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Harnleiterstrikturen sind seltene Komplikationen einer Strahlentherapie, die oftmals spat erkannt werden. Ihre Folgen reichen von harmlosen Dilatationen des Harnleiters bis hin zum Verlust der Nierenfunktion und der potentiellen Gefahr einer lebensbedrohlichen Urosepsis.

The aim of this study is to investigate the measurement invariance of media users’ entertainment experiences as conceptualized by two-process models of entertainment (i.e., enjoyment and appreciation) across different media formats. With this purpose, the present research relates to the recent rise of entertainment research, embracing more and more media types and formats with which entertainment experiences may occur. At the same time, it addresses a methodological issue that has rarely been addressed in communication research. Focusing on one of the most often used measurement instruments in entertainment research, on three different media formats (political talk shows, comedies, and dramas), the study finds evidence for configural, metric, and scalar invariance for the scale. The theoretical and practical implications of the findings are discussed.

This paper reports on the search for heavy neutrinos with masses in the range 140, Physical Review D, 100 (5), ISSN:1550-7998, ISSN:0556-2821, ISSN:1550-2368

BACKGROUND: Elevated Metrorail systems differ from conventional trains by their slower speeds and collisions with pedestrians predominantly occurring at accessible stations or platforms. Here, the orthopedic implications of pedestrians struck by a Metrorail are evaluated, as were the correlations of substance abuse and psychiatric history on injury and death. METHODS: Retrospective cohort study at a single Level-1 trauma center of patients requiring admission with orthopedic injuries following Metrorail impact from 1/2004-2/2017. Demographics, substance abuse, psychiatric history, intentionality, LOS, follow-up, fracture characteristics, and management were studied. RESULTS: 33 patients sustained 104 total orthopedic injuries requiring admission; nine sustained 15 traumatic amputations. There were at least 37 open fractures, with some incomplete data in deceased (5) and amputation (9) patients. Suicide attempts were completed at 35.7% and were associated with a documented psychiatric illness and prior psychiatric evaluation. Spine injuries were associated with increased traumatic brain injuries, rib fractures, and open pelvic ring injuries, yet fewer humerus fractures. Open fractures were significantly predictive of death. 14 patients (42.4%) required ICU admission, and 26 (78.8%) patients required orthopaedic surgery (mean 1.3 ± 1.4 operations). CONCLUSIONS: Metrorail systems are unique sources of orthopaedic injuries requiring high rates of critical care and surgical intervention. Patients sustain multiple injuries, many with amputations. With this mechanism, there is a high rate of open fractures and suicide. Trauma centers should emphasize an extensive evaluation of orthopaedic injuries in this patient setting. Level of Evidence: II

