists: A Survey Based Study.

INTRODUCTION: Patient perpetrated sexual harassment has been studied with family physicians, surgical residents and dermatologists with the prevalence ranging from 27% to 77%. To our knowledge this phenomenon has not yet been studied in urology. METHODS: We surveyed urologists in the United States about their age, employment/training status and their experiences of patient perpetrated sexual harassment. Surveys were anonymous and hosted on a web based platform. Pearson chi-square analysis was used to assess risk factors and descriptive statistics were used to describe prevalence. RESULTS: A total of 190 urologists completed the survey. Patient perpetrated sexual harassment was reported by 49.5% of respondents. Women were more likely to report patient perpetrated sexual harassment when compared with men, at 69% and 23%, respectively (p <0.0001). Being a resident/fellow portended higher rates of patient perpetrated sexual harassment compared to staff/attendings, at 69% and 44%, respectively (p=0.004). Respondents 40 years or younger were more likely to have reported patient perpetrated sexual harassment when compared to those 41 years old or older, at 65% and 39%, respectively (p=0.001). CONCLUSIONS: The results of this survey study suggest that the prevalence of patient perpetrated sexual harassment in the field of urology may be high. Professional societies should perform further investigation into this matter. We suggest proactive development of guidelines and protocols to address patient perpetrated sexual harassment in urology.

Cystoscopically Guided Repair of a Posterior Perforation of Augmented Bladder.

Background: Augmentation cystoplasty for the management of neurogenic bladder is one of the mainstays of pediatric urology. This procedure has multiple well-known complications. The most dangerous of these complications is bladder perforation, which has a mortality rate of 23% to 25% in large part caused by delayed presentation and sepsis. This case report discusses a novel method for identifying the perforation using endourologic techniques to allow for easier repair. Case Presentation: A 24-year-old woman with a history of spina bifida s/p augmentation cystoplasty with appendicovesicostomy and rectus fascia bladder neck sling 5 years ago presented to the emergency department with a 2-day history of decreased oral intake, nausea, vomiting, fevers, diffuse abdominal pain, and distention. She was found on CT cystogram to have a contrast extravasation from the posterior-dependent portion of the bladder and a large retrovesical fluid collection. On exploratory laparotomy, a leak from the posterior portion of the bladder was confirmed. Owing to the conditions in the abdomen and the patient's obese body habitus, the perforation was very difficult to view. A 17F rigid cystoscope was utilized and the perforation was identified on the posterior inferior portion of the bladder at the anastomotic line. A wire was passed through the perforation into the abdomen where it was seen and an 18F council catheter was then placed in an antegrade manner from the abdomen. Placement of the catheter and inflation of the balloon did not cause any additional apparent damage to the bladder mucosa. With the catheter on traction, the dependent bladder could be pulled back into the operative field, allowing complete observation of the defect for water-tight two-layer closure. Conclusion: Bladder perforation after augmentation cystoplasty is a potentially life-threatening complication that can be difficult to repair. This article serves to present a novel way to identify and facilitate repair of the defect intraoperatively using endourologic principles for a posterior defect.

Report of the International Stem Cell Banking Initiative Workshop Activity: Current Hurdles and Progress in Seed-Stock Banking of Human Pluripotent Stem Cells.

This article summarizes the recent activity of the International Stem Cell Banking Initiative (ISCBI) held at the California Institute for Regenerative Medicine (CIRM) in California (June 26, 2016) and the Korean National Institutes for Health in Korea (October 19-20, 2016). Through the workshops, ISCBI is endeavoring to support a new paradigm for human medicine using pluripotent stem cells (hPSC) for cell therapies. Priority considerations for ISCBI include ensuring the safety and efficacy of a final cell therapy product and quality assured source materials, such as stem cells and primary donor cells. To these ends, ISCBI aims to promote global harmonization on quality and safety control of stem cells for research and the development of starting materials for cell therapies, with regular workshops involving hPSC banking centers, biologists, and regulatory bodies. Here, we provide a brief overview of two such recent activities, with summaries of key issues raised. Stem Cells Translational Medicine 2017;6:1956-1962.

Physiological tremor (8-12Hz component) in isometric force control.

