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Fibroblast growth factors (Fgfs) have long been implicated in processes critical to embryonic development, such as cell survival, migration, and differentiation. Several mouse models of organ development ascribe a prosurvival requirement specifically to FGF8. Here, we explore the potential role of prosurvival FGF8 signaling in kidney development. We have previously demonstrated that conditional deletion of Fgf8 in the mesodermal progenitors that give rise to the kidney leads to renal aplasia in the mutant neonate. Deleterious consequences caused by loss of FGF8 begin to manifest by E14.5 when massive aberrant cell death occurs in the cortical nephrogenic zone in the rudimentary kidney as well as in the renal vesicles that give rise to the nephrons. To rescue cell death in the Fgf8 mutant kidney, we inactivate the genes encoding the pro-apoptotic factors BAK and BAX. In a wild-type background, the loss of Bak and Bax abrogates normal cell death and has minimal effect on renal development. However, in Fgf8 mutants, the combined loss of Bak and Bax rescues aberrant cell death in the kidneys and restores some measure of kidney development: 1) the nephron progenitor population is greatly increased; 2) some glomeruli form, which are rarely observed in Fgf8 mutants; and 3) kidney size is rescued by about 50% at E18.5. The development of functional nephrons, however, is not rescued. Thus, FGF8 signaling is required for nephron progenitor survival by regulating BAK / BAX and for subsequent steps involving, as yet, undefined roles in kidney development.

The heart develops in a synchronized sequence of proliferation and differentiation of cardiac progenitor cells (CPCs) from two anatomically distinct pools of cells, the first heart field (FHF) and second heart field (SHF). Congenital heart defects arise upon dysregulation of these processes, many of which are restricted to derivatives of the FHF or SHF. Of the conserved set of signaling pathways that regulate development, the Wnt signaling pathway has long been known for its importance in SHF development. The source of such Wnts has remained elusive, though it has been postulated that these Wnts are secreted from ectodermal or endodermal sources. The central question remains unanswered: Where do these Wnts come from? Here, we show that CPCs autoregulate SHF development via Wnt through genetic manipulation of a key Wnt export protein (Wls), scRNA-seq analysis of CPCs, and use of our precardiac organoid system. Through this, we identify dysregulated developmental trajectories of anterior SHF cell fate, leading to a striking single ventricle phenotype in knockout embryos. We then applied our findings to our precardiac organoid model and found that Wnt2 is sufficient to restore SHF cell fate in our model of disrupted endogenous Wnt signaling. In this study, we provide a basis for SHF cell fate decision—proliferation vs. differentiation—autoregulated by CPCs through Wnt.

[Background]: Fibroblast growth factors (Fgfs) are required for survival and organ formation during embryogenesis. Fgfs often execute their functions redundantly. Previous analysis of Fgf3 mutants revealed effects on inner ear formation and embryonic survival with incomplete penetrance. [Results]: Here, we show that presence of a neomycin resistance gene (neo) replacing the Fgf3 coding region leads to reduced survival during embryogenesis and an increased penetrance of inner ear defects. Fgf3neo/neo mutants showed reduced expression of Fgf4, which is positioned in close proximity to the Fgf3 locus in the mouse genome. Conditional inactivation of Fgf4 during inner ear development on a Fgf3 null background using Fgf3/4 cis mice revealed a redundant requirement between these Fgfs during otic placode induction. In contrast, inactivation of Fgf3 and Fgf4 in the pharyngeal region where both Fgfs are also co-expressed using a Foxg1-Cre driver did not affect development of the pharyngeal arches. However, these mutants showed reduced perinatal survival. [Conclusions]: These results highlight the importance of Fgf signaling during development. In particular, different members of the Fgf family act redundantly to guarantee inner ear formation and embryonic survival., Consejería de Educación, Junta de Castilla y León, Grant/Award Number: CSI143P20; Programa Estratégico Instituto de Biología y Genética Molecular (IBGM), Escalera de Excelencia, Junta de Castilla y León, Grant/Award Numbers: CCVC8485, CLU-2019-02; MEC, Grant/Award Number: BFU2004-00860/BFI

DNA encoded libraries (DELs) represent powerful new technology for finding small molecule ligands for proteins and are increasingly being applied to hit finding in medicinal chemistry. Crucial to the synthesis of high quality DELs is the identification of chemical reactions for their assembly that proceed with very high conversion across a range of different substrates, under conditions compatible with DNA-tagged substrates. Many current chemistries used in DEL synthesis do not meet this requirement, resulting in libraries of low fidelity. Amide couplings are the most commonly used reaction in synthesis of screening libraries and also in DELs. The ability to carry out highly efficient, widely applicable amide couplings in DEL synthesis would therefore be highly desirable. We report a method for amide coupling using micelle forming surfactants, promoted by a modified linker, that is broadly applicable across a wide range of substrates. Most significantly, this works exceptionally well for coupling of DNA-conjugated carboxylic acids (N-to-C) with amines in solution, a procedure that is currently very inefficient. The optimisation of separate procedures for coupling of DNA-conjugated acids and amines by reagent screening and statistically driven optimisation is described. The generality of the method is illustrated by the application to a wide range of examples with unprecedented levels of conversion. The utility of the (N-to-C) coupling of DNA-conjugated acids in DEL synthesis is illustrated by the three cycle synthesis of a fully DNA-encoded compound by two cycles of coupling of an aminoester, with intermediate ester hydrolysis, followed by capping with an amine. This methodology will be of great utility in the synthesis of high fidelity DELs., Highly efficient forward and reverse on-DNA amide couplings were developed exploiting hydrophobic linkers in combination with the micelle forming surfactant TPGS-750M. The method is highly effective for a wide range of substrates in the synthesis of DNA-encoded libraries.

Background Proximal humerus fractures (PHFx) are common orthopedic injuries among the elderly. Although nonoperative management remains the primary treatment modality, more than one-third of PHFx are now treated surgically. Over the past decade, reverse total shoulder arthroplasty (RTSA) has gained popularity as a treatment option for PHFx, both in elderly patients with complex fractures and patients younger than 65 years. While the age range of patients undergoing RTSA for PHFx has expanded, little is known about the impact of age on postoperative complications. The purpose of this study was to examine the relationship between age and 30-day complication rates following RTSA for PHFx. Methods The National Surgical Quality Improvement Program database was queried for patients who underwent RTSA for PHFx between 2006 and 2018. Patient demographic data, surgical characteristics, and adverse outcomes were extracted. Patients were divided into four cohorts by age ( 85 years), and univariate as well as multivariate analyses were performed. Results A total of 1099 patients were identified with a mean age of 72.7 years. Overall, 6.73% of patients experienced one or more complications. Mean operative duration decreased with age (135 minutes in the 85 years old cohort, P 85 years old cohort, P 85 years old cohorts. Age >75 years, preoperative dependent functional status, and ASA class 3 or 4 were found to be independent risk factors for perioperative blood transfusion. Age ≥65 years, female gender, congestive heart failure, preoperative dependent functional status, and ASA class 3 or 4 were found to be independent risk factors for non-home discharge. The rate of unplanned hospital readmission was highest in the >85 years old cohort (17.65%), though this difference did not reach statistical significance. Conclusions While RTSA appears to be a safe treatment option for PHFx in appropriately selected elderly patients, a longer hospitalization and more frequent non-home discharge should be anticipated. Additionally, elderly patients should be closely monitored for postoperative anemia. Level of evidence Level III; Retrospective Cohort Study

Background: Ulnar collateral ligament (UCL) reconstruction has received a unique level of attention in the press and social media. There has also been an increasing use of the internet by patients to seek medical information. Concern exists regarding the quality and comprehensibility of online information when used for patient education. Purpose: To evaluate the quality and comprehensibility of the most-viewed YouTube videos related to the diagnosis and management of UCL injuries. Based on our new evidence-based scoring rubrics, we hypothesized that the quality and comprehensibility of these videos would be poor. Study Design: Cross-sectional study. Methods: The YouTube platform was searched on September 7, 2021, with the terms “UCL injury,” “ulnar collateral ligament injury,” “UCL surgery,” “ulnar collateral ligament surgery,” and “Tommy John surgery,” and the 50 most-viewed videos from each search were compiled, yielding 250 videos. After removal of duplicates and application of exclusion criteria, the 100 most-viewed videos remained. Basic attributes, including duration of video and number of views, were recorded. Each video was then analyzed by 2 independent reviewers and evaluated for 4 key parameters (quality of diagnostic content [QAR-D], quality of treatment content [QAR-T], presence of inaccurate information, and comprehensibility) and graded on a novel scale from 1 to 4 (4 being the most appropriate for patient education). Results: The mean QAR-D was 4.83 ± 3.41 (fair quality), and the mean QAR-T was 2.76 ± 3.26 (poor quality). Physician-led educational videos had both the highest mean QAR-D (6.37) and the highest mean QAR-T (4.34). No correlation was observed between video quality and views/likes. A total of 12 videos included ≥1 inaccuracy. The mean comprehensibility score was 2.66 ± 1.12, with 39 videos falling below the acceptable comprehensibility threshold (score Conclusion: The overall quality of UCL injury–related YouTube content was low. In addition, the absence of correlation between video quality and views/likes suggests that patients are not preferentially utilizing the limited high-quality content that does exist on the YouTube platform. In addition, inaccurate videos were prevalent (12%), and almost half of all videos were deemed inappropriate for patient education in terms of comprehensibility, as defined by our comprehensibility parameter.

Research interest in the benefits of human–animal interaction (HAI) has grown within the scientific community. One current limitation in the HAI literature however, is that the majority of research...

Recent efforts to contain health care costs and move toward value-based health care have intensified, with a continued focus on Medicare expenditures, especially for high-volume procedures. As total shoulder arthroplasty (TSA) volume continues to increase, especially within the Medicare population, it is important for orthopedic surgeons to understand recent trends in the allocation of health care expenditures and potential effects on reimbursements. The purpose of this study was to evaluate trends in annual Medicare utilization and provider reimbursement rates for shoulder arthroplasty procedures between 2012 and 2017.This study tracked annual Medicare claims and payments to shoulder arthroplasty surgeons via publicly available databases and aggregated data at the county level. Descriptive statistics were used to evaluate trends in procedure volume, utilization rate (per 10,000 Medicare beneficiaries), and reimbursement rate. We used adjusted multiple linear regression models to examine associations between county-specific variables (ie, urban or rural, average household income, poverty rate, percentage Medicare population, and race and ethnicity demographics) and procedure volume, utilization rate, and reimbursement rate.Between 2012 and 2017, there was an 81.3% increase in primary TSA volume and 55.5% increase in primary TSA utilization. The Midwest and South had higher utilization rates than the Northeast and West (P.001). TSA utilization rates in metropolitan areas were significantly higher than in rural areas (P.001). Utilization rates for primary TSA procedures also had a significant negative association with poverty rate (P.001). Regarding reimbursements, the Medicare payment per TSA case decreased from 2012 to 2017, with overall inflation-adjusted decreases of 7.1% and 11.8% for primary and revision cases, respectively. TSAs performed in metropolitan areas received significantly higher reimbursements per case than TSAs performed in rural areas ($1108.05 and $1066.40, respectively; P = .002). Furthermore, reimbursements per case were on average higher in the Northeast and West than in the South and Midwest (P.001).Our study confirms that although TSA volume and per capita utilization have increased dramatically since 2012, Medicare Part B reimbursements to surgeons have continued to fall even after the adoption of bundled-payment models for orthopedic procedures. Cost-containment efforts continue to focus on Medicare reimbursements to surgeons, although other expenditures such as hospital payments and operational and implant costs must also be evaluated as part of an overall transition to value-based health care.