Background Observational studies have demonstrated that african american patients with Systemic Sclerosis (SSc) have a more unfavorable prognosis compared with non-African americans. However, no studies have evaluated racial disparities using data from a randomized controlled trial (RCT) where all patients have equal access to care and standard treatment and follow-up during the trial. Objectives To compare morbidity and mortality in african american and non-African american patients who participated in the Scleroderma Lung Study (SLS) I and II.1,2 Methods SLS I randomized 158 SSc patients with interstitial lung disease (ILD) from 13 US SSc centers to 1 year of oral CYC (cyclophosphamide) versus placebo. SLS II randomized 142 SSc-ILD participants from 14 US SSc centers to 1 year of oral CYC, followed by 1 year of placebo, versus 2 years of mycophenolate (MMF). Up to 12 (SLS I) and 5 (SLS II) years after randomization, we contacted enrolled patients or designated surrogates to assess the following: mortality, cause of mortality, and development of organ failure. We used cox proportional hazard modeling to determine the variables associated with survival. Results Baseline characteristics of the SLS I and II cohorts were similar. In SLS I, african american participants (N=26) were younger than non-African american participants (N=132) (43.1 vs. 49.5 years, P=0.015). In SLS II, african american participants (N=33) had slightly increased baseline forced vital capacity (FVC) (69.2 vs 65.6, P=0.038), compared with non-American american participants (N=109). There were no significant baseline differences in the extent of cutaneous sclerosis (Modified Rodnan Skin Score [MRSS]), presence of diffuse cutaneous disease or serological profiles between racial groups. After adjusting for age, MRSS, FVC, there was no difference in long-term mortality outcomes (due to all causes or due to respiratory failure) in african american versus Non-African american SSc-ILD participants in SLS I or II (Figure 1). There was also no difference in time to the development of respiratory failure in african american versus Non-African american SSc-ILD participants in SLS I or II. Conclusion Data from two of the largest RCTs in SSc-ILD demonstrated that african american patients with SSc-ILD have similar morbidity and mortality outcomes compared with non-African american SSc-ILD patients, even after adjusting for age and baseline disease severity. These findings contrast with the racial disparities described in previous observational studies and warrant further investigation. References [1] Tashkin, et al. NEJM2006;354:2655. [2] Tashkin, et al. Lancet Resp Med2016;4:708. Figure 1a. Time to death in african american participants of SLS I (red line) and non-African american participants of SLS I (blue line). Figure 1b. Time to death in african american participants of SLS II (red line) and non-African american participants of SLS II (blue line). Disclosure of interests Elizabeth Volkmann Shareholder of: Pfizer, inc., Consultant for: Boehringer ingelheim, Speakers bureau: Boehringer ingelheim, Ning Li: None declared, Dinesh Khanna Shareholder of: Eicos Sciences, inc, Grant/research support from: Bayer, BMS, Pfizer, Horizon, Consultant for: actelion acceleron, arena, Bayer, BI, BMS, CSL Behring, Corbus, Cytori, GSK, Genentech/Roche, Galapagos, Employee of: Elcos Sciences, inc, Philip Clements: None declared, Daniel Furst Grant/research support from: F. Hoffmann-La Roche, Genentech, Shervin assassi: None declared, Michael Roth Grant/research support from: Genentech/Roche, Robert Elashoff: None declared, Donald Tashkin Consultant for: EMD Serono

Introduction Irritable bowel syndrome (IBS) is one of the most common functional gastrointestinal disorders. A pooled analysis showed a global prevalence of 11.2%. Few studies looked at the prevalence of IBS in health care providers. The aim of this study was to determine the prevalence of IBS among board-certified physicians and surgeons. Methods Board-certified physicians and surgeons in Saudi Arabia were invited to complete a web-based survey. It included questions regarding participant demographics, specialty, practice type and hours worked per week. The Rome IV-validated questionnaire was used to identify subjects with IBS. The primary outcome of the study was the prevalence of IBS among physicians. Secondary outcomes included exploring the effect on IBS prevalence of age, gender, marital status, work hours, specialty, gastroenterology subspecialty and working in a public versus private hospital. Results The final analysis included 594 subjects, with 419 males and a median age of 41. The vast majority (86%) were married. Nearly 90% worked in a public hospital exclusively, and the median number of hours worked per week was 48. The overall prevalence of IBS was 16.3%. In a binary logistic regression model, age (odds ratio [OR] = 0.931, P < 0.0001), gender (OR = 0.504, P = 0.003) and work hours (OR = 2.397, P < 0.0001) significantly predicted the presence of IBS. Marital status and specialty did not predict IBS prevalence. Discussion This cross-sectional study shows that the prevalence of IBS among physicians in Saudi Arabia to be 16.3%. IBS was more common in females, those who worked longer hours and younger physicians. There was no association between practicing certain specialties and IBS. However, the lack of difference in our cohort may be attributed to the relatively small sample size from each specialty.

