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Genetic elements that are inherited at super-Mendelian frequencies could be used in a 'gene drive' to spread an allele to high prevalence in a population with the goal of eliminating invasive species or disease vectors. We recently demonstrated that the gene conversion mechanism underlying a CRISPR-Cas9-mediated gene drive is feasible in mice. Although substantial technical hurdles remain, overcoming these could lead to strategies that might decrease the spread of rodent-borne Lyme disease or eliminate invasive populations of mice and rats that devastate island ecology. Perhaps more immediately achievable at moderate gene conversion efficiency, applications in a laboratory setting could produce complex genotypes that reduce the time and cost in both dollars and animal lives compared with Mendelian inheritance strategies. Here, we discuss what we have learned from early efforts to achieve CRISPR-Cas9-mediated gene conversion, potential for broader applications in the laboratory, current limitations, and plans for optimizing this potentially powerful technology.

Hind limbs undergo dramatic changes in loading conditions during the transition from quadrupedal to bipedal locomotion. For example, the most early diverging bipedal jerboas (Rodentia: Dipodidae) are some of the smallest mammals in the world, with body masses that range between 2–4 g. The larger jerboa species exhibit developmental and evolutionary fusion of the central three metatarsals into a single cannon bone. We hypothesize that small body size and metatarsal fusion are mechanisms to maintain the safety factor of the hind limb bones despite the higher ground reaction forces associated with bipedal locomotion. Using finite-element analysis to model collisions between the substrate and the metatarsals, we found that body size reduction was insufficient to reduce bone stress on unfused metatarsals, based on the scaled dynamics of larger jerboas, and that fused bones developed lower stresses than unfused bones when all metatarsals are scaled to the same size and loading conditions. Based on these results, we conclude that fusion reinforces larger jerboa metatarsals against high ground reaction forces. Because smaller jerboas with unfused metatarsals develop higher peak stresses in response to loading conditions scaled from larger jerboas, we hypothesize that smaller jerboas use alternative dynamics of bipedal locomotion to reduce the impact of collisions between the foot and substrate.

In this review, we examine the current literature regarding the use of cranberry and other complimentary methods for the prevention of catheter-associated urinary tract infections (CAUTIs). Some studies have suggested cranberry products may have a positive effect in reducing the incidence of CAUTIs in patients with normal bladder function receiving short-term catheterization, while other studies have failed to show the benefits of cranberry products for the reduction of CAUTIs. While there is some data suggesting cranberry-derived products may reduce CAUTIs in specific patient populations, there is currently overall insufficient clinical data to recommend broad usage of cranberry products for the reduction of CAUTIs. Many of the studies reviewed have significant limitations in size, design, and lack standardization.

Summary Despite the great diversity of vertebrate limb proportion and our deep understanding of the genetic mechanisms that drive skeletal elongation, little is known about how individual bones reach different lengths in any species. Here, we directly compare the transcriptomes of homologous growth cartilages of the mouse (Mus musculus) and bipedal jerboa (Jaculus jaculus), the latter of which has “mouse-like” arms but extremely long metatarsals of the feet. Intersecting gene-expression differences in metatarsals and forearms of the two species revealed that about 10% of orthologous genes are associated with the disproportionately rapid elongation of neonatal jerboa feet. These include genes and enriched pathways not previously associated with endochondral elongation as well as those that might diversify skeletal proportion in addition to their known requirements for bone growth throughout the skeleton. We also identified transcription regulators that might act as “nodes” for sweeping differences in genome expression between species. Among these, Shox2, which is necessary for proximal limb elongation, has gained expression in jerboa metatarsals where it has not been detected in other vertebrates. We show that Shox2 is sufficient to increase mouse distal limb length, and a nearby putative cis-regulatory region is preferentially accessible in jerboa metatarsals. In addition to mechanisms that might directly promote growth, we found evidence that jerboa foot elongation may occur in part by de-repressing latent growth potential. The genes and pathways that we identified here provide a framework to understand the modular genetic control of skeletal growth and the remarkable malleability of vertebrate limb proportion.