Background: Total shoulder arthroplasty (TSA) is an increasingly common procedure. This study looked at trends in TSA using a nationwide registry, with a focus on patient demographics, comorbidities, and complications. Methods: The American College of Surgeons National Surgical Quality Improvement Program database was queried for patients who underwent TSA from 2005 to 2018. Cohorts were created based on year of surgery: 2005-2010 (N = 1116), 2011-2014 (N = 5920), and 2015-2018 (N = 16,717). Patient demographics, comorbidities, operative time, hospital length of stay, discharge location, and complications within 30 days of surgery were compared between cohorts using bivariate and multivariate analysis. Results: Bivariate analysis revealed significantly more comorbidities among patients in the 2015-2018 cohort compared with the 2005-2010 cohort, specifically American Society of Anesthesiologist class III or IV (57.0% vs. 44.3%, P < .001), morbid obesity (10.8% vs. 7.8%, P < .001), diabetes (17.8% vs. 12.1%, P < .001), and chronic obstructive pulmonary disease (6.7% vs. 4.1%, P = .003). The use of regional anesthesia has decreased (5.6% in 2005-2010 vs. 2.8% in 2015-2018, P < .001), as has operative time (▵: −16 minutes, P < .001) and length of stay (▵: −0.6 days, P < .001). There were also significant decreased rates of perioperative blood transfusion (OR [odds ratio], 0.46), non-home discharge (OR, 0.79), urinary tract infection (OR, 0.47), and sepsis (OR, 0.17), (P < .001 for all comparisons) between the 2005-2010 and 2015-2018 cohorts. Conclusions: Between 2005 and 2018, patients undergoing TSA had increasingly more comorbidities but experienced lower rates of short-term complications, in the context of shorter hospitalizations and more frequent discharge to home.

Lead halide perovskites have a rich landscape of structural and optical properties, which can be explored and possibly controlled by applying high pressure. Despite several reports on high-pressure...

Objectives: The significant psychological impact and prevalence of posttraumatic stress disorder (PTSD) have been thoroughly documented in multiple investigations of patients after anterior cruciate ligament ruptures, but this has not yet been assessed in patients after ulnar collateral ligament (UCL) rupture. Our hypothesis is that symptoms of PTSD are present among baseball players after UCL injury. Methods: Baseball players, from the high school to minor league baseball level who had suffered an acute UCL rupture were recruited at a tertiary care center. Patients completed the Horowitz Impact of Event Scale - Revised (IES-R) to analyze for PTSD symptomatology. Results: A total of 24 patients were enrolled. The mean patient age was 19.2 years (range 15-24 years). Twenty patients (83.3%) were pitchers; 12 pitched exclusively. Six patients surveyed played at the high school level (25%), 15 in college (62.5%), and 3 at the minor league level (12.5%). 100% of patients were male. Over 91% of patients experienced symptoms of intrusion, 87.5% displayed avoidance symptoms, and 79.2% had symptoms of hyperarousal. Twelve patients (50%) scored >24 on the IES-R (PTSD is a clinical concern). 6 patients (25%) reached the threshold for a probable diagnosis of PTSD (³33 on the IES-R). Conclusions: Following UCL rupture, athletes experience substantial emotional trauma, and a significant proportion of patients experience symptoms severe enough to warrant a diagnosis of PTSD.

In spin-polarized itinerant electron systems, collective spin-wave modes arise from dynamical exchange and correlation (xc) effects. We here consider spin waves in doped paramagnetic graphene with adjustable Zeeman-type band splitting. The spin waves are described using time-dependent spin-density-functional response theory, treating dynamical xc effects within the Slater and Singwi-Tosi-Land-Sjolander approximations. We obtain spin-wave dispersions and spin stiffnesses as a function of doping and spin polarization, and discuss prospects for their experimental observation., 14 pages, 8 figures

Background: Machine learning has shown potential in accurately predicting outcomes after orthopedic surgery, thereby allowing for improved patient selection, risk stratification, and preoperative planning. This study sought to develop machine learning models to predict nonhome discharge after total shoulder arthroplasty (TSA). Methods: The American College of Surgeons National Surgical Quality Improvement Program database was queried for patients who underwent elective TSA from 2012 to 2018. Boosted decision tree and artificial neural networks (ANN) machine learning models were developed to predict non-home discharge and 30-day postoperative complications. Model performance was measured using the area under the receiver operating characteristic curve (AUC) and overall accuracy (%). Multivariate binary logistic regression analyses were used to identify variables that were significantly associated with the predicted outcomes. Results: There were 21,544 elective TSA cases identified in the National Surgical Quality Improvement Program registry from 2012 to 2018 that met inclusion criteria. Multivariate logistic regression identified several variables associated with increased risk of nonhome discharge including female sex (odds ratio [OR] = 2.83; 95% confidence interval [CI] = 2.53-3.17; P

Background: Injury to the ulnar collateral ligament of the elbow is common among overhead throwing athletes and can result in significant functional limitations. While surgical reconstruction offers high rates of return to competition, there are no validated or universally accepted guidelines for determining when an athlete can safely resume play. Purpose: To assess the existing scientific literature for return-to-competition criteria utilized after ulnar collateral ligament reconstruction. Study Design: Systematic review and meta-analysis; Level of evidence, 4. Methods: The PubMed database was searched for clinical investigations of ulnar collateral ligament reconstruction in overhead throwing athletes published between January 2000 and June 2020. Only studies that had a minimum follow-up of 1 year and included at least 1 specific return-to-competition criterion were considered. Results: A total of 15 studies were included in the final analysis, encompassing 1156 patients with an average age of 20.7 years (SD, 2.0 years). Baseball players composed 96.3% of patients for whom sport was specified, and 92.4% of baseball players were pitchers. The most common return-to-competition criterion, identified in 87% of studies, was completion of a return-to-throwing program, which started on average 16.7 weeks (range, 12-18 weeks) after surgery. A return-to-mound program was utilized in 53% of studies, starting on average 7.4 months (range, 6-9 months) postoperatively. Minimum time from surgery was used in 73% studies, with players waiting 7 to 12 months (mean, 9.7; SD, 1.4 months) after surgery before return-to-competition consideration. The overall rate of return to competition at the preinjury level or higher was 85.7% (SD, 8.5%) at an average of 12.2 months (SD, 0.6 months). Conclusion: In general, we observed a paucity of literature describing the return-to-competition process after ulnar collateral ligament reconstruction in overhead throwing athletes. Only 3 explicit return-to-competition criteria were identified across all studies: completion of a return-to-throwing program, completion of a return-to-mound program for pitchers, and minimum time from surgery. Increased transparency regarding postoperative rehabilitation protocols and further research are necessary to identify and validate sport-specific return-to-competition criteria, which will ultimately help athletes return to play in a safe and timely fashion after ulnar collateral ligament reconstruction.

We report on the sixth case of an isolated pediatric transolecranon fracture‐dislocation, and the first case utilizing nonoperative management in a cast following closed reduction resulting in an excellent outcome. Our case provides support for nonoperative management of these rare injuries, especially when surgery is not practical or desirable.

This article presents a case study logic model-approach of the Central States Center for Agricultural Safety and Health (CS-CASH) - one of eleven federally funded Agricultural Health and Safety Centers in the United States. We used social network analysis (SNA) to examine how information generated from CS-CASH regarding respiratory personal protective equipment (PPE) use is disseminated across their network of key stakeholders and ultimately to end-users (i.e., agricultural workers). We developed a 22-item instrument based on SNA principles, and administered it to N = 49 CS CASH members and N = 158 external stakeholders. Questions focused on demographics, work setting, roles, and SNA concepts for betweenness, centrality, reciprocity, and density. Findings showed that CS-CASH has an extensive information sharing network for respiratory PPE, and there is high reciprocity with vigorous bi-directional communication; however, the network is fragmented and lacks diversity in key stakeholder roles needed to broadly diffuse information into practice. Implications are to (1) create new connections with a more diverse group of external stakeholders beyond academic and non-profit organizations, and (2) leverage primary network gatekeepers to build connections within the respiratory PPE group and with gatekeepers in the unconnected networks, thereby maximizing diffusion of information across the overall CS-CASH network. The case study has implications for evaluators and project directors looking to improve outcomes for enhanced use of respiratory PPE among end-users by working through external stakeholders who can enhance the information flow for dissemination and diffusion to practice.

In the fibrous filtration of particles in gas and liquid flows, loading is the act of particles depositing onto fibers. Loaded particles alter the filter microstructure and can have a profound influence on the pressure drop across a filter medium. Of interest is therefore a simple approach to predict the pressure drop across a loaded filter, accounting for both fibers and loaded, spherical particles. In the present study, we use computational fluid dynamics simulations to develop a simple predictive model for the pressure drop across fibrous media composed of a combination of cylindrical fibers and spherical particles. Specifically, the pressure drop is calculated via an in-house written code to solve the incompressible viscous flow equations in a periodic domain, with the particles and fibers accounted for via the immersed boundary method. For calculations, we generate randomly oriented three-dimensional virtual fibrous networks with prescribed microstructures, including network total solidity, fiber orientation angle distribution, fiber radius distribution, and particle radius distribution (both polydisperse). We find that irrespective of network geometry, by defining a single effective network diameter, the product of the dimensionless pressure drop per unit length and the Reynolds number can be expressed solely a function of the total solidity of the network (particle solidity plus fiber solidity) for fiber solidities in 0.03–0.20 range and particle solidities in the 0.0–0.08 range. The effective diameter, employed in both non-dimensionalization of the pressure drop and the Reynolds number definition, is found to depend upon the first and second moments of the fiber diameter distribution functions, and the second and third moments of the particle diameter distribution functions. We develop a regression equation to fit calculation results; the functional form of the equation is based upon a linear combination of the low and high solidity limits for the permeability term in Darcy’s Law. We additionally apply this pressure drop relationship in loading simulations to examine the evolution of filter pressure drop and figure of merit as loading proceeds. Test results on model filters show that the pressure drop increases significantly as loading proceeds, with loading of the front regions of filters contributing most significantly to the pressure drop. Interestingly, model results suggest that the figure of merit first increases upon loading and then decreases, justifying preloading of filters to increase performance.

Significance Pentosan polysulfate sodium (PPS) maculopathy is a clinical entity characterized by a pigmentary maculopathy in the setting of chronic exposure to PPS. Pentosan polysulfate sodium is indicated for discomfort related to interstitial cystitis/painful bladder syndrome. Given a reported interstitial cystitis/painful bladder syndrome prevalence up to 2%, recognition is critical to mitigate visual sequelae. Purpose We present an observational case report demonstrating typical findings of PPS maculopathy in a patient originally diagnosed with a pattern macular dystrophy. We demonstrate the importance of medical history, medication profile review, and multimodal imaging in the diagnosis and management. The patient provided written informed consent for medical information and images to be published. Case report A 55-year-old White woman presented with a painless, bilateral loss of vision and bilateral pigmentary maculopathy that was initially diagnosed as pattern macular dystrophy. Detailed review of medical history, medication profile, and subsequent studies, including optical coherence tomography, near-infrared reflectance imaging, fundus autofluorescence, fluorescein angiography, and genetic studies, ultimately led to the diagnosis of PPS maculopathy. Pentosan polysulfate sodium was discontinued, and ongoing surveillance with multimodal imaging was encouraged. Conclusions Because toxic maculopathies are an uncommon diagnosis, screening and recognition of PPS maculopathy are critical in the primary eye care setting. Discontinuation of the insulting agent may be necessary to prevent potentially severe and irreversible vision loss in the at-risk population.