Constitutive Models for Rubber XI 11th Eruopean conference on constitutive models for Rubber, ECCMR XI, Nantes, France, 25 Jun 2019 - 27 Jun 2019; Leiden, Netherlands : CRC Press/Balkema 20-23 (2019)., Strain induced crystallization (SIC) is one of the .most influencing factors for the outstanding mechanical properties of natural rubber. It was extensively investigated within the last decades (e.g. Zhang et al. 2013, Brüning 2014). In practical use, and mainly in the case of pre-cracked respectively damaged samples, the strain field around the crack tip is highly inhomogeneous. This will influence the strain induced crys-tallization. Therefore, the effective crystallite distribution and orientation around the crack tip will be as well inhomogeneous. In contrast to the uniaxial tensile load of rubber with fibre symmetrical distribution of crystallites, in pure shear samples no fibre symmetry is found. The crystallite orientation with respect to the sample geometry will be investigated via x-ray scattering. and the results are used to describe the crystallization under inhomogeneous stretching conditions., Published by CRC Press/Balkema, Leiden, Netherlands

The Hawaiian Archipelago is one of the largest and most isolated island chains in the world, and its marine ecosystems are well-studied. Research on Hawaiian mesophotic coral ecosystems (MCEs) began in the 1960s and has intensified during the past decade. In Hawai‘i, rich communities of macroalgae, corals and other invertebrates, and fishes inhabit MCEs and are associated with increased water clarity and decreasing average current strength with depth. Extensive calcified and fleshy macroalgal beds are found both in discrete patches, dense beds, and meadows over both hard and soft substrates. Several species of corals typical of shallow reefs extend to depths of ~60 m. The dominant corals below 60 m are in the genus Leptoseris, which can form extensive coral reefs spanning tens of km2. Few octocoral species inhabit shallow reefs and upper MCEs (30–70 m) but are diverse at the deepest range of MCEs (>130 m). Sponges do not represent a major structural component of MCEs. Many species of fishes occur on both shallow reefs and MCEs, but MCEs harbor more endemic species (up to 100% endemism). Several new species of macroalgae, corals and other invertebrates, and fishes have recently been documented. Over 60% of the territorial waters surrounding the archipelago are protected as the Papahānaumokuākea Marine National Monument; however, no specific protections exist for MCEs. Generally, threats affecting Hawai‘i’s shallow reefs also affect MCEs to varying degrees. MCEs may be more insulated from some threats but more vulnerable than shallow reefs to others (e.g., water clarity).

Global primary production is driven largely by oxygenic photosynthesis, with algae as major contributors. The green alga Chromochloris zofingiensis reversibly switches off photosynthesis in the presence of glucose in the light and augments production of biofuel precursors (triacylglycerols) and the high-value antioxidant astaxanthin. Here we used forward genetics to reveal that this photosynthetic and metabolic switch is mediated by the glycolytic enzyme hexokinase (CzHXK1). In contrast to wild-type, glucose-treated hxk1 mutants do not shut off photosynthesis or accumulate astaxanthin, triacylglycerols, or cytoplasmic lipid droplets. We show that CzHXK1 is critical for the regulation of genes related to photosynthesis, ketocarotenoid synthesis and fatty acid biosynthesis. Sugars play fundamental regulatory roles in gene expression, physiology, metabolism, and growth in plants and animals, and we introduce a relatively simple, emerging model system to investigate conserved eukaryotic sugar sensing and signaling at the base of the green lineage., In plants, exogenous glucose represses photosynthesis but this phenomenon has been little studied in green algae. Roth et. al. discover through a forward genetics screen in C. zofingiensis that hexokinase 1 is needed to turn off photosynthesis in the presence of glucose and for glucose-mediated upregulation of lipid metabolism.

This chapter provides a fundamental and basic introduction to most popular control systems implemented in our current world. In fact, all control systems in our world belong to nonlinear time-variant systems (NLTV), which mean that the outputs of all systems are always changed and varied with the time period and different outputs can be achieved at different time moments. Also the input–output relationship is not linear. Therefore, it is very difficult or even challenging to analyze and study this kind of NLTV because of their nonlinear and time-variant properties, sometimes, it may be impossible to do this kind of analysis if multiple different voltage sources (DC and AC) are included in that system. In order to reduce this difficulty and make our analysis simple, in most cases, we need to simplify this kind of NLTV systems to approximate them to linear time-invariant (LTI) systems. The advantage of this simplification is by approximating the NLTV systems to the LTI systems, we can use superposition principle to divide our analysis into two separate parts: DC analysis and AC analysis. Eventually, we can combine these two analyses together to get the final results. The superposition principle only works for the LTI systems.