The experiment investigated the influence of physiological tremor (8-12Hz band) on the variability of isometric force control as a function of force level and hand dominance. Subjects were instructed to match a constant force level target line on a computer screen and minimize error in a uni-manual isometric finger abduction task at 5%, 25%, 45%, 65%, and 85% of their maximal voluntary contraction (MVC). The experimental protocol was performed independently with the left and right hands in separate blocks of performance. Tremor amplitude was enhanced at an increasing rate with increments of force level and was correlated with both performance outcome (Root mean square error - RMSE) and time-dependent regularity (Sample Entropy) of the force signal. No significant findings in force variability (dispersion or irregularity) were found between the dominant and non-dominant hands. Physiological tremor has a small but direct influence on the dispersion and time dependent structure of the variability of isometric force control but its relative influence on force amplitude decreases with increments of force level.

Injury Surveillance and Safety Considerations for Large-Format Lead-Acid Batteries Used in Mining Applications.

Large lead-acid batteries are predominantly used throughout the mining industry to power haulage, utility, and personnel-carrier vehicles. Without proper operation and maintenance, the use of these batteries can introduce mechanical and electrical hazards, particularly in the confined, and potentially dangerous, environment of an underground coal mine. A review of the Mine Safety and Health Administration accident/illness/injury database reveals that a significant number of injuries occur during the maintenance and repair of lead-acid batteries. These injuries include burns from electrical arcing and acid exposure, as well as strained muscles and crushed hands. The National Institute for Occupational Safety and Health investigated the design and implementation of these batteries to identify safety interventions that can mitigate these inherent hazards. This paper promotes practical design modifications, such as reducing the size and weight of battery assembly lids in conjunction with lift assists, as well as using five-pole cable connectors to improve safety.

Alzheimer disease research in the 21st century: past and current failures, new perspectives and funding priorities.

Much of Alzheimer disease (AD) research has been traditionally based on the use of animals, which have been extensively applied in an effort to both improve our understanding of the pathophysiological mechanisms of the disease and to test novel therapeutic approaches. However, decades of such research have not effectively translated into substantial therapeutic success for human patients. Here we critically discuss these issues in order to determine how existing human-based methods can be applied to study AD pathology and develop novel therapeutics. These methods, which include patient-derived cells, computational analysis and models, together with large-scale epidemiological studies represent novel and exciting tools to enhance and forward AD research. In particular, these methods are helping advance AD research by contributing multifactorial and multidimensional perspectives, especially considering the crucial role played by lifestyle risk factors in the determination of AD risk. In addition to research techniques, we also consider related pitfalls and flaws in the current research funding system. Conversely, we identify encouraging new trends in research and government policy. In light of these new research directions, we provide recommendations regarding prioritization of research funding. The goal of this document is to stimulate scientific and public discussion on the need to explore new avenues in AD research, considering outcome and ethics as core principles to reliably judge traditional research efforts and eventually undertake new research strategies.

TeamSTEPPS Improves Operating Room Efficiency and Patient Safety.

The objective was to evaluate the effect of TeamSTEPPS on operating room efficiency and patient safety. TeamSTEPPS consisted of briefings attended by all health care personnel assigned to the specific operating room to discuss issues unique to each case scheduled for that day. The operative times, on-time start rates, and turnover times of all cases performed by the urology service during the initial year with TeamSTEPPS were compared to the prior year. Patient safety issues identified during postoperative briefings were analyzed. The mean case time was 12.7 minutes less with TeamSTEPPS (P < .001). The on-time first-start rate improved by 21% with TeamSTEPPS (P < .001). The mean room turnover time did not change. Patient safety issues declined from an initial rate of 16% to 6% at midyear and remained stable (P < 0.001). TeamSTEPPS was associated with improved operating room efficiency and diminished patient safety issues in the operating room.

Dual Receptor-Targeted Theranostic Nanoparticles for Localized Delivery and Activation of Photodynamic Therapy Drug in Glioblastomas.

Targeting gold nanoparticles (AuNPs) with two or more receptor binding peptides has been proposed to address intratumoral heterogeneity of glioblastomas that overexpress multiple cell surface receptors to ultimately improve therapeutic efficacy. AuNPs conjugated with peptides against both the epidermal growth factor and transferrin receptors and loaded with the photosensitizer phthalocyanine 4 (Pc 4) have been designed and compared with monotargeted AuNPs for in vitro and in vivo studies. The (EGFpep+Tfpep)-AuNPs-Pc 4 with a particle size of ∼41 nm improved both specificity and worked synergistically to decrease time of maximal accumulation in human glioma cells that overexpressed two cell surface receptors as compared to cells that overexpressed only one. Enhanced cellular association and increased cytotoxicity were achieved. In vivo studies show notable accumulation of these agents in the brain tumor regions.