Introduction Over the past two decades, various factors have led to fewer opportunities for hands-on learning in the operating room among orthopaedic surgery trainees. Innovative training platforms using anatomic models, cadaveric specimens, and augmented reality have been devised to address this deficiency in surgical training, but such training tools are often costly with limited accessibility. Cognitive training is a low-cost training technique that improves physical performance by refining the way in which information is mentally processed and has long been used by professional athletes and world-class musicians. More recently, cognitive training tools have been developed for several orthopaedic surgery procedures, but the overall utility of cognitive training in orthopaedic surgery remains unknown. Methods The purpose of this study was to review the existing literature regarding the use of cognitive training in orthopaedic surgery and to summarize the results of investigations comparing cognitive training tools with other methods of learning. To that effect, the PubMed and Embase databases were systematically reviewed for articles related to cognitive training in orthopaedic surgery. Results Eleven publications met the inclusion criteria, including six randomized controlled trials. Cognitive task analysis and mental rehearsal were the most common forms of cognitive training identified. All 11 publications supported the use of cognitive training in orthopaedic surgery training. In the six randomized controlled trials, the utilization of cognitive training was associated with notably improved surgical performance and increased knowledge compared with traditional methods of learning. Discussion Based on the limited evidence presented in this review, cognitive training represents a promising, low-cost adjunct to traditional orthopaedic surgery training. Further efforts should be directed at developing and evaluating additional cognitive training tools for orthopaedic surgery trainees.

To determine the association between surgical timing and short-term morbidity and mortality in elderly patients who sustain hip fractures using a national trauma database (OTA/AO 31A1-3, 31B1-3).Retrospective cohort study.Level I-IV trauma centers in the United States.All patients ≥65 years of age who underwent surgery for hip fracture from 2011 to 2013.Time to surgery of24, 24-48, and48 hours from admission.Primary outcome was mortality by hospital discharge. Secondary outcomes were complications of myocardial infarction, cardiac arrest, acute respiratory distress syndrome (ARDS), unplanned reintubation, pneumonia, stroke, severe sepsis, and intensive care unit length of stay.Twenty-seven thousand fifty-eight patients were included in the study. Relative to the24 hours cohort, patients in the48 hours cohort were at increased risk for mortality (OR 1.89, 95% CI 1.52-2.33, P0.001), ARDS (OR 2.57, 95% CI 1.94-3.39, P0.001 for ARDS), myocardial infarction (OR 2.19, 95% CI 1.64-2.94, P0.0001), pneumonia (OR 2.04, 95% CI 1.71-2.44, P0.001), severe sepsis (OR 2.34, 95% CI 1.52-3.58, P = 0.003), and intensive care unit stay (OR 2.48, 95% CI 2.25-2.74, P0.0001). A subgroup analysis showed that healthier patients (modified Charlson Comorbidity Index less than 5) who had surgery48 hours were not at increased risk of mortality.For elderly patients with hip fractures, delaying surgery for more than 48 hours may be associated with increased short-term morbidity and mortality. This association may be pronounced for patients with more medical comorbidities.Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Despite the myriad of surgical procedures available for the treatment of a failed rotator cuff repair, significant overlap exists between complications associated with the various treatment options. Most complications can be classified into one of three categories: First, operative management of a failed rotator cuff repair can simply fail. Failure can be further characterized as mechanical, clinical, or the need for revision surgery. For instance, the retear rate after revision arthroscopic rotator cuff repair at 2 years is 40%, nearly double that of primary arthroscopic repair [ (Am J Sports Med. 2015;43(3):557–64)]. Second, complications can occur as a direct result of the surgical intervention. The major complications in this category include infection, nerve injury, and shoulder stiffness. Third, medical complications, such as venous thromboembolism, may arise as a secondary consequence of the surgical procedure. A few notable complications do not fit neatly into these categories but are worth mentioning. Allografts, xenografts, and synthetic materials used in augmentation of rotator cuff repairs, superior capsular reconstruction and subacromial balloon spacers can induce a foreign body response (J Shoulder Elbow Surg. 2018;27(9):1622–8; J Bone Joint Surg Am. 2006;88(6):1238–44; Int Orthop. 2015;39(12):2403–14; Subacromial “biodegradable spacer” in the management of irreparable rotator cuff tears: radiological findings, 2018, Vienna, Austria). Finally, reverse total shoulder arthroplasty for massive irreparable rotator cuff tears can lead to a number of unique complications including dislocation, intraoperative and postoperative fracture, and inferior scapular notching.

The development of key structures within the mature vertebrate hindbrain requires the migration of neural crest (NC) cells and motor neurons to their appropriate target sites. Functional analyses in multiple species have revealed a requirement for the transcription factor gastrulation-brain-homeobox 2 (Gbx2) in NC cell migration and positioning of motor neurons in the developing hindbrain. In addition, loss of Gbx2 function studies in mutant mouse embryos, Gbx2neo, demonstrate a requirement for Gbx2 for the development of NC-derived sensory neurons and axons constituting the mandibular branch of the trigeminal nerve (CNV). Our recent GBX2 target gene identification study identified multiple genes required for the migration and survival of NC cells (e.g., Robo1, Slit3, Nrp1). In this report, we performed loss-of-function analyses using Gbx2neo mutant embryos, to improve our understanding of the molecular and genetic mechanisms regulated by Gbx2 during anterior hindbrain and CNV development. Analysis of Tbx20 expression in the hindbrain of Gbx2neo homozygotes revealed a severely truncated rhombomere (r)2. Our data also provide evidence demonstrating a requirement for Gbx2 in the temporal regulation of Krox20 expression in r3. Lastly, we show that Gbx2 is required for the expression of Nrp1 in a subpopulation of trigeminal NC cells, and correct migration and survival of cranial NC cells that populate the trigeminal ganglion. Taken together, these findings provide additional insight into molecular and genetic mechanisms regulated by Gbx2 that underlie NC migration, trigeminal ganglion assembly, and, more broadly, anterior hindbrain development.

The strong spin–orbit coupling (SOC) in lead halide perovskites, when inversion symmetry is lifted, has provided opportunities for investigating the Rashba effect in these systems. Moreover, the strong orbital moment, which, in turn, impacts the spin-pair in singlet and triplet electronic states, plays a significant role in enhancing the optoelectronic properties in the presence of external magnetic fields in lead halide perovskites. Here, we investigate the effect of weak magnetic fields (

Background: Anterior cruciate ligament (ACL) reconstruction is the standard of care for patients after an ACL tear, as poor historical outcomes were observed after primary ACL repair. Certain subgroups of patients, however, have been shown to have outcomes equivalent to reconstruction after undergoing ACL repair and therefore may benefit from the potential advantages offered by avoiding reconstruction. It is important to accurately and consistently identify and indicate these candidates for ACL repair. Purpose/Hypothesis: The purpose of this study was to determine the inter- and intraobserver reliability of magnetic resonance imaging (MRI) evaluation for the reparability of ACL tears and to identify imaging factors that may lead to surgeon uncertainty or disagreement in decision making. Our hypothesis was that the orthopaedic surgeons surveyed would not be able to reliably agree on the reparability of an ACL using MRI scans alone. Study Design: Cohort study (diagnosis); Level of evidence, 3. Methods: We administered 2 surveys to 6 fellowship-trained orthopaedic sports medicine surgeons. Each surgeon reviewed preoperative MRI scans for 20 patients and answered a series of questions, ultimately determining whether they would choose an ACL reconstruction or repair for the patient based on the imaging alone. The same survey was repeated 6 weeks later. Kappa values for inter- and intraobserver reliability of their decision making were then calculated. Results: The average kappa for interobserver reliability in the 2 surveys was 0.22, and the average kappa for intraobserver reliability was 0.34. Interobserver reliability among the surgeons in this group was poor to moderate; intraobserver reliability was slightly better. The choice for ACL repair was significantly correlated with proximal tear locations ( r = 0.854; P < .001), good-quality ACL tissue remnant ( r = 0.929; P < .001), and how many surgeons believed that the tear only involved a single bundle ( r = 0.590; P = .006). Conclusion: The surgeons surveyed in this study did not consistently agree on candidates for ACL repair using MRI alone.

During vertebrate development, the presomitic mesoderm (PSM) periodically segments into somites, which will form the segmented vertebral column and associated muscle, connective tissue, and dermis. The periodicity of somitogenesis is regulated by a segmentation clock of oscillating Notch activity. Here, we examined mouse mutants lacking onlyFgf4orFgf8, which we previously demonstrated act redundantly to prevent PSM differentiation.Fgf8is not required for somitogenesis, butFgf4mutants display a range of vertebral defects. We analyzedFgf4mutants by quantifying mRNAs fluorescently labeled by hybridization chain reaction within Imaris-based volumetric tissue subsets. These data indicate that FGF4 maintainsHes7levels and normal oscillatory patterns. To support our hypothesis that FGF4 regulates somitogenesis throughHes7, we demonstrate genetic synergy betweenHes7andFgf4, but not withFgf8. Our data indicate thatFgf4is potentially important in a spectrum of human Segmentation Defects of the Vertebrae caused by defective Notch oscillations.

Category: Midfoot/Forefoot Introduction/Purpose: Lateral column lengthening (LCL) is a surgical procedure used to manage forefoot abduction occurring in patients with stage IIB Adult Acquired Flat Foot Deformity (AAFD). This procedure utilizes an opening wedge osteotomy of the calcaneus which is then filled with autograft, allograft, or a titanium wedge. The primary aim of this study was to compare the radiographic outcomes of these different bone substitutes in the setting of stage IIB AAFD with the use of LCL. Methods: All patients who underwent LCL from October 2008 until October 2018 were retrospectively reviewed. Preoperative weight bearing radiographs, initial postoperative radiographs and 1-year weight bearing radiographs were reviewed. The following radiographic measurements were recorded: talonavicular uncoverage angle, incongruency angle, and calcaneal pitch. Results: A total of 44 patients were included in our study. The mean age of the cohort was 54 (range 18-74). The study cohort was divided into two groups. There were 17 (38.7%) patients that received a titanium wedge and 27 (61.5%) that received autograft or allograft. Patients that underwent LCL with the autograft/allograft group were significantly older (p=0.006). Patients who underwent LCL with a titanium wedge had a significantly higher preoperative talonavicular angle (p=0.013). There were no significant differences in post-operative talonavicular uncoverage angle, incongruency angle or calcaneal pitch at 6 months or 1 year. Conclusion: Adult acquired flat foot deformity is a difficult disorder to treat surgically. Lateral column lengthening is a common surgical procedure used to treat forefoot abduction that occurs. Our results show that at 6 months and 1 year no radiographic difference exists between autograft/allograft bone substitutes versus titanium wedge in LCL. Future research should evaluate the differences in patient reported outcomes between autograft/allograft versus titanium wedge bone substitutes. [Table: see text]

Hunting for wild meat in the tropics provides subsistence and income for millions 29 of people. Methods have remained relatively unchanged since the introduction of 30 shotguns and battery-powered incandescent flashlights, but due to the short life of batteries in such flashlights, nocturnal hunting has been limited. However, brighter, 32 more efficient light-emitting diode (LED) flashlights, have recently been adopted by 33 hunters. Brighter spotlights increase the freezing response of many species, and 34 greater battery life allows hunters to pursue game for longer and more frequently. 35 Hunters interviewed in African and South American forests, disclosed that LEDs 36 increase the frequency and efficiency of nocturnal hunting, and the number of kills 37 made. These changes were reflected in harvest data in Brazil. The drastic change in 38 efficiency brought about by LEDs, well known to hunters around the world, poses a 39 significant threat to wildlife. We consider the implications for communities, governments, 40 wildlife managers and conservationists

Little information is available on the functional activity of leukocytes after arthroplasty or the expansion of populations with immune suppressive properties during the acute post-operative period. Synovial fluid and matched pre- and post-surgical blood samples were collected from total hip and knee arthroplasty patients (THA and TKA, respectively) to examine the impact of surgery on peripheral blood leukocyte frequency, bactericidal activity, and inflammatory mediator expression. For spinal surgeries, inflammatory mediator production by peripheral blood mononuclear cells (PBMCs) pre- and post-surgery was examined. An expansion of immune suppressive granulocytic myeloid-derived suppressor cells (G-MDSCs) was observed following arthroplasty, which correlated with significantly increased serum interleukin-10 (IL-10) levels. Analysis of synovial fluid from THA and TKAs revealed reduced granulocyte colony-stimulating factor (G-CSF) and soluble CD40 ligand (sCD40L) and increased interleukin-6 (IL-6), monocyte chemoattractant protein 2 (CCL2) and Fms-like tyrosine kinase 3 ligand (Flt-3L) compared to pre- and post-surgical serum. For the spinal surgery cohort, stimulation of PBMCs isolated post-surgery with bacterial antigens produced significantly less pro-inflammatory (IL-1&alpha, IL-1&beta, interleukin-1 receptor antagonist (IL-1RA), IL-12p40, growth-related oncogene-&alpha, /GRO-&alpha, (CXCL1) and 6Ckine (CCL21)) and more anti-inflammatory/tissue repair mediators (IL-10, G-CSF and granulocyte-macrophage colony-stimulating factor (GM-CSF)) compared to PBMCs recovered before surgery. The observed bias towards systemic anti-inflammatory changes without concomitant increases in pro-inflammatory responses may influence susceptibility to infection following orthopaedic surgery in the context of underlying co-morbidities or risk factors.