In the last chapter, we provided very detailed discussions about the fuzzy logic control systems, including the fundamental theoretical knowledge of the fuzzy technologies and fuzzy inference systems, such as fuzzy sets, membership functions, control rules, lookup tables, and basic operations of a FIS. Following the theoretical introductions, a powerful tool, MATLAB® Fuzzy Logic Toolbox, is introduced and discussed with some real examples. Also, the MATLAB® Simulink, a powerful and useful simulation tool, is analyzed and discussed with a real DC motor control system. In this chapter, we will provide a more realistic implementation discussion about how to apply a FLC in a typical DC motor control system with a microcontroller programming project.

In Chap. 5, we provided detailed discussions about the classical linear control systems or PID control systems with various design methods. One of the most important and critical key requirements to design and implement a PID control system is that the dynamic model of the process or plant is the prerequisite condition . However, in some actual applications, sometimes it is very difficult or impossible to obtain those models. Therefore, it looks like that it is impossible to design any appropriate controller for those control systems.

In this chapter, we discussed most popular mathematical models for most often used systems in our world. In Sect. 4.2, various mathematical models for most popular physical systems are introduced and analyzed, which include the mechanical rotational system, electrical circuit system, and electromechanical system. Following this introduction, the relationship between the step response and the poles of a system is analyzed, and a discussion about the time-domain specifications for step responses is given. Some important properties related to system models, such as final value theorem, steady-state errors, stability, and linear approximation of physical systems, are discussed in Sect. 4.4. Some popular and powerful MATLAB functions provided by the Control System Toolbox are introduced in detail since these functions are helpful and useful for the system modeling and conversion operations. The discussion about system identifications is provided in Sect. 4.5. Some popular and important identification methods provided by MATLAB® System Identification Toolbox are discussed in Sect. 4.6. A case study is provided in Sect. 4.7 to show users how to practically perform the identification process for a typical DC motor using the MATLAB® System Identification ToolboxTM. The QEI and PWM modules in TM4C123GH6PM MCU system are also introduced in this section since we need to use these modules to interface the motor amplifiers and motor optical encoders to build and collect the real data required by the identification process.

In the point of view of control types, the fuzzy logic control technology can be divided into two categories: type-1 and type-2. So far, the fuzzy logic control technologies discussed in all previous chapters in this book belong to the type-1 fuzzy logic controls. In type-1 FLC, each membership function has a definite value or a membership degree based on the current input or output value. Also, the control rules have a two-to-one, multi-to-one, or multi-to-multi definite single-value relationship, and the fuzzy inference system output is a crisp single-value output. However, some shortcomings are involved with this kind of fuzzy inference system.

The main topic of this chapter is concentrated on the PID control system design and analysis. Three popular methods, root locus, Bode plot, and state space, are introduced and discussed in details with quite a few example projects. Starting from Sect. 5.2, the root locus strategy is discussed with some special properties used in this method. The effects of poles and zeros on time-domain specifications are discussed. Then the sketching of root locus by manually is introduced. Two typical compensators, phase lead (PD) and phase lag (PI), are introduced and analyzed with some examples. Some popular and powerful computer-aided design and analysis tools with root locus method, such as MATLAB root locus design functions and SISOTool, are discussed in details. The PID controller design with Bode plot frequency response method is introduced and analyzed in Sect. 5.3. Three popular computer-aided design tools, SISOTool, PIDTuner, and MATLAB Simulink, are discussed with some actual example systems. The Nyquist stability criterion is also introduced and discussed with some useful MATLAB functions. The PID controller design with state-space method is introduced in Sect. 5.4. Some important and related properties and features are discussed in detail in this part. An actual PID closed-loop controller for a real DC motor system is discussed as a case study in Sect. 5.5. A real DC motor, Mitsumi 448 PPR Motor, is utilized as a target plant for this closed-loop control system to help users to build a real control system with TM4C123GH6PM MCU system. The detailed control programming codes are provided with detailed discussions.