Transferrin receptor-targeted theranostic gold nanoparticles for photosensitizer delivery in brain tumors.

Therapeutic drug delivery across the blood-brain barrier (BBB) is not only inefficient, but also nonspecific to brain stroma. These are major limitations in the effective treatment of brain cancer. Transferrin peptide (Tfpep) targeted gold nanoparticles (Tfpep-Au NPs) loaded with the photodynamic pro-drug, Pc 4, have been designed and compared with untargeted Au NPs for delivery of the photosensitizer to brain cancer cell lines. In vitro studies of human glioma cancer lines (LN229 and U87) overexpressing the transferrin receptor (TfR) show a significant increase in cellular uptake for targeted conjugates as compared to untargeted particles. Pc 4 delivered from Tfpep-Au NPs clusters within vesicles after targeting with the Tfpep. Pc 4 continues to accumulate over a 4 hour period. Our work suggests that TfR-targeted Au NPs may have important therapeutic implications for delivering brain tumor therapies and/or providing a platform for noninvasive imaging.

Urological outcomes in the omphalocele exstrophy imperforate anus spinal defects (OEIS) complex: experience with 80 patients.

OBJECTIVE: To review the urological management and outcomes of patients with the OEIS (omphalocele, exstrophy of the bladder, imperforate anus, spinal abnormalities) complex. PATIENTS AND METHODS: 80 patients with the OEIS complex managed at a single institution between 1974 and 2009 were reviewed. RESULTS: 37 had initial closure at our institution (2 failed - 5%); 22 with successful closure were referred for incontinence; 15 failed closure at an outside institution (2 of whom are awaiting closure); 6 are skin-covered variants. Osteotomy was performed in 39/43 (91%) with successful closure versus 8/17 (47%) who failed initial bladder closure. 40 were dry (56%), but most needed additional urinary reconstruction: 2 had small bowel neobladders; 32 (84%) had augmentation cystoplasty; 30 (79%) had a continent catheterizable channel; only 9 (24%) were continent with an intact urethra. Bladder neck reconstruction allowed dryness in 7 (18%). 45 patients had XY genotype--19 had female gender assignment at birth. All patients with XX genotype had female gender assignment. CONCLUSIONS: Osteotomy improves success of initial bladder closure. A bladder neck procedure, catheterizable channel, and augmentation cystoplasty will be required in the majority of patients to attain urinary dryness.

Enhanced long-term depression and impaired reversal learning in phosphodiesterase 4B-knockout (PDE4B-/-) mice.

3'-5'-Cyclic adenosine monophosphate (cAMP) is known to be an important regulator of synaptic plasticity. The effects of cAMP are mediated through downstream effectors such as protein kinase A (PKA), Ca(2+) and cAMP-response element binding protein (CREB). The phosphodiesterase 4 (PDE4) family of enzymes, which is comprised of four genes and at least 25 protein isoforms, mediates the hydrolysis of cAMP, yet little is presently known about the contribution of specific PDE4 isoforms to synaptic plasticity and cognitive behavior. The purpose of the present studies was to determine the contribution of the PDE4B gene in mediating synaptic plasticity and cognitive behavior. Electrophysiological recordings from hippocampal slice preparations of mice deficient in the PDE4B gene (PDE4B(-/-)) showed that knockout animals displayed markedly enhanced basal postsynaptic responses to stimulation and long-term depression as compared to wild-type littermates. Interestingly, no genotypic differences were noted in long-term potentiation experiments following several different induction protocols. On the behavioral level PDE4B(-/-) mice displayed impaired reversal learning in the Morris water maze compared to wild-type littermates, but no differences in acquisition and retention of spatial memory and fear conditioning. Taken together, these results suggest that the PDE4B gene may play a role in synaptic activity and long-term depression and is involved in spatial reversal memory. Our findings support the view that various PDE4 isoforms are non-redundant and have distinct neurological roles.

Failed exstrophy closure.