A transcription factor gradient conveys positional information in the vertebrate limb bud., The positional information theory proposes that a coordinate system provides information to embryonic cells about their position and orientation along a patterning axis. Cells interpret this information to produce the appropriate pattern. During development, morphogens and interpreter transcription factors provide this information. We report a gradient of Meis homeodomain transcription factors along the mouse limb bud proximo-distal (PD) axis antiparallel to and shaped by the inhibitory action of distal fibroblast growth factor (FGF). Elimination of Meis results in premature limb distalization and HoxA expression, proximalization of PD segmental borders, and phocomelia. Our results show that Meis transcription factors interpret FGF signaling to convey positional information along the limb bud PD axis. These findings establish a new model for the generation of PD identities in the vertebrate limb and provide a molecular basis for the interpretation of FGF signal gradients during axial patterning.

Summary Introduction The UTD Classification System risk stratifies postnatal UTD into three groups: low risk (UTD P1), intermediate risk (UTD P2), and high risk (UTD P3). In the original consensus document, a functional scan is not recommended for UTD P1 and is left to the discretion of the clinician for UTD P2 and P3. Objective This study aims to understand which patients with postnatal urinary tract dilation would benefit from a functional study. We investigated how different elements of the UTD classification system predict differential renal function (DRF) and diuretic half-life (T½) on MAG3 scan in infants undergoing evaluation for prenatally detected UTD. Study design This is a multicenter retrospective chart review of infants 6 months of age or younger evaluated for prenatal UTD, correlating their first MAG3 scan and first postnatal renal ultrasound (RUS). Multivariable logistic regression was used to find UTD elements predictive of DRF 20 min. Results A total of 517 patients met study criteria. Median age at time of RUS and MAG3 renal scan was 48 days (IGR 31–81) and 63 days (IQR 45–98), respectively. DRF 20 min was found in 31% of kidneys with UTD P2 and 79% of kidneys with UTD P3. An abnormal ureter (OR 2.7, 95% CI 1.2–6.0) and parenchymal thinning (OR 16, 95% CI 5.8–41.4) were significant at predicting DRF 20 min, as did each cm increase in the anterior-posterior renal pelvic diameter (APRPD) (OR 4.8, 95% CI 3.0–7.7). Discussion The UTD system discriminates well and correlates with the likelihood of finding adverse features on diuretic renography. Patients in the UTD P3 high-risk category had a significantly higher incidence of decreased differential renal function and delayed drainage than those in UTD P1 and P2. Of the individual components of the UTD Classification system, the presence of parenchymal thinning was the most important factor in predicting both decreased differential renal function and delayed drainage. Conclusion Given the high incidence of poor function and delayed drainage seen in the UTD P3 group, we believe a functional study should be recommended in the evaluation of these patients. Our findings support leaving the performance of a functional study at the discretion of the physician for UTD P2. Download : Download high-res image (83KB) Download : Download full-size image Summary Figure . Percentage of patients with DRF 20 min across the different UTD Classification Risk Groups.

During vertebrate development, the presomitic mesoderm (PSM) is periodically segmented into somites, which will form the segmented vertebral column and associated muscle, connective tissue, and dermis. The periodicity of somitogenesis is regulated by a segmentation clock of oscillating Notch activity. Here, we examined mouse mutants lacking onlyFgf4orFgf8, which we previously demonstrated act redundantly to prevent PSM differentiation.Fgf8is not required for somitogenesis, butFgf4mutants display a range of vertebral defects. We analyzedFgf4mutants by quantifying mRNAs fluorescently labeled by hybridization chain reaction within Imaris-based volumetric tissue subsets. These data indicate that FGF4 controls Notch pathway oscillations through the transcriptional repressor, HES7. This hypothesis is supported by demonstrating a genetic synergy betweenHes7andFgf4, but not withFgf8. Thus,Fgf4is an essential Notch oscillation regulator and potentially important in a spectrum of human Segmentation Defects of the Vertebrae caused by defective Notch oscillations.