This chapter provides a fundamental and basic introduction to one of the updated microcontroller units (MCU) LaunchPad™, Tiva™ C Series TM4C123G made by Texas Instruments™. Both theoretic introductions about modern control technologies with simulations and hands-on techniques with actual control programming codes are provided in this chapter. This combination will enable students to easily and successfully implement theoretic knowledge to real process (DC motors) to build a complete control system.

As one of the most popular sports in the world, soccer injury rates involving the knee continue to rise. An alarming trend of knee injuries, including increased anterior cruciate ligament ruptures, underscores the need to review our current understanding of these injuries in soccer players. This article includes a critical review of the epidemiology of knee injuries in soccer, anterior cruciate ligament and other ligamentous injuries, cartilage and meniscal injury, post-traumatic osteoarthritis, as well as current prevention initiatives.

The T2K experiment measures muon neutrino disappearance and electron neutrino appearance in accelerator-produced neutrino and antineutrino beams. With an exposure of $14.7(7.6)\times 10^{20}$ protons on target in neutrino (antineutrino) mode, 89 $\nu_e$ candidates and 7 anti-$\nu_e$ candidates were observed while 67.5 and 9.0 are expected for $\delta_{CP}=0$ and normal mass ordering. The obtained $2\sigma$ confidence interval for the $CP$ violating phase, $\delta_{CP}$, does not include the $CP$-conserving cases ($\delta_{CP}=0,\pi$). The best-fit values of other parameters are $\sin^2\theta_{23} = 0.526^{+0.032}_{-0.036}$ and $\Delta m^2_{32}=2.463\pm0.065\times10^{-3} \mathrm{eV}^2/c^4$.

Light and nutrients are critical regulators of photosynthesis and metabolism in plants and algae. Many algae have the metabolic flexibility to grow photoautotrophically, heterotrophically, or mixotrophically. Here, we describe reversible Glc-dependent repression/activation of oxygenic photosynthesis in the unicellular green alga Chromochloris zofingiensis. We observed rapid and reversible changes in photosynthesis, in the photosynthetic apparatus, in thylakoid ultrastructure, and in energy stores including lipids and starch. Following Glc addition in the light, C. zofingiensis shuts off photosynthesis within days and accumulates large amounts of commercially relevant bioproducts, including triacylglycerols and the high-value nutraceutical ketocarotenoid astaxanthin, while increasing culture biomass. RNA sequencing reveals reversible changes in the transcriptome that form the basis of this metabolic regulation. Functional enrichment analyses show that Glc represses photosynthetic pathways while ketocarotenoid biosynthesis and heterotrophic carbon metabolism are upregulated. Because sugars play fundamental regulatory roles in gene expression, physiology, metabolism, and growth in both plants and animals, we have developed a simple algal model system to investigate conserved eukaryotic sugar responses as well as mechanisms of thylakoid breakdown and biogenesis in chloroplasts. Understanding regulation of photosynthesis and metabolism in algae could enable bioengineering to reroute metabolism toward beneficial bioproducts for energy, food, pharmaceuticals, and human health.

Introduction This document is a summary of the French Intergroup guidelines regarding the management of hepatocellular carcinoma (HCC) published in March 2019. Method It is a collaborative work under the auspices of most of the French medical societies involved in the management of HCC. It is based on the previous guidelines published in 2017. Recommendations are graded in 3 categories according to the level of evidence of data found in the literature. Results The diagnosis and staging of HCC is essentially based on clinical, biological and imaging features. A pathological analysis obtained by a biopsy of tumoral and non-tumoral liver is recommended. HCCs can be divided into 2 groups, taking into account not only the tumor stage, but also liver function. HCCs accessible to curative treatments are tumors that are in Milan criteria or with an AFP score ≤ 2, mainly treated by surgical resection, local ablation or liver transplantation. Intermediate and advanced HCCs with no liver insufficiency, accessible only to palliative treatments, benefit from TACE, SIRT or systemic therapy according to the presence or absence of macrovascular invasion or extrahepatic spread. Conclusion Such recommendations are in permanent optimization and each individual case must be discussed in a multidisciplinary expert board.