Children with bladder exstrophy present a formidable surgical challenge. Like all major reconstructive surgeries, the best hope for a favorable outcome lies in achieving success in the first operative attempt. Regardless of the surgical approach, however, complications do occur. A failed exstrophy closure is a major complication with significant implications on the long-term surgical outcome and ultimate fate of the urinary tract. Successful repeat exstrophy closure can be accomplished in most cases when performed in conjunction with pelvic osteotomy and proper postoperative immobilization. Modern staged repair of exstrophy, complete primary repair of exstrophy, and immediate continent urinary diversion have been advocated by different groups in the management of a failed exstrophy closure. It is apparent that compared with children who undergo successful primary closure, a failed closure with subsequent successful repeat closure makes the child much less likely to achieve sufficient bladder growth to be considered for bladder neck reconstruction, and furthermore, makes them less likely to have a successful bladder neck reconstruction even when they are an acceptable candidate. Although acceptable dryness rates after repeat closure can ultimately be obtained, they are typically at the expense of a commitment to intermittent catheterization and continent diversion.

Epidemiologic insights into pediatric kidney stone disease.

The epidemiology of pediatric kidney stone has not yet been as rigorously defined as that of adult kidney stone disease. Herein, we review our recent epidemiologic works characterizing pediatric stone disease using the Kids' Inpatient Database (KID). Specifically we investigated the age and gender distribution of pediatric kidney stone disease, changes in disease prevalence over time, and medical comorbidities associated with this disorder. We identified patients by International Classification of Disease 9th Edition (ICD-9) codes for renal and ureteral calculi as the primary diagnosis. Medical comorbidities were identified using specific comorbidity software. Statistical comparisons between children with and without stone disease were performed. In the first decade of life, stone disease was more prevalent among males than females; however, in the second decade of life females were more commonly affected. Of note, there was a significant increase in treated stone disease across both genders between 1997 and 2003. We also found that the risk of kidney stone diagnosis in children younger than 6 years of age was significantly associated with hypertension and diabetes mellitus. The gender distribution among pediatric stone formers varies significantly by age, although overall females have a greater prevalence than males. There is also a strong association of stone disease and both diabetes and hypertension, although this was only observed in children less than 6 years of age. Taken all together, these findings suggest that urolithiasis in the young child is a complex systemic disease process.

Neuro-orthopedic manifestations of the omphalocele exstrophy imperforate anus spinal defects complex.

PURPOSE: The omphalocele-exstrophy-imperforate anus-spinal defects complex is a severe multisystem congenital defect. To comprehensively care for these patients one must appreciate the neurological and orthopedic impact on the overall health of the child. MATERIALS AND METHODS: We retrospectively reviewed the medical records of 73 children with omphalocele-exstrophy-imperforate anus-spinal defects who were treated at our institution, identifying neurological and orthopedic anomalies, ambulatory ability and voiding status. RESULTS: No neurological data were available on 5 patients. Of the remaining 68 patients 9 had no spinal anomaly, 57 had spina bifida, 1 had hemivertebrae and 1 had coccygeal hypoplasia. We further classified the 47 spina bifida cases as spina bifida occulta in 6, meningocele/lipomeningocele in 12, myelomeningocele/lipomyelomeningocele in 24 and sacral agenesis in 6. Of the patients with spina bifida 35 had cord tethering. Commonly identified orthopedic anomalies were vertebral malformation in 59 patients, scoliosis in 25, clubfoot in 14 and limb length discrepancy in 8. Ambulatory status in 62 patients of walking age revealed that 37 ambulated fully, 15 ambulated with devices, 2 ambulated minimally with devices and 8 were wheelchair bound. Continence data were available on 61 closed cases. Of these patients 26 were incontinent, including 3 with conduit diversion, 1 with ureterostomy and 1 with vesicostomy. A total of 35 patients were socially continent, of whom 30 catheterized via a continent abdominal stoma and 5 voided/catheterized via the urethra. CONCLUSIONS: Early evaluation for neurosurgical and orthopedic anomalies is vital in these children. Despite the high incidence of spinal pathology most patients ambulate without assistance. Few children with omphalocele-exstrophy-imperforate anus-spinal defects achieve continence via the urethra. Vigilant followup is necessary to identify potentially correctable conditions.

Crystal structures of IL-2-inducible T cell kinase complexed with inhibitors: insights into rational drug design and activity regulation.