MC3 Working Group: Rehan Akbani21, Pavana Anur22, Matthew H. Bailey1,2,3, Alex Buchanan9, Kami Chiotti9, Kyle Covington12,23, Allison Creason9, Li Ding1,2,3,20, Kyle Ellrott9, Yu Fan21, Steven Foltz1,2, Gad Getz8,14,15,16, Walker Hale12, David Haussler24,25, Julian M. Hess8,26, Carolyn M. Hutter27, Cyriac Kandoth28, Katayoon Kasaian29,30, Melpomeni Kasapi27, Dave Larson1 , Ignaty Leshchiner8, John Letaw31, Singer Ma32, Michael D. McLellan1,3,20, Yifei Men32, Gordon B. Mills33,34, Beifang Niu35, Myron Peto22, Amie Radenbaugh24, Sheila M. Reynolds36, Gordon Saksena8, Heidi Sofia27, Chip Stewart8, Adam J. Struck31, Joshua M. Stuart24,37, Wenyi Wang21, John N. Weinstein38, David A. Wheeler12,13, Christopher K. Wong24,39, Liu Xi12 & Kai Ye40,41 21Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. 22Molecular and Medical Genetics, OHSU Knight Cancer Institute, Oregon Health and Science University, Portland, OR 97239, USA. 23Castle Biosciences Inc, Friendswood, TX 77546, USA. 24UC Santa Cruz Genomics Institute, University of California Santa Cruz, Santa Cruz, CA 95064, USA. 25Howard Hughes Medical Institute, University of California Santa Cruz, Santa Cruz, CA 95064, USA. 26Massachusetts General Hospital Center for Cancer Research, Charlestown, MA 02114, USA. 27National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20894, USA. 28Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. 29Ontario Institute for Cancer Research, Toronto, ON M5G 0A3, Canada. 30Canada’s Michael Smith Genome Sciences Centre, BC Cancer, Vancouver, BC V5Z 4S6, Canada. 31Computational Biology Program, School of Medicine, Oregon Health and Science University, Portland, OR 97239, USA. 32DNAnexus Inc, Mountain View, CA 94040, USA. 33Department of Systems Biology, UT MD Anderson Cancer Center, Houston, TX 77030, USA. 34Precision Oncology, OHSU Knight Cancer Institute, Oregon Health and Science University, Portland, OR 97239, USA. 35Computer Network Information Center, Chinese Academy of Sciences, Beijing, China. 36Institute for Systems Biology, Seattle, WA 98109, USA. 37Department of Biomolecular Engineering, University of California Santa Cruz, Santa Cruz, CA 95064, USA. 38Department of Bioinformatics and Computational Biology and Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. 39Biomolecular Engineering Department, University of California Santa Cruz, Santa Cruz, CA 95064, USA. 40School of Elect, PCAWG novel somatic mutation calling methods working group: Matthew H. Bailey1,2,3, Beifang Niu35, Matthias Bieg42,43, Paul C. Boutros6,44,45,46, Ivo Buchhalter43,47,48, Adam P. Butler49, Ken Chen50, Zechen Chong51, Li Ding1,2,3,20, Oliver Drechsel52,53, Lewis Jonathan Dursi6,7, Roland Eils47,48,54,55, Kyle Ellrott9, Shadrielle M. G. Espiritu6, Yu Fan21, Robert S. Fulton1,3,20, Shengjie Gao56, Josep L. l. Gelpi57,58, Mark B. Gerstein5,18,19, Gad Getz8,14,15,16, Santiago Gonzalez59,60, Ivo G. Gut52,61, Faraz Hach62,63, Michael C. Heinold47,48, Julian M. Hess8,26, Jonathan Hinton49, Taobo Hu64, Vincent Huang6, Yi Huang65,66, Barbara Hutter43,67,68, David R. Jones49, Jongsun Jung69, Natalie Jäger47, Hyung-Lae Kim70, Kortine Kleinheinz47,48, Sushant Kumar5,19, Yogesh Kumar64, Christopher M. Lalansingh6, Ignaty Leshchiner8, Ivica Letunic71, Dimitri Livitz8, Eric Z. Ma64, Yosef E. Maruvka8,26,72, R. Jay Mashl1,2, Michael D. McLellan1,3,20, Andrew Menzies49, Ana Milovanovic57, Morten Muhlig Nielsen73, Stephan Ossowski52,53,74, Nagarajan Paramasivam43,47, Jakob Skou Pedersen73,75, Marc D. Perry76,77, Montserrat Puiggròs57, Keiran M. Raine49, Esther Rheinbay8,14,72, Romina Royo57, S. Cenk Sahinalp62,78,79, Gordon Saksena8, Iman Sarrafi62,78, Matthias Schlesner47,80, Jared T. Simpson6,17, Lucy Stebbings49, Chip Stewart8, Miranda D. Stobbe52,61, Jon W. Teague49, Grace Tiao8, David Torrents57,81, Jeremiah A. Wala8,14,82, Jiayin Wang1,40,66, Wenyi Wang21, Sebastian M. Waszak60, Joachim Weischenfeldt60,83,84, Michael C. Wendl1,10,11, Johannes Werner47,85, Zhenggang Wu64, Hong Xue64, Sergei Yakneen60, Takafumi N. Yamaguchi6, Kai Ye40,41, Venkata D. Yellapantula20,86, Christina K. Yung76 & Junjun Zhang76, PCAWG Consortium: Lauri A. Aaltonen87, Federico Abascal49, Adam Abeshouse88, Hiroyuki Aburatani89, David J. Adams49, Nishant Agrawal90, Keun Soo Ahn91, Sung-Min Ahn92, Hiroshi Aikata93, Rehan Akbani21, Kadir C. Akdemir50, Hikmat Al-Ahmadie88, Sultan T. Al-Sedairy94, Fatima Al-Shahrour95, Malik Alawi96,97, Monique Albert98, Kenneth Aldape99,100, Ludmil B. Alexandrov49,101,102, Adrian Ally30, Kathryn Alsop103, Eva G. Alvarez104,105,106, Fernanda Amary107, Samirkumar B. Amin108,109,110, Brice Aminou76, Ole Ammerpohl111,112, Matthew J. Anderson113, Yeng Ang114, Davide Antonello115, Pavana Anur22, Samuel Aparicio116, Elizabeth L. Appelbaum1,117, Yasuhito Arai118, Axel Aretz119, Koji Arihiro93, Shun-ichi Ariizumi120, Joshua Armenia121, Laurent Arnould122, Sylvia Asa123,124, Yassen Assenov125, Gurnit Atwal6,126,127, Sietse Aukema112,128, J. Todd Auman129, Miriam R. Aure130, Philip Awadalla6,126, Marta Aymerich131, Gary D. Bader126, Adrian Baez-Ortega132, Matthew H. Bailey1,2,3, Peter J. Bailey133, Miruna Balasundaram30, Saianand Balu134, Pratiti Bandopadhayay8,135,136, Rosamonde E. Banks137, Stefano Barbi138, Andrew P. Barbour139,140, Jonathan Barenboim6, Jill Barnholtz-Sloan141,142, Hugh Barr143, Elisabet Barrera59, John Bartlett98,144, Javier Bartolome57, Claudio Bassi115, Oliver F. Bathe145,146, Daniel Baumhoer147, Prashant Bavi148, Stephen B. Baylin149,150, Wojciech Bazant59, Duncan Beardsmore151, Timothy A. Beck152,153, Sam Behjati49, Andreas Behren154, Beifang Niu35, Cindy Bell155, Sergi Beltran52,61, Christopher Benz156, Andrew Berchuck157, Anke K. Bergmann158, Erik N. Bergstrom101,102, Benjamin P. Berman159,160,161, Daniel M. Berney162, Stephan H. Bernhart163,164,165, Rameen Beroukhim8,14,82, Mario Berrios166, Samantha Bersani167, Johanna Bertl73,168, Miguel Betancourt169, Vinayak Bhandari6,44, Shriram G. Bhosle49, Andrew V. Biankin133,170,171,172, Matthias Bieg42,43, Darell Bigner173, Hans Binder163,164, Ewan Birney59, Michael Birrer72, Nidhan K. Biswas174, Bodil Bjerkehagen147,175, Tom Bodenheimer134, Lori Boice176, Giada Bonizzato177, Johann S. De Bono178, Arnoud Boot179,180, Moiz S. Bootwalla166, Ake Borg181, Arndt Borkhardt182, Keith A. Boroevich183,184, Ivan Borozan6, Christoph Borst185, Marcus Bosenberg186, Mattia Bosio52,53,57, Jacqueline Boultwood187, Guillaume Bourque188,189, Paul C. Boutros6,44,45,46, G. Steven Bova190, David T. Bowen49,191, Reanne Bowlby30, David D. L. Bowtell103, Sandrine Boyault192, Rich Boyce59, Jeffrey Boyd193, Alvis Brazma59, Paul Brennan194, Daniel S. Brewer195,196, Arie B. Brinkman197, Robert G. Bristow44,198,199,200,201, Russell R. Broaddus99, Jane E. Brock202, Malcolm Brock203, Annegien Broeks204, Angela N. Brooks8,24,37,82, Denise Brooks30, Benedikt Brors67,205,206, Søren Brunak207,208, Timothy J. C. Bruxner113,209, Alicia L. Bruzos104,105,106, Alex Buchanan9, Ivo Buchhalter43,47,48, Christiane Buchholz210, Susan Bullman8,82, Hazel Burke211, Birgit Burkhardt212, Kathleen H. Burns213,214, John Busanovich8,215, Carlos D. Bustamante216,217, Adam P. Butler49, Atul J. Butte218, Niall J. Byrne76, Anne-Lise Børresen-Dale130,219, Samantha J. Caesar-Johnson220, Andy Cafferkey59, Declan Cahill221, Claudia Calabrese59,60, Carlos Caldas222,223, Fabien Calvo224, Niedzica Camacho178, Peter J. Campbell49,225, Elias Campo226,227, Cinzia Cantù177, Shaolong Cao21, Thomas E. Carey228, Joana Carlevaro-Fita229,230,231, Rebecca Carlsen30, Ivana Cataldo167,177, Mario Cazzola232, Jonathan Cebon154, Robert Cerfolio233, Dianne E. Chadwick234, Dimple Chakravarty235, Don Chalmers236, Calvin Wing Yiu Chan47,237, Kin Chan238, Michelle Chan-Seng-Yue148, Vishal S. Chandan239, David K. Chang133,170, Stephen J. Chanock240, Lorraine A. Chantrill170,241, Aurélien Chateigner76,242, Nilanjan Chatterjee149,243, Kazuaki Chayama93, Hsiao-Wei Chen114,121, Jieming Chen218, Ken Chen50, Yiwen Chen21, Zhaohong Chen244, Andrew D. Cherniack8,82, Jeremy Chien245, Yoke-Eng Chiew246,247, Suet-Feung Chin222,223, Juok Cho8, Sunghoon Cho248, Jung Kyoon Choi249, Wan Choi250, Christine Chomienne251, Zechen Chong51, Su Pin Choo252, Angela Chou170,246, Angelika N. Christ113, Elizabeth L. Christie103, Eric Chuah30, Carrie Cibulskis8, Kristian Cibulskis8, Sara Cingarlini253, Peter Clapham49, Alexander Claviez254, Sean Cleary148,255, Nicole Cloonan256, Marek Cmero257,258,259, Colin C. Collins62, Ashton A. Connor255,260, Susanna L. Cooke133, Colin S. Cooper178,196,261, Leslie Cope149, Vincenzo Corbo138,177, Matthew G. Cordes1,262, Stephen M. Cordner263, Isidro Cortés-Ciriano264,265,266, Kyle Covington12,23, Prue A. Cowin267, Brian Craft24, David Craft8,268, Chad J. Creighton269, Yupeng Cun270, Erin Curley271, Ioana Cutcutache179,180, Karolina Czajka272, Bogdan Czerniak99,273, Rebecca A. Dagg274, Ludmila Danilova149, Maria Vittoria Davi275, Natalie R. Davidson276,277,278,279,280, Helen Davies49,281,282, Ian J. Davis283, Brandi N. Davis-Dusenbery284, Kevin J. Dawson49, Francisco M. De La Vega216,217,285, Ricardo De Paoli-Iseppi211, Timothy Defreitas8, Angelo P. Dei Tos286, Olivier Delaneau287,288,289, John A. Demchok220, Jonas Demeulemeester290,291, German M. Demidov52,53,74, Deniz Demircioğlu292,293, Nening M. Dennis221, Robert E. Denroche148, Stefan C. Dentro49,290,294, Nikita Desai76, Vikram Deshpande72, Amit G. Deshwar295, Christine Desmedt296,297, Jordi Deu-Pons298,299, Noreen Dhalla30, Neesha C. Dhani300, Priyanka Dhingra301,302, Rajiv Dhir303, Anthony DiBiase304, Klev Diamanti305, Li Ding1,2,3,20, Shuai Ding306, Huy Q. Dinh159, Luc Dirix307, HarshaVardhan Doddapaneni12, Nilgun Donmez62,78, Michelle T. Dow244, Ronny Drapkin308, Oliver Drechsel52,53, Ruben M. Drews223, Serge Serge49, Tim Dudderidge150,221, Ana Dueso-Barroso57, Andrew J. Dunford8, Michael Dunn309, Lewis Jonathan Dursi6,7, Fraser R. Duthie133,310, Ken Dutton-Regester311, Jenna Eagles272, Douglas F. Easton312,313, Stuart Edmonds314, Paul A. Edwards223,315, Sandra E. Edwards178, Rosalind A. Eeles178,221, Anna Ehinger316, Juergen Eils54,55, Roland Eils47,48,54,55, Adel El-Naggar99,273, Matthew Eldridge223, Kyle Ellrott9, Serap Erkek60, Georgia Escaramis53,317,318, Shadrielle M. G. Espiritu6, Xavier Estivill53,319, Dariush Etemadmoghadam103, Jorunn E. Eyfjord320, Bishoy M. Faltas280, Daiming Fan321, Yu Fan21, William C. Faquin72, Claudiu Farcas244, Matteo Fassan322, Aquila Fatima323, Francesco Favero324, Nodirjon Fayzullaev76, Ina Felau220, Sian Fereday103, Martin L. Ferguson325, Vincent Ferretti76,326, Lars Feuerbach205, Matthew A. Field327, J. Lynn Fink57,113, Gaetano Finocchiaro328, Cyril Fisher221, Matthew W. Fittall290, Anna Fitzgerald329, Rebecca C. Fitzgerald282, Adrienne M. Flanagan330, Neil E. Fleshner331, Paul Flicek59, John A. Foekens332, Kwun M. Fong333, Nuno A. Fonseca59,334, Christopher S. Foster335,336, Natalie S. Fox6, Michael Fraser6, Scott Frazer8, Milana Frenkel-Morgenstern337, William Friedman338, Joan Frigola298, Catrina C. Fronick1,262, Akihiro Fujimoto184, Masashi Fujita184, Masashi Fukayama339, Lucinda A. Fulton1 , Robert S. Fulton1,3,20, Mayuko Furuta184, P. Andrew Futreal340, Anja Füllgrabe59, Stacey B. Gabriel8, Steven Gallinger148,255,260, Carlo Gambacorti-Passerini341, Jianjiong Gao121, Shengjie Gao56, Levi Garraway82, Øystein Garred342, Erik Garrison49, Dale W. Garsed103, Nils Gehlenborg8,343, Josep L. l. Gelpi57,58, Joshy George110, Daniela S. Gerhard344, Clarissa Gerhauser345, Jeffrey E. Gershenwald346,347, Mark B. Gerstein5,18,19, Moritz Gerstung59,60, Gad Getz8,14,15,16, Mohammed Ghori49, Ronald Ghossein348, Nasra H. Giama349, Richard A. Gibbs12, Anthony J. Gill170,350, Pelvender Gill351, Dilip D. Giri348, Dominik Glodzik49, Vincent J. Gnanapragasam352,353, Maria Elisabeth Goebler354, Mary J. Goldman24, Carmen Gomez355, Santiago Gonzalez59,60, Abel Gonzalez-Perez298,299,356, Dmitry A. Gordenin357, James Gossage358, Kunihito Gotoh359, Ramaswamy Govindan3, Dorthe Grabau360, Janet S. Graham133,361, Robert C. Grant148,260, Anthony R. Green315, Eric Green27, Liliana Greger59, Nicola Grehan282, Sonia Grimaldi177, Sean M. Grimmond362, Robert L. Grossman363, Adam Grundhoff97,364, Gunes Gundem88, Qianyun Guo75, Manaswi Gupta8, Shailja Gupta365, Ivo G. Gut52,61, Marta Gut52,61, Jonathan Göke292,366, Gavin Ha8, Andrea Haake111, David Haan37, Siegfried Haas185, Kerstin Haase290, James E. Haber367, Nina Habermann60, Faraz Hach62,63, Syed Haider6, Natsuko Hama118, Freddie C. Hamdy351, Anne Hamilton267, Mark P. Hamilton368, Leng Han369, George B. Hanna370, Martin Hansmann371, Nicholas J. Haradhvala8,72, Olivier Harismendy102,372, Ivon Harliwong113, Arif O. Harmanci5,373, Eoghan Harrington374, Takanori Hasegawa375, David Haussler24,25, Steve Hawkins223, Shinya Hayami376, Shuto Hayashi375, D. Neil Hayes134,377,378, Stephen J. Hayes379,380, Nicholas K. Hayward211,311, Steven Hazell221, Yao He381, Allison P. Heath382, Simon C. Heath52,61, David Hedley300, Apurva M. Hegde38, David I. Heiman8, Michael C. Heinold47,48, Zachary Heins88, Lawrence E. Heisler152, Eva Hellstrom-Lindberg383, Mohamed Helmy384, Seong Gu Heo385, Austin J. Hepperla134, José María Heredia-Genestar386, Carl Herrmann47,48,387, Peter Hersey211, Julian M. Hess8,26, Holmfridur Hilmarsdottir320, Jonathan Hinton49, Satoshi Hirano388, Nobuyoshi Hiraoka389, Katherine A. Hoadley134,390, Asger Hobolth75,168, Ermin Hodzic78, Jessica I. Hoell182, Steve Hoffmann163,164,165,391, Oliver Hofmann392, Andrea Holbrook166, Aliaksei Z. Holik53, Michael A. Hollingsworth393, Oliver Holmes209,311, Robert A. Holt30, Chen Hong205,237, Eun Pyo Hong385, Jongwhi H. Hong394, Gerrit K. Hooijer395, Henrik Hornshøj73, Fumie Hosoda118, Yong Hou56,396, Volker Hovestadt397, William Howat352, Alan P. Hoyle134, Ralph H. Hruban149, Jianhong Hu12, Taobo Hu64, Xing Hua240, Kuan-lin Huang1,398, Mei Huang176, Mi Ni Huang179,180, Vincent Huang6, Yi Huang65,66, Wolfgang Huber60, Thomas J. Hudson272,399, Michael Hummel400, Jillian A. Hung246,247, David Huntsman401, Ted R. Hupp402, Jason Huse88, Matthew R. Huska403, Barbara Hutter43,67,68, Carolyn M. Hutter27, Daniel Hübschmann48,54,404,405,406, Christine A. Iacobuzio-Donahue348, Charles David Imbusch205, Marcin Imielinski407,408, Seiya Imoto375, William B. Isaacs409, Keren Isaev6,44, Shumpei Ishikawa410, Murat Iskar397, S. M. Ashiqul Islam244, Michael Ittmann411,412,413, Sinisa Ivkovic284, Jose M. G. Izarzugaza414, Jocelyne Jacquemier415, Valerie Jakrot211, Nigel B. Jamieson133,172,416, Gun Ho Jang148, Se Jin Jang417, Joy C. Jayaseelan12, Reyka Jayasinghe1 , Stuart R. Jefferys134, Karine Jegalian418, Jennifer L. Jennings419, Seung-Hyup Jeon250, Lara Jerman60,420, Yuan Ji421,422, Wei Jiao6, Peter A. Johansson311, Amber L. Johns170, Jeremy Johns272, Rory Johnson230,423, Todd A. Johnson183, Clemency Jolly290, Yann Joly424, Jon G. Jonasson320, Corbin D. Jones425, David R. Jones49, David T. W. Jones426,427, Nic Jones428, Steven J. M. Jones30, Jos Jonkers204, Young Seok Ju49,249, Hartmut Juhl429, Jongsun Jung69, Malene Juul73, Randi Istrup Juul73, Sissel Juul374, Natalie Jäger47, Rolf Kabbe47, Andre Kahles276,277,278,279,430, Abdullah Kahraman431,432,433, Vera B. Kaiser434, Hojabr Kakavand211, Sangeetha Kalimuthu148, Christof von Kalle405, Koo Jeong Kang91, Katalin Karaszi351, Beth Karlan435, Rosa Karlić436, Dennis Karsch437, Katayoon Kasaian29,30, Karin S. Kassahn113,438, Hitoshi Katai439, Mamoru Kato440, Hiroto Katoh410, Yoshiiku Kawakami93, Jonathan D. Kay117, Stephen H. Kazakoff209,311, Marat D. Kazanov441,442,443, Maria Keays59, Electron Kebebew444,445, Richard F. Kefford446, Manolis Kellis8,447, James G. Kench170,350,448, Catherine J. Kennedy246,247, Jules N. A. Kerssemakers47, David Khoo273, Vincent