Simple Summary In this study, efficacy and safety of embolization alone and trans-arterial chemoembolization were compared in 265 patients with intermediate stage hepatocellular carcinoma. Trans-arterial chemoembolization was associated with a significant increase of complete radiological response, but without significant impact on overall response, and survival outcomes after propensity score matching. Both techniques showed similar safety profiles. To this day, embolization alone and trans-arterial chemoembolization are two available options in the treatment of intermediate stage hepatocellular carcinoma. Abstract No definitive conclusion could be reached about the role of chemotherapy in adjunction of embolization in the treatment of hepatocellular carcinoma (HCC). We aim to compare radiological response, toxicity and long-term outcomes of patients with hepatocellular carcinoma (HCC) treated by trans-arterial bland embolization (TAE) versus trans-arterial chemoembolization (TACE). We retrospectively included 265 patients with HCC treated by a first session of TACE or TAE in two centers. Clinical and biological features were recorded before the treatment and radiological response was assessed after the first treatment using modified Response Evaluation Criteria in Solid Tumors (mRECIST) criteria. Correlation between the treatment and overall, progression-free and transplantation-free survival was performed after adjustment using a propensity score matching: 86 patients were treated by bland embolization and 179 patients by TACE, including 44 patients with drug-eluting beads and 135 with lipiodol TACE, 89.8% of patients were male with a median age of 65 years old. Cirrhosis was present in 90.9% of patients with a Child Pugh score A in 84% of cases. After adjustment, no difference in the rate of AE, including liver failure, was observed between the two treatments. TACE was associated with a significant increase in complete radiological response (odds ratio (OR) = 8.5 (95% confidence interval (CI): 2.8–25.4)) but not in the overall response rate (OR = 2.2 (95% CI = 0.8–5.8)). No difference in terms of overall survival (p = 0.3905), progression-free survival (p = 0.4478) and transplantation-free survival (p = 0.9020) was observed between TACE and TAE. TACE was associated with a higher rate of complete radiological response but without any impact on overall radiological response, progression-free survival and overall survival compared to TAE.

Purpose: Studies have shown the prevalence of iron deficiency anemia (IDA) increasing worldwide, and currently the literature is limited on the impact of IDA on outcomes following revision total hip arthroplasty (RTHA). Therefore, the purpose of this study was to determine whether IDA patients undergoing RTHA have longer: 1) in-hospital lengths of stay (LOS); 2) medical complications; and 3) costs of care. Materials and Methods: A retrospective query of a nationwide administrative claims database was performed. Using Boolean command operations, the study group consisted of all patients in the database undergoing RTHA with IDA; whereas, patients without IDA served as controls. To reduce the effects of confounding, study group patients were matched to controls in a 1:5 ratio by age, sex, and medical comorbidities yielding 92,948 patients with (n=15,508) and without (n=77,440) IDA undergoing revision THA. A P-value less than 0.001 was considered statistically significant. Results: IDA patients were found to have significantly longer in-hospital LOS (5 days vs. 4 days, P