Aims Recommendations for the management of women with suspected uncomplicated lower urinary tract infections (UTIs) include presumptive antibiotics with or without obtaining a urine culture (UCx). However, with increasing antibiotic resistance, efforts to decrease antibiotic usage are vital. Therefore, the objective of this study was to determine if the presumptive treatment of women with suspected uncomplicated UTIs is contributing to unnecessary antibiotic usage. Methods We retrospectively reviewed all nonpregnant female patients presenting to our student health services clinic with UTI symptoms from December 2016 to May 2017 who had UCx sent. Clinical information, symptoms, office urine dip, and UCx results were reviewed. Patients with positive and negative UCx were compared. Results A total of 67 patients were included for analysis. Presenting symptoms included dysuria (59/60, 98%), frequency (41/45, 91%), and urgency (27/27, 100%). Office urine dip was performed on 33 of 67 (49%) patients. Dips were positive for leukocytes (88%), blood (79%), and nitrites (18%). All patients in the study were prescribed antibiotics, most commonly nitrofurantoin (82%). Culture results were negative in 29 of 67 (43%). There were no significant differences in duration of symptoms, presenting symptoms, or urine dip results between patients with a negative UCx and those with a positive UCx. Conclusions In our study, we found a significant negative UCx rate in women with symptoms of uncomplicated UTI, representing a cohort of patients who were exposed to antibiotics unnecessarily. In addition, we found no difference in presenting symptoms or urine dip results to help distinguish patients with a positive UCx.

Objective:About one-third of patients with depression fail to achieve remission despite treatment with multiple antidepressants. This study compared the efficacy and safety of switching patients wi...

Objective To assess the application and perceived usefulness of the Accreditation Council for Graduation Medical Education Milestones system for resident evaluation among urology program directors (PDs). Materials and Methods We conducted an online survey of 133 urology PDs. The survey addressed several domains: (1) demographic information, (2) logistics and implementation of the faculty Clinical Competency Committee meetings, and (3) perceived overall effectiveness and usefulness of the Milestones assessments. Results Eighty-eight responses were obtained (66% response rate). A total of 42/88 programs (48%) described the Milestones as very or somewhat unhelpful in resident evaluation, with a comparable proportion (44%) responding Milestones assessments never or almost never accurately distinguished between residents. Respondents felt higher scores on all domains of the Milestones were completely or somewhat uncorrelated to higher in-service examination scores (58%), with a smaller fraction (49%) deeming they were not predictive of board passage rates. Overall, 30% of respondents answered neutrally as to whether they felt the Milestones format has led to better resident formative feedback, and 35% were neutral as to the implications of this system toward promoting professional development. Conclusion The Accreditation Council for Graduation Medical Education Milestones system for resident evaluation was initiated to create a uniform competency-based assessment system; however, a sizable proportion of urology PDs in our cohort did not find the Milestones system helpful or accurate in assessing residents or predicting future successes. Given the Milestones system is still in its infancy, the utility of this system within urology has yet to be fully assessed.

Highly efficient genotype conversion systems have potential to facilitate the study of complex genetic traits using laboratory mice and to limit loss of biodiversity and disease transmission caused by wild rodent populations. We previously showed that such a system of genotype conversion from heterozygous to homozygous after a sequence targeted CRISPR/Cas9 double strand DNA break is feasible in the female mouse germline. In the male germline, however, all double strand breaks were instead repaired by end joining mechanisms to form an ‘insertion/deletion’ (indel) mutation. These observations suggested that timing Cas9 expression to coincide with meiosis I is critical to favor conditions when homologous chromosomes are aligned and interchromosomal homology directed repair (HDR) mechanisms predominate. Here, using a Cas9 knock-in allele at the Spo11 locus, we show that meiotic expression of Cas9 does indeed mediate genotype conversion in the male as well as in the female germline. However, the low frequency of both HDR and indel mutation in both male and female germlines suggests that Cas9 may be expressed from the Spo11 locus at levels too low for efficient double strand DNA break formation. We suggest that more robust Cas9 expression initiated during early meiosis I may improve the efficiency of genotype conversion and further increase the rate of ‘super-Mendelian’ inheritance from both male and female mice.

Naturalists leading up to the early 20(th) century were captivated by the diversity of limb form and function and described its development in a variety of species. The advent of discoveries in genetics followed by molecular biology led to focused efforts in few ‘model’ species, namely mouse and chicken, to understand conserved mechanisms of limb axis specification and development of the musculoskeletal system. ‘Non-traditional’ species largely fell by the wayside until their recent resurgence into the spotlight with advances in next-generation sequencing technologies (NGS). In this review, we focus on how the use of NGS has provided insights into the development, loss, and diversification of amniote limbs. Coupled with advances in chromatin interrogation techniques and functional tests in vivo, NGS is opening possibilities to understand the genetic mechanisms that govern the remarkable radiation of vertebrate limb form and function.

The development and evolution of multicellular body plans is complex. Many distinct organs and body parts must be reproduced at each generation, and those that are traceable over long time scales are considered homologous. Among the most pressing and least understood phenomena in evolutionary biology is the mode by which new homologs, or "novelties" are introduced to the body plan and whether the developmental changes associated with such evolution deserve special treatment. In this chapter, we address the concepts of homology and evolutionary novelty through the lens of development. We present a series of case studies, within insects and vertebrates, from which we propose a developmental model of multicellular organ identity. With this model in hand, we make predictions regarding the developmental evolution of body plans and highlight the need for more integrative analysis of developing systems.