Khoo221, Narong Khuntikeo115,449, Ekta Khurana301,302,450,451, Helena Kilpinen117, Hark Kyun Kim452, Hyung-Lae Kim70, Hyung-Yong Kim415, Hyunghwan Kim250, Jaegil Kim8, Jihoon Kim453, Jong K. Kim454, Youngwook Kim455,456, Tari A. King457,458,459, Wolfram Klapper128, Kortine Kleinheinz47,48, Leszek J. Klimczak460, Stian Knappskog49,461, Michael Kneba437, Bartha M. Knoppers424, Youngil Koh462,463, Jan Komorowski305,464, Daisuke Komura410, Mitsuhiro Komura375, Gu Kong415, Marcel Kool426,465, Jan O. Korbel59,60, Viktoriya Korchina12, Andrey Korshunov465, Michael Koscher465, Roelof Koster466, Zsofia Kote-Jarai178, Antonios Koures244, Milena Kovacevic284, Barbara Kremeyer49, Helene Kretzmer164,165, Markus Kreuz467, Savitri Krishnamurthy99,468, Dieter Kube469, Kiran Kumar8, Pardeep Kumar221, Sushant Kumar5,19, Yogesh Kumar64, Ritika Kundra114,121, Kirsten Kübler8,14,72, Ralf Küppers470, Jesper Lagergren383,471, Phillip H. Lai166, Peter W. Laird472, Sunil R. Lakhani473, Christopher M. Lalansingh6, Emilie Lalonde6, Fabien C. Lamaze6, Adam Lambert351, Eric Lander8, Pablo Landgraf474,475, Luca Landoni115, Anita Langerød130, Andrés Lanzós230,231,423, Denis Larsimont476, Erik Larsson477, Mark Lathrop189, Loretta M. S. Lau478, Chris Lawerenz55, Rita T. Lawlor177, Michael S. Lawrence8,72,183, Alexander J. Lazar99,108, Xuan Le479, Darlene Lee30, Donghoon Lee5, Eunjung Alice Lee480, Hee Jin Lee417, Jake June-Koo Lee264,266, Jeong-Yeon Lee481, Juhee Lee482, Ming Ta Michael Lee340, Henry Lee-Six49, Kjong-Van Lehmann276,277,278,279,430, Hans Lehrach483, Dido Lenze400, Conrad R. Leonard209,311, Daniel A. Leongamornlert49,178, Ignaty Leshchiner8, Louis Letourneau484, Ivica Letunic71, Douglas A. Levine88,485, Lora Lewis12, Tim Ley486, Chang Li56,396, Constance H. Li6,44, Haiyan Irene Li30, Jun Li21, Lin Li56, Shantao Li5, Siliang Li56,396, Xiaobo Li56,396, Xiaotong Li5, Xinyue Li56, Yilong Li49, Han Liang21, Sheng-Ben Liang234, Peter Lichter68,397, Pei Lin8, Ziao Lin8,487, W. M. Linehan488, Ole Christian Lingjærde489, Dongbing Liu56,396, Eric Minwei Liu88,301,302, Fei-Fei Liu201,490, Fenglin Liu381,491, Jia Liu492, Xingmin Liu56,396, Julie Livingstone6, Dimitri Livitz8, Naomi Livni221, Lucas Lochovsky5,19,110, Markus Loeffler467, Georgina V. Long211, Armando Lopez-Guillermo493, Shaoke Lou5,19, David N. Louis72, Laurence B. Lovat117, Yiling Lu38, Yong-Jie Lu162,494, Youyong Lu495,496,497, Claudio Luchini167, Ilinca Lungu144,148, Xuemei Luo152, Hayley J. Luxton117, Andy G. Lynch223,315,498, Lisa Lype36, Cristina López111,112, Carlos López-Otín499, Eric Z. Ma64, Yussanne Ma30, Gaetan MacGrogan500, Shona MacRae501, Geoff Macintyre223, Tobias Madsen73, Kazuhiro Maejima184, Andrea Mafficini177, Dennis T. Maglinte166,502, Arindam Maitra174, Partha P. Majumder174, Luca Malcovati232, Salem Malikic62,78, Giuseppe Malleo115, Graham J. Mann211,246,503, Luisa Mantovani-Löffler504, Kathleen Marchal505,506, Giovanni Marchegiani115, Elaine R. Mardis1,193,507, Adam A. Margolin31, Maximillian G. Marin37, Florian Markowetz223,315, Julia Markowski403, Jeffrey Marks508, Tomas Marques-Bonet61,81,386,509, Marco A. Marra30, Luke Marsden351, John W. M. Martens332, Sancha Martin49,510, Jose I. Martin-Subero81,511, Iñigo Martincorena49, Alexander Martinez-Fundichely301,302,451 Yosef E. Maruvka8,26,72, R. Jay Mashl1,2, Charlie E. Massie223, Thomas J. Matthew37, Lucy Matthews178, Erik Mayer221,512, Simon Mayes513, Michael Mayo30, Faridah Mbabaali272, Karen McCune514, Ultan McDermott49, Patrick D. McGillivray19, Michael D. McLellan1,3,20, John D. McPherson148,272,515, John R. McPherson179,180, Treasa A. McPherson260, Samuel R. Meier8, Alice Meng516, Shaowu Meng134, Andrew Menzies49, Neil D. Merrett115,517, Sue Merson178, Matthew Meyerson8,14,82, William U. Meyerson4,5, Piotr A. Mieczkowski518, George L. Mihaiescu76, Sanja Mijalkovic284, Ana Mijalkovic Mijalkovic-Lazic284, Tom Mikkelsen519, Michele Milella253, Linda Mileshkin103, Christopher A. Miller1 , David K. Miller113,170, Jessica K. Miller272, Gordon B. Mills33,34, Ana Milovanovic57, Sarah Minner520, Marco Miotto115, Gisela Mir Arnau267, Lisa Mirabello240, Chris Mitchell103, Thomas J. Mitchell49,315,352, Satoru Miyano375, Naoki Miyoshi375, Shinichi Mizuno521, Fruzsina Molnár-Gábor522, Malcolm J. Moore300, Richard A. Moore30, Sandro Morganella49, Quaid D. Morris127,490, Carl Morrison523,524, Lisle E. Mose134, Catherine D. Moser349, Ferran Muiños298,299, Loris Mularoni298,299, Andrew J. Mungall30, Karen Mungall30, Elizabeth A. Musgrove133, Ville Mustonen525,526,527, David Mutch528, Francesc Muyas52,53,74, Donna M. Muzny12, Alfonso Muñoz59, Jerome Myers529, Ola Myklebost461, Peter Möller530, Genta Nagae89, Adnan M. Nagrial170, Hardeep K. Nahal-Bose76, Hitoshi Nakagama531, Hidewaki Nakagawa184, Hiromi Nakamura118, Toru Nakamura388, Kaoru Nakano184, Tannistha Nandi532, Jyoti Nangalia49, Mia Nastic284, Arcadi Navarro61,81,386, Fabio C. P. Navarro19, David E. Neal223,352, Gerd Nettekoven533, Felicity Newell209,311, Steven J. Newhouse59, Yulia Newton37, Alvin Wei Tian Ng534, Anthony Ng535, Jonathan Nicholson49, David Nicol221, Yongzhan Nie321,536, G. Petur Nielsen72, Morten Muhlig Nielsen73, Serena Nik-Zainal49,281,282,537, Michael S. Noble8, Katia Nones209,311, Paul A. Northcott538, Faiyaz Notta148,539, Brian D. O’Connor76,540, Peter O’Donnell541, Maria O’Donovan282, Sarah O’Meara49, Brian Patrick O’Neill542, J. Robert O’Neill543, David Ocana59, Angelica Ochoa88, Layla Oesper544, Christopher Ogden221, Hideki Ohdan93, Kazuhiro Ohi375, Lucila Ohno-Machado244, Karin A. Oien523,545, Akinyemi I. Ojesina546,547,548, Hidenori Ojima549, Takuji Okusaka550, Larsson Omberg551, Choon Kiat Ong552, Stephan Ossowski52,53,74, German Ott553, B. F. Francis Ouellette76,554, Christine P’ng6, Marta Paczkowska6, Salvatore Paiella115, Chawalit Pairojkul523, Marina Pajic170, Qiang Pan-Hammarström56,555, Elli Papaemmanuil49, Irene Papatheodorou59, Nagarajan Paramasivam43,47, Ji Wan Park385, Joong-Won Park556, Keunchil Park557,558, Kiejung Park559, Peter J. Park264,266, Joel S. Parker518, Simon L. Parsons124, Harvey Pass560, Danielle Pasternack272, Alessandro Pastore276, Ann-Marie Patch209,311, Iris Pauporté251, Antonio Pea115, John V. Pearson209,311, Chandra Sekhar Pedamallu8,14,82, Jakob Skou Pedersen73,75, Paolo Pederzoli115, Martin Peifer270, Nathan A. Pennell561, Charles M. Perou129,518, Marc D. Perry76,77, Gloria M. Petersen562, Myron Peto22, Nicholas Petrelli563, Robert Petryszak59, Stefan M. Pfister426,465,564, Mark Phillips424, Oriol Pich298,299, Hilda A. Pickett478, Todd D. Pihl565, Nischalan Pillay566, Sarah Pinder567, Mark Pinese170, Andreia V. Pinho568, Esa Pitkänen60, Xavier Pivot569, Elena Piñeiro-Yáñez95, Laura Planko533, Christoph Plass345, Paz Polak8,14,15, Tirso Pons570, Irinel Popescu571, Olga Potapova572, Aparna Prasad52, Shaun R. Preston573, Manuel Prinz47, Antonia L. Pritchard311, Stephenie D. Prokopec6, Elena Provenzano574, Xose S. Puente499, Sonia Puig176, Montserrat Puiggròs57, Sergio Pulido-Tamayo505,506, Gulietta M. Pupo246, Colin A. Purdie575, Michael C. Quinn209,311, Raquel Rabionet52,53,576, Janet S. Rader577, Bernhard Radlwimmer397, Petar Radovic284, Benjamin Raeder60, Keiran M. Raine49, Manasa Ramakrishna49, Kamna Ramakrishnan49, Suresh Ramalingam578, Benjamin J. Raphael579, W. Kimryn Rathmell580, Tobias Rausch60, Guido Reifenberger475, Jüri Reimand6,44, Jorge Reis-Filho348, Victor Reuter348, Iker Reyes-Salazar298, Matthew A. Reyna579, Sheila M. Reynolds36, Esther Rheinbay8,14,72, Yasser Riazalhosseini189, Andrea L. Richardson323, Julia Richter111,128, Matthew Ringel581, Markus Ringnér181, Yasushi Rino582, Karsten Rippe405, Jeffrey Roach583, Lewis R. Roberts349, Nicola D. Roberts49, Steven A. Roberts584, A. Gordon Robertson30, Alan J. Robertson113, Javier Bartolomé Rodriguez57, Bernardo Rodriguez-Martin104,105,106, F. Germán Rodríguez-González83,332, Michael H. A. Roehrl44,123,148,234,585,586, Marius Rohde587, Hirofumi Rokutan440, Gilles Romieu588, Ilse Rooman170, Tom Roques262, Daniel Rosebrock8, Mara Rosenberg8,72, Philip C. Rosenstiel589, Andreas Rosenwald590, Edward W. Rowe221,591, Romina Royo57, Steven G. Rozen179,180,592, Yulia Rubanova17,127, Mark A. Rubin423,593,594,595,596, Carlota Rubio-Perez298,299,597, Vasilisa A. Rudneva60, Borislav C. Rusev177, Andrea Ruzzenente598, Gunnar Rätsch276,277,278,279,280,430, Radhakrishnan Sabarinathan298,299,599, Veronica Y. Sabelnykova6, Sara Sadeghi30, S. Cenk Sahinalp62,78,79, Natalie Saini357, Mihoko Saito-Adachi440, Gordon Saksena8, Adriana Salcedo6, Roberto Salgado600, Leonidas Salichos5,19, Richard Sallari8, Charles Saller601, Roberto Salvia115, Michelle Sam272, Jaswinder S. Samra115,602, Francisco Sanchez-Vega114,121, Chris Sander276,603,604, Grant Sanders134, Rajiv Sarin605, Iman Sarrafi62,78, Aya Sasaki-Oku184, Torill Sauer489, Guido Sauter520, Robyn P. M. Saw211, Maria Scardoni167, Christopher J. Scarlett170,606, Aldo Scarpa177, Ghislaine Scelo194, Dirk Schadendorf68,607, Jacqueline E. Schein30, Markus B. Schilhabel589, Matthias Schlesner47,80, Thorsten Schlomm84,608, Heather K. Schmidt1 , Sarah-Jane Schramm246, Stefan Schreiber609, Nikolaus Schultz121, Steven E. Schumacher8,323, Roland F. Schwarz59,403,405,610, Richard A. Scolyer211,448,602, David Scott428, Ralph Scully611, Raja Seethala612, Ayellet V. Segre8,613, Iris Selander260, Colin A. Semple434, Yasin Senbabaoglu276, Subhajit Sengupta614, Elisabetta Sereni115, Stefano Serra585, Dennis C. Sgroi72, Mark Shackleton103, Nimish C. Shah352, Sagedeh Shahabi234, Catherine A. Shang329, Ping Shang211, Ofer Shapira8,323, Troy Shelton271, Ciyue Shen603,604, Hui Shen615, Rebecca Shepherd49, Ruian Shi490, Yan Shi134, Yu-Jia Shiah6, Tatsuhiro Shibata118,616, Juliann Shih8,82, Eigo Shimizu375, Kiyo Shimizu617, Seung Jun Shin618, Yuichi Shiraishi375, Tal Shmaya285, Ilya Shmulevich36, Solomon I. Shorser6, Charles Short59, Raunak Shrestha62, Suyash S. Shringarpure217, Craig Shriver619, Shimin Shuai6,126, Nikos Sidiropoulos83, Reiner Siebert112,620, Anieta M. Sieuwerts332, Lina Sieverling205,237, Sabina Signoretti202,621, Katarzyna O. Sikora177, Michele Simbolo138, Ronald Simon520, Janae V. Simons134, Jared T. Simpson6,17, Peter T. Simpson473, Samuel Singer115,458, Nasa Sinnott-Armstrong8,217, Payal Sipahimalani30, Tara J. Skelly390, Marcel Smid332, Jaclyn Smith622, Karen Smith-McCune514, Nicholas D. Socci276, Heidi J. Sofia27, Matthew G. Soloway134, Lei Song240, Anil K. Sood623,624,625, Sharmila Sothi626, Christos Sotiriou244, Cameron M. Soulette37, Paul N. Span627, Paul T. Spellman22, Nicola Sperandio177, Andrew J. Spillane211, Oliver Spiro8, Jonathan Spring628, Johan Staaf181, Peter F. Stadler163,164,165, Peter Staib629, Stefan G. Stark277,279,618,630, Lucy Stebbings49, Ólafur Andri Stefánsson631, Oliver Stegle59,60,632, Lincoln D. Stein6,126, Alasdair Stenhouse633, Chip Stewart8, Stephan Stilgenbauer634, Miranda D. Stobbe52,61, Michael R. Stratton49, Jonathan R. Stretch211, Adam J. Struck31, Joshua M. Stuart24,37, Henk G. Stunnenberg396,635, Hong Su56,396, Xiaoping Su99, Ren X. Sun6, Stephanie Sungalee60, Hana Susak52,53, Akihiro Suzuki89,636, Fred Sweep637, Monika Szczepanowski128, Holger Sültmann67,638, Takashi Yugawa617, Angela Tam30, David Tamborero298,299, Benita Kiat Tee Tan639, Donghui Tan518, Patrick Tan180,532,592,640, Hiroko Tanaka375, Hirokazu Taniguchi616, Tomas J. Tanskanen641, Maxime Tarabichi49,290, Roy Tarnuzzer220, Patrick Tarpey642, Morgan L. Taschuk152, Kenji Tatsuno89, Simon Tavaré223,643, Darrin F. Taylor113, Amaro Taylor-Weiner8, Jon W. Teague49, Bin Tean Teh180,592,640,644,645, Varsha Tembe246, Javier Temes104,105, Kevin Thai76, Sarah P. Thayer393, Nina Thiessen30, Gilles Thomas646, Sarah Thomas221, Alan Thompson221, Alastair M. Thompson633, John F. Thompson211, R. Houston Thompson647, Heather Thorne103, Leigh B. Thorne176, Adrian Thorogood424, Grace Tiao8, Nebojsa Tijanic284, Lee E. Timms272, Roberto Tirabosco648, Marta Tojo106, Stefania Tommasi649, Christopher W. Toon170, Umut H. Toprak48,650, David Torrents57,81, Giampaolo Tortora651,652, Jörg Tost653, Yasushi Totoki118, David Townend654, Nadia Traficante103, Isabelle Treilleux655,656, Jean-Rémi Trotta61, Lorenz H. P. Trümper469, Ming Tsao124,539, Tatsuhiko Tsunoda183,657,658,659, Jose M. C. Tubio104,105,106, Olga Tucker660, Richard Turkington661, Daniel J. Turner513, Andrew Tutt323, Masaki Ueno376, Naoto T. Ueno662, Christopher Umbricht151,213,663, Husen M. Umer305,664, Timothy J. Underwood665, Lara Urban59,60, Tomoko Urushidate616, Tetsuo Ushiku339, Liis Uusküla-Reimand666,667, Alfonso Valencia57,81, David J. Van Den Berg166, Steven Van Laere307, Peter Van Loo290,291, Erwin G. Van Meir668, Gert G. Van den Eynden307, Theodorus Van der Kwast123, Naveen Vasudev137, Miguel Vazquez57,669, Ravikiran Vedururu267, Umadevi Veluvolu518, Shankar Vembu490,670, Lieven P. C. Verbeke506,671, Peter Vermeulen307, Clare Verrill351,672, Alain Viari177, David Vicente57, Caterina Vicentini177, K. Vijay Raghavan365, Juris Viksna673, Ricardo E. Vilain674, Izar Villasante57, Anne Vincent-Salomon635, Tapio Visakorpi190, Douglas Voet8, Paresh Vyas311,351, Ignacio Vázquez-García49,86,675,676, Nick M. Waddell209, Nicola Waddell209,311, Claes Wadelius677, Lina Wadi6, Rabea Wagener111,112, Jeremiah A. Wala8,14,82, Jian Wang56, Jiayin Wang1,40,66, Linghua Wang12, Qi Wang465, Wenyi Wang21, Yumeng Wang21, Zhining Wang220, Paul M. Waring523, Hans-Jörg Warnatz483, Jonathan Warrell5,19, Anne Y. Warren352,678, Sebastian M. Waszak60, David C. Wedge49,294,679, Dieter Weichenhan345, Paul Weinberger680, John N. Weinstein38, Joachim Weischenfeldt60,83,84, Daniel J. Weisenberger166, Ian Welch681, Michael C. Wendl1,10,11, Johannes Werner47,85, Justin P. Whalley61,682, David A. Wheeler12,13, Hayley C. Whitaker117, Dennis Wigle683, Matthew D. Wilkerson518, Ashley Williams244, James S. Wilmott211, Gavin W. Wilson6,148, Julie M. Wilson148, Richard K. Wilson1,684, Boris Winterhoff685, Jeffrey A. Wintersinger17,127,384, Maciej Wiznerowicz686,687, Stephan Wolf688, Bernice H. Wong689, Tina Wong1,30, Winghing Wong690, Youngchoon Woo250, Scott Wood209,311, Bradly G. Wouters44, Adam J. Wright6, Derek W. Wright133,691, Mark H. Wright217, Chin-Lee Wu72, Dai-Ying Wu285, Guanming Wu692, Jianmin Wu170, Kui Wu56,396, Yang Wu179,180, Zhenggang Wu64, Liu Xi12, Tian Xia693, Qian Xiang76, Xiao Xiao66, Rui Xing497, Heng Xiong56,396, Qinying Xu209,311, Yanxun Xu694, Hong Xue64, Shinichi Yachida118,695, Sergei Yakneen60, Rui Yamaguchi375, Takafumi N. Yamaguchi6, Masakazu Yamamoto120, Shogo Yamamoto89, Hiroki Yamaue376, Fan Yang490, Huanming Yang56, Jean Y. Yang696, Liming Yang220, Lixing Yang697, Shanlin Yang306, Tsun-Po Yang270, Yang Yang369, Xiaotong Yao408,698, Marie-Laure Yaspo483, Lucy Yates49, Christina Yau156, Chen Ye56,396, Kai Ye40,41, Venkata D. Yellapantula20,86, Christopher J. Yoon249, Sung-Soo Yoon463, Fouad Yousif6, Jun Yu699, Kaixian Yu700, Willie Yu701, Yingyan Yu702, Ke Yuan223,510,703, Yuan Yuan21, Denis Yuen6, Takashi Yugawa617, Christina K. Yung76, Olga Zaikova704, Jorge Zamora49,104,105,106, Marc Zapatka397, Jean C. Zenklusen220, Thorsten Zenz67, Nikolajs Zeps705,706, Cheng-Zhong Zhang8,707, Fan Zhang381, Hailei Zhang8, Hongwei Zhang494, Hongxin Zhang121, Jiashan Zhang220, Jing Zhang5, Junjun Zhang76, Xiuqing Zhang56, Xuanping Zhang66,369, Yan Zhang5,708,709, Zemin Zhang381,710, Zhongming Zhao711, Liangtao Zheng381, Xiuqing Zheng381, Wanding Zhou615, Yong Zhou56, Bin Zhu240, Hongtu Zhu700,712, Jingchun Zhu24, Shida Zhu56,396, Lihua Zou713, Xueqing Zou49, Anna deFazio246,247,714, Nicholas van As221, Carolien H. M. van Deurzen715, Marc J. van de Vijver523, L. van’t Veer716 & Christian von Mering433,717, The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts.