Red blood cell disorders like Sickle Cell Disease (SCD) and β-thalassemias are caused by mutations within the gene for the hemoglobin β (HBβ) subunit. A fetal ortholog of HBβ, hemoglobin γ (HBγ) can prevent or reduce disease-related pathophysiology in these disorders by forming nonpathogenic complexes with the required hemoglobin α-subunit. Globin expression is developmentally regulated, with a reduction in production of the fetal ortholog (γ)occurring shortly after birth and a concomitant increase in the levels of the adult ortholog (β). It has been postulated that maintaining expression of the anti-sickling γ ortholog may be of therapeutic benefit in children and adults with SCD. Indeed, individuals with the SCD mutation who also have genetic variants that maintain HBγ expression at clinically meaningful levels do not present with SCD-related symptoms. Parallel target identification efforts using CRISPR and the Fulcrum proprietary, annotated chemical probe screening set in HUDEP2 cells identified a protein complex as a key regulator of HbF expression. Structure-guided medicinal chemistry optimization led to the design of FTX-6058, a novel, potent and selective small molecule with desirable DMPK properties suitable for clinical testing. FTX-6058 treatment of differentiated primary CD34+ cells from multiple healthy donors demonstrated target engagement and potent upregulation of HBG1/2 mRNA and HbF protein. Across multiple healthy and SCD donors, FTX-6058 treatment resulted in a clinically desirable globin profile (e.g., up to 30% absolute HbF) accompanied by pancellular HbF expression, resembling the phenotype of SCD mutation carriers with hereditary persistence of fetal hemoglobin. FTX-6058 demonstrated a superior pharmacological profile relative to hydroxyurea and other small molecule compounds whose putative mechanism of action is to induce HbF. FTX-6058 treatment resulted in robust target engagement and subsequent elevation of the endogenous mouse Hbb-bh1 mRNA in wildtype CD-1 mice and, importantly, also elevation of the human HBG1 mRNA and HbF protein in the Townes SCD mouse model. Preclinical studies using a variety of in vitro and in vivo models have demonstrated the potential of FTX-6058 as a novel HbF-inducing small molecule that could be beneficial to patients with SCD and β-thalassemias. FTX-6058 was shown to be potent and selective in vitro, was well tolerated and elicited a desirable exposure-response relationship in multiple preclinical rodent models with once-a-day oral dosing and at plasma concentrations predicted to be achievable in patients. IND enabling studies for FTX-6058 have been completed. Disclosures Rahl: Fulcrum Therapeutics: Ended employment in the past 24 months. Efremov:Fulcrum Therepeutics: Current Employment, Current equity holder in publicly-traded company. Stuart:Fulcrum Therapeutics: Current Employment, Current equity holder in publicly-traded company. Xie:Fulcrum Therapeutics: Current Employment. Roth:Fulcrum Therepeutics: Current Employment, Current equity holder in publicly-traded company. Barnes:Fulcrum Therapeutics: Ended employment in the past 24 months. Appiah:Fulcrum Therapeutics: Current equity holder in publicly-traded company, Ended employment in the past 24 months. Peters:Fulcrum Therapeutics: Current Employment. Li:Fulcrum Therapeutics: Ended employment in the past 24 months. Kazmirski:Fulcrum Therapeutics: Ended employment in the past 24 months. Bruno:Fulcrum Therapeutics: Current Employment. Stickland:Fulcrum Therepeutics: Current Employment, Current equity holder in publicly-traded company. Ronco:Fulcrum Therepeutics: Current Employment, Current equity holder in publicly-traded company. Cadavid:Fulcrum Therapeutics: Current Employment, Current equity holder in publicly-traded company. Thompson:Fulcrum Therepeutics: Current Employment, Current equity holder in publicly-traded company. Wallace:Fulcrum Therepeutics: Current Employment, Current equity holder in publicly-traded company. Moxham:Fulcrum Therepeutics: Current Employment, Current equity holder in publicly-traded company.

Conventional chemotherapeutics remain essential treatments for most cancers, but their combination with other anticancer drugs (including targeted therapeutics) is often complicated by unpredictable synergies and multiplicative toxicities. As cytotoxic anticancer chemotherapeutics generally function through induction of apoptosis, we hypothesized that a molecularly targeted small molecule capable of facilitating a central and defining step in the apoptotic cascade, the activation of procaspase-3 to caspase-3, would broadly and predictably enhance activity of cytotoxic drugs. Here we show that procaspase-activating compound 1 (PAC-1) enhances cancer cell death induced by 15 different FDA-approved chemotherapeutics, across many cancer types and chemotherapeutic targets. In particular, the promising combination of PAC-1 and doxorubicin induces a synergistic reduction in tumor burden and enhances survival in murine tumor models of osteosarcoma and lymphoma. This PAC-1/doxorubicin combination was evaluated in 10 pet dogs with naturally occurring metastatic osteosarcoma or lymphoma, eliciting a biologic response in 3 of 6 osteosarcoma patients and 4 of 4 lymphoma patients. Importantly, in both mice and dogs, coadministration of PAC-1 with doxorubicin resulted in no additional toxicity. On the basis of the mode of action of PAC-1 and the high expression of procaspase-3 in many cancers, these results suggest the combination of PAC-1 with cytotoxic anticancer drugs as a potent and general strategy to enhance therapeutic response., Direct procaspase-3 activation is a general strategy to sensitize cancer to diverse antitumor drugs, highlighted by efficacy of procaspase-activating compound 1 + doxorubicin in pet dogs with metastatic osteosarcoma and lymphoma.