The development and evolution of multicellular body plans is complex. Many distinct organs and body parts must be reproduced at each generation, and those that are traceable over long time scales are considered homologous. Among the most pressing and least understood phenomena in evolutionary biology is the mode by which new homologs, or "novelties" are introduced to the body plan and whether the developmental changes associated with such evolution deserve special treatment. In this chapter, we address the concepts of homology and evolutionary novelty through the lens of development. We present a series of case studies, within insects and vertebrates, from which we propose a developmental model of multicellular organ identity. With this model in hand, we make predictions regarding the developmental evolution of body plans and highlight the need for more integrative analysis of developing systems.

Haematopoietic stem and progenitor cells (HSPCs) have been the focus of developmental and regenerative studies, yet our understanding of the signalling events regulating their specification remains incomplete. We demonstrate that supt16h, a component of the Facilitates chromatin transcription (FACT) complex, is required for HSPC formation. Zebrafish supt16h mutants express reduced levels of Notch-signalling components, genes essential for HSPC development, due to abrogated transcription. Whereas global chromatin accessibility in supt16h mutants is not substantially altered, we observe a specific increase in p53 accessibility, causing an accumulation of p53. We further demonstrate that p53 influences expression of the Polycomb-group protein PHC1, which functions as a transcriptional repressor of Notch genes. Suppression of phc1 or its upstream regulator, p53, rescues the loss of both Notch and HSPC phenotypes in supt16h mutants. Our results highlight a relationship between supt16h, p53 and phc1 to specify HSPCs via modulation of Notch signalling.

Gene drive organisms (GDOs), whose genomes have been genetically engineered to spread a desired allele through a population, have the potential to transform the way societies address a wide range of daunting public health and environmental challenges. The development, testing, and release of GDOs, however, are complex and often controversial. A key challenge is to clarify the appropriate roles of developers and others actively engaged in work with GDOs in decision-making processes, and, in particular, how to establish partnerships with relevant authorities and other stakeholders. Several members of the gene drive community previously proposed safeguards for laboratory experiments with GDOs (1) that, in the absence of national or international guidelines, were considered essential for responsible laboratory work to proceed. Now, with GDO development advancing in laboratories (2–5), we envision similar safeguards for the potential next step: ecologically and/or genetically confined field trials to further assess the performance of GDOs. A GDO's propensity to spread necessitates well-developed criteria for field trials to assess its potential impacts (6). We, as a multidisciplinary group of GDO developers, ecologists, conservation biologists, and experts in social science, ethics, and policy, outline commitments below that we deem critical for responsible conduct of a field trial and to ensure that these technologies, if they are introduced, serve the public interest.

INTRODUCTION AND OBJECTIVE:Burnout is a common problem confronting physicians in the workforce today. Prior studies have demonstrated a high prevalence of burnout among both practicing urologists a...

INTRODUCTION AND OBJECTIVE:The current AUA guidelines for asymptomatic microhematuria (AMH) recommends in patients with negative initial workup, annual urinalyses (UAs) should be obtained and repea...

OBJECTIVE To assess the differences between the male and female urology resident applicant pool. Urology is a competitive field with a selective match process. Women have historically been a minority in medicine. Although this has equalized, women continue to be underrepresented in urology. MATERIALS AND METHODS All application submitted through the Electronic Residency Application Service to the Columbia University Department of Urology for the 2015 and 2016 match were reviewed. The differences between the cohorts of matched female and male urology applicants were assessed. RESULTS Two hundred fifty-six students in 2015 and 259 students in 2016 submitted applications to Columbia and completed rank lists (60% of the national cohort in 2015 and 62% in 2016). We did find that the overall male applicant pool had a slightly lower number of honors (3 vs 2, P = .02) and higher United States Medical Licensing Examination (USMLE) step 1 score (238 vs 234, P