While much recent research has examined flamingo unipedal resting, as well as laterality in the resting behaviours of these birds, the phenomenon of unihemispheric sleep is not well documented in flamingos, and the potential relationship between unihemispheric sleep and these other aspects of flamingo resting behaviour has not been thoroughly explored. In the present report, unihemispheric sleep was studied in Caribbean Flamingos (Phoenicopterus ruber) (n=17) at the Philadelphia Zoo (Philadelphia, PA, USA). Specifically, we examined whether unihemispheric sleep, as measured by contralateral eye closure, is associated with unipedal resting and lateral behavioural side choice in resting Caribbean Flamingos. Results over three studies evidenced that Caribbean Flamingos do engage in unihemispheric sleep, and suggested that unihemispheric sleep is not related to unipedal resting or lateral neck-resting behaviour. Moreover, Harker and Harker's (2010) hypothesis that unipedal resting in flamingos is brought on by the impending onset of unihemispheric sleep was tested, with results failing to support this notion.

Background: Online video-sharing platforms such as YouTube have become popular sources of medical information for patients. However, concern exists regarding the quality of such non–peer reviewed content. In fact, a previous investigation found the majority of YouTube information related to femoroacetabular impingement (FAI) to be of poor quality. Purpose: To provide an updated assessment of the quality of FAI-related videos available on YouTube. Study Design: Cross-sectional study. Methods: The terms FAI, femoroacetabular impingement, and hip impingement were searched on YouTube, and exclusion criteria were applied to the first 100 results for each term. The diagnostic and treatment content of each video was graded and assigned a quality assessment rating based on a previously used rubric. Video characteristics (e.g. duration, views, “likes”) were compared using both quality assessment rating and video source. Results: A total of 142 videos were included in the final analysis. The most common video source was educational (48.6%), followed by physician-sponsored (30.3%). The majority of videos were graded as “somewhat useful” for both diagnostic and treatment content (59.4% and 61.6%, respectively); however, treatment content was rated “not useful” more often than diagnostic information (20.3% vs. 8.7%, respectively). Videos rated as “somewhat useful” received the most views per day on average, while educational videos were the most viewed by source (views and views per day). Educational videos had more views and likes on average than physician-sponsored videos ( P < .05), but all other comparisons of video characteristics by source were not significant. Video duration was the only characteristic found to vary significantly by quality assessment rating ( P < .001 for both diagnostic and treatment analyses), with higher-quality videos tending to be longer. Videos rated as “excellent” and “very useful” had mean durations >30 minutes but were viewed the least. Conclusion: The overall quality of FAI-related content on YouTube remains low. Clinicians should be familiar with medical information available to patients on the internet, as it can influence patients’ perspectives and shared decision-making processes. This review substantiates the need for more publicly available, high-quality video content regarding the diagnosis and treatment of FAI.