IL-2-inducible T cell kinase plays an essential role in T cell receptor signaling and is considered a drug target for the treatment of Th2-mediated inflammatory diseases. By applying high-throughput protein engineering and crystallization, we have determined the X-ray crystal structures of IL-2-inducible T cell kinase in complex with its selective inhibitor BMS-509744 and the broad-spectrum kinase inhibitors sunitinib and RO5191614. Sunitinib uniquely stabilizes IL-2-inducible T cell kinase in the helix C-in conformation by inducing side chain conformational changes in the ATP-binding site. This preference of sunitinib to bind to an active kinase conformation is reflective of its broad-spectrum kinase activity. BMS-509744 uniquely stabilizes the activation loop in a substrate-blocking inactive conformation, indicating that structural changes described for Src family kinases are also involved in the regulation of IL-2-inducible T cell kinase activity. The observed BMS-509744 binding mode allows rationalization of structure-activity relationships reported for this inhibitor class and facilitates further structure-based drug design. Sequence-based analysis of this binding mode provides guidance for the rational design of inhibitor selectivity.

Failed exstrophy closure: management and outcome.

OBJECTIVE: In a series of failed exstrophy closures, to identify determinants of successful repeat closure and the impact of failed closure on the fate of the lower urinary tract and continence status. PATIENTS AND METHODS: We performed a retrospective review of operative notes and medical records of patients with a history of one or more failed exstrophy closures in 1978-2007. The primary surgical endpoints were failure rate of repeat closure attempts, mode of continence surgery and continence outcome. Continence was defined as achieving a dry interval of >3h and voiding through the urethra. RESULTS: We identified 122 patients (85 male/37 female) who had undergone repeat closure following failure. The success rate of repeat closure attempts at our institution was 98%. Of the 94 patients who had undergone successful repeat closure, definitive continence management and had their dryness evaluated, 38 were candidates for bladder neck reconstruction and 17(18%) were continent. Of the remaining patients, 90% were able to attain dryness, but at the expense of clean intermittent catheterization and continent urinary diversion. CONCLUSION: A failed exstrophy closure has significant implications for long-term surgical outcome. Reclosure can be accomplished in the majority of cases. In comparison to patients with successful primary closure, the rates of urethral continence following successful repeat closure were lower.

Oligodendroglial and pan-neural crest expression of Cre recombinase directed by Sox10 enhancer.

Utilizing a recently identified Sox10 distal enhancer directing Cre expression, we report S4F:Cre, a transgenic mouse line capable of inducing recombination in oligodendroglia and all examined neural crest derived tissues. Assayed using R26R:LacZ reporter mice expression was detected in neural crest derived tissues including the forming facial skeleton, dorsal root ganglia, sympathetic ganglia, enteric nervous system, aortae, and melanoblasts, consistent with Sox10 expression. LacZ reporter expression was also detected in non-neural crest derived tissues including the oligodendrocytes and the ventral neural tube. This line provides appreciable differences in Cre expression pattern from other transgenic mouse lines that mark neural crest populations, including additional populations defined by the expression of other SoxE proteins. The S4F:Cre transgenic line will thus serve as a powerful tool for lineage tracing, gene function characterization, and genome manipulation in these populations.

Modified Young-Dees-Leadbetter bladder neck reconstruction after exstrophy repair.

PURPOSE: We describe the application and results of modified Young-Dees-Leadbetter bladder neck reconstruction after successful complete primary repair in the newborn period. MATERIALS AND METHODS: The records of 34 patients referred for a continence procedure after successful exstrophy closure were extracted from an institutionally approved database. Patient characteristics and surgical outcomes were assessed. RESULTS: A total of 31 male and 3 female patients were identified, of whom 27 and 1, respectively, underwent osteotomy at initial closure. No patients attained urinary continence and so they were referred for a continence procedure. Nine patients did not have adequate bladder capacity for bladder neck repair (mean bladder capacity 63 ml, range 20 to 80). In those with suitable capacity mean capacity was 119 ml (range 85 to 180) and they underwent bladder neck reconstruction at a mean age of 4.9 years. Of the 25 patients who underwent bladder neck repair 14 (56%) were dry during the day and night, 5 (20%) were dry during the day but wet at night and 6 (24%) were totally incontinent. Pelvic osteotomies were performed at initial closure in 14 totally continent patients (100%) and in 4 (80%) with daytime continence but in no totally incontinent patients. All continent patients underwent hypospadias repair before age 1 year and none required ureteral reimplantation before bladder neck repair. CONCLUSIONS: A number of patients require bladder neck reconstruction to achieve continence after successful initial closure with complete primary repair. The modified Young-Dees-Leadbetter technique provides reasonable results with daytime and nighttime dryness attained by more than half of the patients.