Objective To compare postoperative infectious outcomes of bladder biopsies performed in the office without antibiotic prophylaxis vs those done with preoperative antibiotic prophylaxis in the operating room (OR). Materials and Methods Our institutional review board-approved database was retrospectively reviewed for patients who underwent bladder biopsy in the office or in the OR between July 2014 and August 2015. All patients with bladder biopsies performed in the OR and none in the office received preoperative antibiotic prophylaxis. Patient characteristics and post-procedural outcomes including bacteriuria, urinary tract infection (UTI), and febrile UTI were recorded. The rates of these outcomes were compared between the 2 groups using the chi-square test. Patients were excluded from analysis if they experienced a UTI or were prescribed antibiotics within 30 days before their procedure. Results In all, 216 biopsies were identified (106 in the office and 110 in the OR). No difference was noted in the rate of UTI (0.94% vs 0.91%, P = .98), or febrile UTI (0% vs 0.91%, P = .33) between those undergoing bladder biopsy in the office and those in the OR. There was no difference in the incidence of new urinary symptoms (2.8% vs 5.5%, P = .33) or post-procedural bacteriuria (3.8% vs 3.6%, P = .96). Conclusion Since the introduction of the mandated use of antibiotics for routine procedures such as bladder biopsy, antibiotic use has markedly increased. Our data suggest that the preoperative antibiotic prophylaxis that is recommended may not confer benefit to select patients. At a time when antibiotic stewardship is of utmost importance, guidelines regarding its use should be reconsidered.

Objective To report the prevalence of research misrepresentation among urology residency applicants and assess its effect on match success. Materials and Methods All applications to the Columbia University urology residency program for the 2014-2015 match cycle were reviewed. “In-press,” “accepted,” and “submitted” manuscripts were verified using PubMed, Google Scholar, and journal websites. Misrepresentation for “in-press” and “accepted” manuscripts was defined as: (1) nonexistent manuscript, (2) nonauthorship of existent manuscript, (3) self-promotion to a higher author rank, and/or (4) existent manuscript in a nonpeer-reviewed publication. Logistic regression was performed to identify associated factors of misrepresentation and of match success. Results Of 257 applicants, 204 (79.4%) reported 1098 total manuscripts and 142 (55.3%) reported 371 unpublished manuscripts. About 5% (13 of 257) of applicants misrepresented 1 or more publications: 10 listed nonexistent manuscripts, 1 listed a publication for which he/she was listed a lower author rank than reported, 1 listed an accepted manuscript in a nonpeer-reviewed publication and for which he/she was not listed as an author, and 1 listed 4 in-press manuscripts in a nonpeer-reviewed publication. Only 55.8% (139 of 249) of “submitted” manuscripts were published within 12 months, with 41% (51 of 139) published in a journal of a lower impact factor than the reported journal of submission. Higher number of unpublished manuscripts was associated with misrepresentation. Higher Step 1 score, number of away sub-internships, and publication ratio were associated with match success. Conclusion Research misrepresentation is a persistent issue in urology residency applications. However, misrepresentation in this cohort did not confer a significant advantage in match success.

Objective:To assess health-related quality of life (HRQoL) and health status of patients with treatment resistant depression (TRD), treated with esketamine nasal spray+oral antidepressant (ESK+AD) vs oral antidepressant+placebo nasal spray (AD+PBO) using European Quality of Life Group-5-Dimension-5-Level (EQ-5D-5L). The EQ-5D-5L descriptive system consists of five domains relevant for patients with depression (mobility, self-care, usual activities, pain, anxiety/depression) and the EQ-Visual Analogue Scale (EQ-VAS).Methods:Data from TRANSFORM-2 (NCT02418585), a randomized, double-blind short-term study were analyzed. Patients (18-64 years inclusive) with TRD were included. Patient reported health status change using EQ-5D-5L and EQ-VAS was measured from baseline to end of 4-week induction phase (endpoint). Each domain of EQ-5D-5L included 5 levels of perceived problems (L1: no problems; L5: extreme problems).Results:Full analysis set included 223 patients (ESK+AD: 114; AD+PBO: 109). At endpoint, mean (SD) change in health status index was 0.288 (0.2317) for ESK+AD group and 0.231 (0.2506) for AD+PBO group with higher score reflecting higher levels of functioning. At endpoint, percentage of patients reporting problems (grouped L2-L5 responses for each dimension) in ESK+AD vs AD+PBO group: mobility (13.5% vs 25.7%), self-care (16.2% vs 30.5%), usual activities (55.0% vs 71.4%), pain (38.7% vs 52.4%), and anxiety/depression (71.2% vs 78.1%). Mean (SD) change in EQ-VAS score at endpoint was 29.1 (26.32) for ESK+AD and 20.9 (26.60) for AD+PBO group.Conclusion:Greater improvement in HRQoL and health status using EQ-5D-5L and EQ-VAS was observed among patients with TRD treated with ESK+AD vs AD+PBO.Funding Acknowledgements:This study was sponsored by Janssen Research and Development, LLC.