Despite their prevalent use amongst avian species, particularly in Budgerigars, the relationship between mirror use and social behaviors is in need of elucidation. After establishing social behavior measures (e.g., agonistic and pair-bond data) in a colony of Budgerigars, mirrors were introduced and subsequent use was documented. Results illustrated a significant relationship between mirror use and pair-bonds, such that mirror use increased with increasing pair-bond strength. The authors posit that individual differences in gregariousness may best account for the obtained results, with certain birds seeking more social stimulation than others, whether it be from a pair-bond or from its own reflected mirror image. Additionally, the trends observed within agonistic behaviors were consistent with previous avian literature such that those who initiated more encounters also won more encounters and that there was a preference to be closer to birds that win more encounters.

Background:Shoulder instability is a common and potentially debilitating injury among collision sport athletes that can lead to long-term damage of the glenohumeral joint. Limited data exist regarding instability among elite athletes in the National Football League (NFL).Purpose:To describe the epidemiology of shoulder instability in the NFL from 2012 through 2017.Study Design:Descriptive epidemiology study.Methods:The NFL’s injury database was reviewed for shoulder instability injuries resulting in missed time during the study inclusion dates. Injuries were classified by type and direction, as well as timing, setting, and mechanism. Median missed time was determined for the different types and directions of instability. Incidence rates for game-related injuries were calculated based on timing during the season and player position. Finally, the relationship between player position and instability direction was assessed.Results:During the 6-year study period, 355 players sustained 403 missed-time shoulder instability injuries. Most injuries occurred during games (65%) via a contact mechanism (85%). The overall incidence rate of game-related instability was 3.6 injuries per 100,000 player-plays and was highest during the preseason (4.9 per 100,000 player-plays). The defensive secondary position accounted for the most injuries, but quarterbacks had the highest incidence rate in games (5.5 per 100,000 player-plays). Excluding unspecified events (n = 128; 32%), 70% (n = 192) of injuries were subluxations and 30% (n = 83) were dislocations; 75% of dislocations were anterior, while subluxations were more evenly distributed between the anterior and posterior directions (45% vs 52%, respectively). Players missed substantially more time after dislocation compared with subluxation (median, 47 days vs 13 days, respectively). When instability direction was known, the majority of instability events among quarterbacks and offensive linemen were posterior (73% and 53%, respectively), while anterior instability was most common for all other positions.Conclusion:Shoulder instability is a common injury in the NFL and can result in considerable missed time. Dislocations occur less frequently than subluxations but lead to greater time lost. While most dislocations are anterior, more than half of subluxations are posterior, which is likely the result of repetitive microtrauma to the posterior capsulolabral complex sustained during sport-specific motions such as blocking. The risk of instability varies by player position, and position may also influence instability direction.

Large and medium-bodied rainforest canopy mammals are typically surveyed using line transects, but these are labour intensive and usually ignore nocturnal species. Camera traps have become the preferred tool for assessing terrestrial mammal communities, but have rarely been used for arboreal species. Here, we compare the efficiency of arboreal camera trapping with line transects for inventorying medium and large-sized arboreal mammals, and assess the viability of using camera traps in trees to model habitat occupancy. We installed 42 camera traps, spaced 2 km apart, in the canopy of the Maijuna-Kichwa Regional Conservation Area, Peru and walked 2014 km of diurnal line transects on 22 trails at the same site. We compared the efficiency of each method using species accumulation curves. We applied a multi-species occupancy model, while examining the effect of camera height on detection probabilities, including the distance from a village and from a river as covariates to examine variability in habitat occupancy. In 3147 camera days, 18 species of arboreal medium and large-sized mammals were detected by cameras, while 11 species were recorded on line transects. Ten of these species were detected by both methods. Diurnal species were detected more quickly and with less effort using arboreal camera trapping than using diurnal line transects at the same site, although some species were more easily detected during line transects. Habitat occupancy was positively correlated with distance from the village for two species, and negatively correlated with distance from the river for one. Detection probabilities increased modestly with camera height. Practical limitations of arboreal camera trapping include the requirement for specialized climbing techniques, as well as increased potential for false triggers, requiring extended processing time. Arboreal camera trapping is an efficient method for inventorying arboreal mammals and a viable option for studying their distribution relative to environmental or anthropogenic variables when abundance or density estimates are not required.

Osteophytes are a typical radiographic finding during osteoarthritis (OA). Osteophytes are thought to form in response to joint instability; however, the time course of osteophyte formation and joint stabilization following joint injury is not well understood. In this study, we investigated the time course of osteophyte formation and joint function following non-invasive knee injury in mice. We hypothesized that initial joint instability following knee injury would initiate osteophyte formation, which would in turn restabilize the joint and reduce range of motion (ROM). Mice were subjected to non-invasive anterior cruciate ligament (ACL) rupture. Anterior-posterior (AP) joint laxity, ROM, and chondro/osteophyte formation were measured immediately after injury, and 2, 4, 6, and 8 weeks post-injury. Chondrophyte areas at each time point were measured with histology, while mineralized osteophyte volume was determined using micro-computed tomography. Immediately after ACL rupture, AP joint laxity was increased twofold, while ROM was increased 11.7%. Chondrophytes appeared by 2 weeks post-injury, corresponding with a decrease in AP joint laxity and ROM. By 8 weeks post-injury, considerable osteophyte formation was observed around the joint, AP joint laxity returned to control levels, and joint ROM decreased to 61% of control values. These data support a role for chondro/osteophytes in joint restabilization after injury, and provide crucial insight into the time course and pathology of joint degeneration during OA development in the mouse. Statement of Clinical Significance: Results from this study increase understanding of conditions leading to osteophyte formation.© 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:466-473, 2017.

During vertebrate embryogenesis the interdigital mesenchyme is removed by programmed cell death (PCD), except in species with webbed limbs. Although bone morphogenetic proteins (BMPs) have long been known to be players in this process, it is unclear if they play a direct role in the interdigital mesenchyme or if they only act indirectly, by affecting fibroblast growth factor (FGF) signaling. A series of genetic studies have shown that BMPs act indirectly by regulating the withdrawal of FGF activity from the apical ectodermal ridge (AER); this FGF activity acts as a cell survival factor for the underlying mesenchyme. Other studies using exogenous factors to inhibit BMP activity in explanted mouse limbs suggest that BMPs do not act directly in the mesenchyme. To address the question of whether BMPs act directly, we used an interdigit-specific Cre line to inactivate several genes that encode components of the BMP signaling pathway, without perturbing the normal downregulation of AER-FGF activity. Of three Bmps expressed in the interdigital mesenchyme, Bmp7 is necessary for PCD, but Bmp2 and Bmp4 both have redundant roles, with Bmp2 being the more prominent player. Removing BMP signals to the interdigit by deleting the receptor gene, Bmpr1a, causes a loss of PCD and syndactyly, thereby unequivocally proving that BMPs are direct triggers of PCD in this tissue. We present a model in which two events must occur for normal interdigital PCD: the presence of a BMP death trigger and the absence of an FGF survival activity. We demonstrate that neither event is required for formation of the interdigital vasculature, which is necessary for PCD. However, both events converge on the production of reactive oxygen species that activate PCD.