Significance Multiple myeloma (MM) and triple-negative breast cancer (TNBC) are dependent on 26S proteasome for malignancy. We have previously shown that the proteasome-regulating kinase DYRK2 is a viable target for both MM and TNBC. Here we identified a specific DYRK2 inhibitor, LDN192960, which alleviates both MM and TNBC progression via mechanisms including partial inhibition of proteasome activity. At this time we report a single drug target for 2 diverse cancers and highlight the importance of identifying proteasome regulators., Dependence on the 26S proteasome is an Achilles’ heel for triple-negative breast cancer (TNBC) and multiple myeloma (MM). The therapeutic proteasome inhibitor, bortezomib, successfully targets MM but often leads to drug-resistant disease relapse and fails in breast cancer. Here we show that a 26S proteasome-regulating kinase, DYRK2, is a therapeutic target for both MM and TNBC. Genome editing or small-molecule mediated inhibition of DYRK2 significantly reduces 26S proteasome activity, bypasses bortezomib resistance, and dramatically delays in vivo tumor growth in MM and TNBC thereby promoting survival. We further characterized the ability of LDN192960, a potent and selective DYRK2-inhibitor, to alleviate tumor burden in vivo. The drug docks into the active site of DYRK2 and partially inhibits all 3 core peptidase activities of the proteasome. Our results suggest that targeting 26S proteasome regulators will pave the way for therapeutic strategies in MM and TNBC.

Many species that run or leap across sparsely vegetated habitats, including horses and deer, evolved the severe reduction or complete loss of foot muscles as skeletal elements elongated and digits were lost, and yet the developmental mechanisms remain unknown. Here, we report the natural loss of foot muscles in the bipedal jerboa, Jaculus jaculus. Although adults have no muscles in their feet, newborn animals have muscles that rapidly disappear soon after birth. We were surprised to find no evidence of apoptotic or necrotic cell death during stages of peak myofiber loss, countering well-supported assumptions of developmental tissue remodeling. We instead see hallmarks of muscle atrophy, including an ordered disassembly of the sarcomere associated with upregulation of the E3 ubiquitin ligases, MuRF1 and Atrogin-1. We propose that the natural loss of muscle, which remodeled foot anatomy during evolution and development, involves cellular mechanisms that are typically associated with disease or injury., eLife digest Intrinsic muscles are a group of muscles deep inside the hands and feet. They help to control the precise movements required, for example, for a pianist to play their instrument or for certain animals to climb with remarkable agility. Some animals, such as horses and deer, have evolved in such a way that they no longer grasp objects with hands and feet. Where intrinsic muscles were once present in the hands and feet of their ancestors, these animals now have strong ligaments that prevent over-extension of the wrist and ankle joints during hard landings. Given their size, it is difficult to study horses and deer in the laboratory and understand how they lost their intrinsic muscles during evolution. Tran et al. therefore focused on a small rodent called the lesser Egyptian jerboa, which also displays long legs with strong ligaments and no intrinsic muscles. Newborn jerboas have foot muscles that look very much like the intrinsic muscles found in mice, but these muscles disappear within 4 days of birth. A mechanism called programmed cell death is often responsible for specific tissues disappearing during development, but the experiments of Tran et al. revealed that this was not the case in jerboas. Instead, their intrinsic muscles were degraded by processes triggered by genes that disassemble underused muscles. In mice and humans, fasting, nerve injuries, or immobility trigger this type of muscle degradation, but in jerboas these processes appear to be a normal part of development. This unexpected discovery shows that development and disease-like processes are linked, and that more studies of nontraditional research animals may help scientists better understand these connections.

The extraordinary malleability of the vertebrate limb supports a variety of locomotor functions including running and leaping in cursorial and saltatorial species. In many of these animals, the metatarsals and/or metacarpals are disproportionately elongated to increase stride length and fused into a single larger element, likely to resist fracture due to increased ground reaction forces. Despite the fact that metapodial fusion evolved convergently in modern birds, ungulates, and jerboas, the developmental basis has only been explored in chickens, which diverged from the mammalian lineage approximately 300 million years ago. Here, we use the lesser Egyptian jerboa, Jaculus jaculus, to understand the cellular processes that unite three distinct metatarsal elements into a single cannon bone in a mammal, and we revisit the developing chicken to assess similarities and differences in the localization of osteoblast and osteoclast activities. In both species, adjacent metatarsals align along flat surfaces, osteoblasts cross the periosteal membrane to unite the three elements in a single circumference, and osteoclasts resorb bone at the interfaces leaving a single marrow cavity. However, although spatial and temporal partitioning of osteoblast and osteoclast activities reshape three bones into one in both species, the localization of osteoclasts is distinct. While osteoclasts are uniformly distributed throughout the endosteum of chicken metatarsals, these catabolic cells are highly localized to resorb bone at the interfaces of neighboring jerboa metatarsals. Each species therefore provides an opportunity to better understand the mechanisms that partition osteoblasts and osteoclasts to alter the shape of bone during development and evolution.

The variety of limb skeletal proportions enables a remarkable diversity of behaviors that include powered flight in bats and flipper-propelled swimming in whales using extremes of a range of homologous limb architectures. Even within human limbs, bone lengths span more than an order of magnitude from the short finger and toe bones to the long arm and leg bones. Yet all of this diversity arises from embryonic skeletal elements that are each a very similar size at formation. In this review article, I survey what is and is not yet known of the development and evolution of skeletal proportion at multiple hierarchical levels of biological organization. These include the cellular parameters of skeletal elongation in the cartilage growth plate, genes associated with differential growth, and putative gene regulatory mechanisms that would allow both covariant and independent evolution of the forelimbs and hindlimbs and of individual limb segments. Although the genetic mechanisms that shape skeletal proportion are still largely unknown, and most of what is known is limited to mammals, it is becoming increasingly apparent that the diversity of bone lengths is an emergent property of a complex system that controls elongation of individual skeletal elements using a genetic toolkit shared by all.

INTRODUCTION AND OBJECTIVES:No-show appointments weigh heavily, leading to under-utilized resources and decreased productivity for urologists. There is concern that increased lag-time (time between...

Growth plates are narrow discs of cartilage, ultimately required for longitudinal growth of all mammals including humans. However, originally the growth plate and articular cartilage were a single anatomical entity, an epiphyseal cartilage, as appeared in early tetrapods and in mammalian development. The reason, why the growth plates evolved as spatially separate organs, remains unknown. Here, we demonstrate that the epiphyseal growth plate first appeared as an individual organ in amniotes due to the formation of a novel bony structure, the secondary ossification center (SOC), which spatially separates articular cartilage and the growth plate. Since amniotes translocate their entire growth period on land, we next explored the role of mechanical demands faced by bones growing under weight-bearing conditions. Comparison of mammals whose limbs are subjected to greater or lesser mechanical demands (i.e., Chiropterans (bats), Cetaceans (whales) and Dipodidae (jerboa)) revealed that the presence of an SOC is correlated to the extent of these demands. Mathematical modelling in combination with physical and biological experiments showed that the SOC reduces shear and normal stresses within the growth plate, allowing epiphyseal chondrocytes to withstand a six-fold higher load before undergoing caspase-dependent apoptosis via the YAP-p73 pathway. Furthermore, the hypertrophic chondrocytes, the cells primarily responsible for bone elongation were least mechanically stiff and most sensitive to weight bearing. Our results demonstrate that evolution of the epiphyseal cartilage into a separate organ allows epiphyseal chondrocytes to withstand the high mechanical stress placed on them by the terrestrial environment.

Introduction Match outcome studies allow applicants and counselors to adequately prepare and make informed decisions. We sought to characterize predictors of success in URMP (Urology Residency Match Program) using standard application data. Methods All residency applications received at our department for the 2015 URMP, representing 56% of the national applicant pool, were prospectively entered in an applicant database. Data pertaining to applicant demographics and academic achievement were collected. Nationally published medical school and urology residency rankings were abstracted into tiers. The primary outcome was successful matching into urology and the secondary outcome was quality of the matched residency by ranking. Logistic and linear univariate and multiple regression modeling was performed to detect associations among all independent and outcome variables. Results The final analysis included 244 applicants, of whom 191 (78.3%) successfully matched. On multivariable analysis significant positive predictors included the number of honors grades (p = 0.047, OR 1.4), away subinternships (p = 0.013, OR 1.8) and USMLE (United States Medical Licensing Examination) Step 1 score (median 245 vs 232, p = 0.024). Negative predictors included noncurrent medical school senior status (p = 0.044, OR 0.24) and lower ranked medical school tier (p = 0.003, OR 0.78). Medical school tier (p Conclusions Based on an institutional sample of the national applicant cohort we identified multiple independent predictors of URMP outcome. This may be useful for applicant counseling in preparation for the match process, although findings may not be applicable to all candidates.

Aims Due to a paucity of evidence-based guidelines, anecdotal practice patterns often dictate clinical management of recurrent urinary tract infection (UTI) in women. Our aim was to identify pathologic findings of the urinary tract through cystoscopy and imaging in women with recurrent UTI, and to determine if specific risk factors are associated with a higher rate of abnormal findings. Methods In a single-institutional cohort, cystoscopy was performed for women with recurrent UTI between 1/2010 and 7/2014. All eligible patients were included in a maintained database and those with gross or microscopic hematuria were excluded. Abdominopelvic imaging was recommended and included in study data when completed. Associations between clinical risk factors (history of renal transplant, urogynecologic surgery, or urolithiasis) and abnormal findings were analyzed by Fisher's exact test. Results A total of 163 women (mean age 60.6 years) were included in final analysis. Abdominopelvic imaging was available in 133 (82%) cases. Cystoscopy identified 9 (5.5%) cases of significant clinical findings. Of these only 5 (3.8%) cases were uniquely identified on cystoscopy and missed on imaging modalities. When imaging was normal, cystoscopy was also normal in 94% of cases. The examined clinical risk factors were not associated with higher risk of abnormal cystoscopy (P = 0.49) or imaging (P = 0.42). Conclusions Cystoscopy performed solely for recurrent UTI is low yield in patients with normal imaging studies, but a small number of abnormal findings may be missed by foregoing this element of the patient workup. No studied risk factor was predictive of an abnormal workup. Neurourol. Urodynam. 36:692–696, 2017. © 2016 Wiley Periodicals, Inc.

Urinary tract infections (UTIs) in women represent one of the most common disease entities in both the ambulatory and hospital setting. Nearly 60 % of all women will experience at least one UTI in their lifetime leading to billions of dollars of healthcare spending. There are several important factors on both a pathogen and host level that support bacterial colonization with ultimate progression to infection in otherwise healthy patients. In an era of increasing healthcare costs and limited face-to-face evaluation time, establishing the correct diagnosis can prove challenging and leads to misguided and sometimes excessive treatment. Ultimately, a stronger focus on preventative strategies may help to reduce the impact of uncomplicated UTIs on women.

A gene drive biases the transmission of one of two copies of a gene such that it is inherited more frequently than by random segregation. Highly efficient gene drive systems were recently developed in insects, which leverage the sequence-targeted DNA cleavage activity of CRISPR/Cas9 and endogenous homology directed repair mechanisms to convert heterozygous genotypes to homozygosity1–4. If implemented in laboratory rodents, similar systems would enable the rapid assembly of currently impractical genotypes that involve multiple homozygous genes (e.g., to model multigenic human diseases). However, such a system has not yet been demonstrated in mammals. Here, we utilize an “active genetic” element that encodes a guide RNA embedded in the mouse Tyrosinase gene to evaluate whether targeted gene conversion can occur when CRISPR/Cas9 is active in the early embryo or in the developing germline. Although Cas9 efficiently induces double strand DNA breaks in the early embryo and male germline, these breaks are not resolved by homology directed repair. However, Cas9 expression limited to the female germline forms double strand breaks that are resolved by homology directed repair, which copies the active genetic element from the donor to the receiver chromosome and increases its rate of inheritance in the next generation. These results demonstrate feasibility of CRISPR/Cas9-mediated systems that bias inheritance in mice, which have potential to transform the use of rodent models in basic and biomedical research.

Objective To investigate the rate of bladder cancer in patients undergoing cystoscopic evaluation for asymptomatic microscopic hematuria (AMH) in order to identify groups at sufficiently low-risk for bladder cancer in whom invasive testing may be avoided. Methods We performed a retrospective review of patients who underwent cystoscopic evaluation for AMH between 2010 and 2018. Age, gender, smoking status, history of pelvic radiation, and number of red blood cells per high-power field on urine microscopy were recorded. We used logistic regression to explore the association between specific risk factors and a diagnosis of bladder cancer on cystoscopy. Results Among the 2118 patients who underwent cystoscopy for AMH, 25 patients (1.2%) were diagnosed with a bladder cancer, all of which were nonmuscle invasive urothelial carcinoma. There were no bladder cancers detected in patients under the age of 50. Older age and positive smoking history were significantly associated with bladder cancer. Conclusion Bladder cancer was an uncommon finding on cystoscopy among patients being evaluated for AMH, especially in younger patients. We confirmed several known risk factors for bladder cancer, including older age and smoking history. Further studies are required to evaluate the utility of cystoscopy for identifying latent bladder cancers in low-risk patients.

Evidence-based screening and treatment for bacteriuria is crucial to prevent increasing antibiotic resistance. The Infectious Disease Society of America (IDSA) previously released guidelines on the management of asymptomatic bacteriuria (ASB) and uncomplicated urinary tract infections (UTIs) in women. The study's objective was to assess physicians' practices in managing women with bacteriuria relative to these guideline recommendations.Cross-sectional data from physicians were collected using an anonymous questionnaire. Multivariable logistic regression analyses identified independent predictors of adherence to guidelines.Data were collected from 260 physicians. Over half of physicians surveyed were unfamiliar with IDSA guidelines and overtreat ASB. Variables independently associated with overtreatment of ASB included a non-academic practice and practicing as an OBGYN. Nearly one third (30.1%) of physicians reported prescribing an antibiotic other than a recommended first-line agent for uncomplicated cystitis. Relative to internists, OBGYNs and urologists were more likely to prescribe a recommended first-line agent to women with uncomplicated cystitis. Of those who correctly selected a first-line agent, 29.8% prescribed a longer than recommended duration of therapy. IDSA guideline awareness was not associated with physicians' practices in managing women with bacteriuria.Most physicians surveyed were unfamiliar with guidelines related to managing ASB and uncomplicated UTIs in women, likely contributing to overscreening and overtreatment of ASB and the use of inappropriate antibiotic regimens in treating uncomplicated cystitis. However, optimal antibiotic prescribing was not associated with knowledge of IDSA guidelines, suggesting that guideline dissemination alone may not alter practice patterns among physicians managing women with bacteriuria.

A gene drive biases the transmission of a particular allele of a gene such that it is inherited at a greater frequency than by random assortment. Recently, a highly efficient gene drive was developed in insects, which leverages the sequence-targeted DNA cleavage activity of CRISPR/Cas9 and endogenous homology directed repair mechanisms to convert heterozygous genotypes to homozygosity. If implemented in laboratory rodents, this powerful system would enable the rapid assembly of genotypes that involve multiple genes (e.g., to model multigenic human diseases). Such complex genetic models are currently precluded by time, cost, and a requirement for a large number of animals to obtain a few individuals of the desired genotype. However, the efficiency of a CRISPR/Cas9 gene drive system in mammals has not yet been determined. Here, we utilize an active genetic “CopyCat” element embedded in the mouse Tyrosinase gene to detect genotype conversions after Cas9 activity in the embryo and in the germline. Although Cas9 efficiently induces double strand DNA breaks in the early embryo and is therefore highly mutagenic, these breaks are not resolved by homology directed repair. However, when Cas9 expression is limited to the developing female germline, resulting double strand breaks are resolved by homology directed repair that copies the CopyCat allele from the donor to the receiver chromosome and leads to its super-Mendelian inheritance. These results demonstrate that the CRISPR/Cas9 gene drive mechanism can be implemented to simplify complex genetic crosses in laboratory mice and also contribute valuable data to the ongoing debate about applications to combat invasive rodent populations in island communities.

A gene drive biases the transmission of one of the two copies of a gene such that it is inherited more frequently than by random segregation. Highly efficient gene drive systems have recently been developed in insects, which leverage the sequence-targeted DNA cleavage activity of CRISPR-Cas9 and endogenous homology-directed repair mechanisms to convert heterozygous genotypes to homozygosity

Objective To assess the incidence of violations to the National Resident Matching Program Code of Conduct during the Urology Match. Materials and Methods We sent a survey to all 285 applicants to a single urologic program during 2017 Match cycle; the questions pertained to illegal interview questions, postinterview communication, second-look qualifications, and the applicant's perceived impact of these factors. Results At total of 166 responses were obtained (response rate 58%). Ninety-six (58%) applicants received follow-up communication from at least 1 program, the majority from multiple programs. Of those who received postinterview communication, 13% reported verbal communication, and 19% felt misled by communication to believe they had a higher chance of matching at a program. Fifty (30%) respondents did a second-look visit, and 44% reported feeling obligated to do so in order to match. Finally, 141 of 166 (85%) applicants reported being asked illegal questions regarding personal life, rank list, and/or other interviews. Female applicants reported being asked illegal questions significantly more frequently than male applicants (P Conclusion During the 2017 Urology Match, a high proportion of applicants experienced violations of the National Resident Matching Program Code of Conduct. Violations included illegal questions, postinterview written and verbal communication, and pressure to do second-look visits. These findings corroborate numerous anecdotal reports, and may provide the groundwork to improve the fairness of the residency application process for the future.

Urinary tract infections are among the most common infections seen in both the ambulatory inpatient and nursing facility settings. Due to unique characteristics of the geriatric population, including physiology, comorbidities, and social history, incidences of these infections increase with age requiring special attention. Here, we provide an overview of the etiology, diagnosis, treatment, and prevention of urinary tract infections with focus on the geriatric patient.

The statistician George E. P. Box stated, 'Essentially all models are wrong, but some are useful.' (Box GEP, Draper NR: Empirical Model-Building and Response Surfaces. Wiley; 1987). Modeling biological processes is challenging for many of the reasons classically trained developmental biologists often resist the idea that black and white equations can explain the grayscale subtleties of living things. Although a simplified mathematical model of development will undoubtedly fall short of precision, a good model is exceedingly useful if it raises at least as many testable questions as it answers. Self-organizing Turing models that simulate the pattern of digits in the hand replicate events that have not yet been explained by classical approaches. The union of theory and experimentation has recently identified and validated the minimal components of a Turing network for digit pattern and triggered a cascade of questions that will undoubtedly be well-served by the continued merging of disciplines.