Background: The purpose of this study was to assess the effect of insurance type (Medicaid, Medicare, and private insurance) on access to foot and ankle surgeons for total ankle arthroplasty. Methods: We called 240 foot and ankle surgeons who performed total ankle arthroplasty in 8 representative states (California, Massachusetts, Ohio, New York, Florida, Georgia, Texas, and North Carolina). The caller requested an appointment for a fictitious patient to be evaluated for a total ankle arthroplasty. Each office was called 3 times to assess the responses for Medicaid, Medicare, and BlueCross. From each call, we recorded appointment success or failure and any barriers to an appointment, such as need for a referral. Results: Patients with Medicaid were less likely to receive an appointment compared to patients with Medicare (19.8% vs 92.0%, P < .0001) or BlueCross (19.8% vs 90.4%, P < .0001) and experienced more requests for referrals compared to patients with Medicare (41.9% vs 1.6%, P < .0001) or BlueCross (41.9% vs 4%, P < .0001). Waiting periods were longer for patients with Medicaid compared to those with Medicare (22.6 days vs 11.7 days, P = .004) or BlueCross (22.6 days vs 10.7 days, P = .001). Reimbursement rates did not correlate with appointment success rate or waiting period. Conclusion: Despite the passage of the PPACA, patients with Medicaid continue to have difficulty finding a surgeon who will provide care, increased need for a primary care referral, and longer waiting periods for appointments. Level of Evidence: Level II, prognostic study.

Companies are increasingly allocating more of their marketing spending to social media programs. Yet there is little research about how social media use is associated with consumer–brand relationships. We conducted three studies to explore how individual and national differences influence the relationship between social media use and customer brand relationships. The first study surveyed customers in France, the U.K. and U.S. and compared those who engage with their favorite brands via social media with those who do not. The findings indicated that social media use was positively related with brand relationship quality and the effect was more pronounced with high anthropomorphism perceptions (the extent to which consumers' associate human characteristics with brands). Two subsequent experiments further validated these findings and confirmed that cultural differences, specifically uncertainty avoidance, moderated these results. We obtained robust and convergent results from survey and experimental data using both student and adult consumer samples and testing across three product categories (athletic shoes, notebook computers, and automobiles). The results offer cross-national support for the proposition that engaging customers via social media is associated with higher consumer–brand relationships and word of mouth communications when consumers anthropomorphize the brand and they avoid uncertainty.

After spending eight years as a full-time academic administrator at Lafayette College in Easton, PA – one of only a handful of institutions where discipline-specific engineering programs are embedded in an undergraduate-only, liberal arts environment – I returned to full-time teaching in fall 2015. I began teaching civil engineering at Lafayette in 1991 and became department head in 2003, the start of an administrative journey that eventually reduced my teaching load to zero. From 2006 until 2014, I served as an American Council on Education fellow, the interim director of engineering, and then associate provost for academic operations.

Based on assumptions from entertainment theory, an online-study (N?=?419) was conducted to investigate the differential relationships between enjoyment and appreciation of a video clip that dealt with the features of natural gas as fuel for cars, objective and subjective knowledge about the content of that clip, and behavioral intentions of dealing with the topic of natural gas. Structural equation modeling revealed that enjoyment was directly positively related to objective and subjective knowledge. However, objective knowledge did not predict and subjective knowledge was only weakly associated with behavioral intentions. Appreciation, in contrast, was directly negatively related to knowledge acquisition and not related to subjective knowledge, but was the best predictor for behavioral intentions. These results point to the distinct processes and relationships of different entertainment experiences. Implications for entertainment-education and online video portals are discussed. We analyzed responses to an educational, entertaining online video about natural gas.We examined how entertainment experiences are related to knowledge and behavioral intentions.Enjoyment was positively associated with objective and subjective knowledge.Appreciation was the best direct predictor of behavioral intentions.We discuss implications for entertainment-education and online video portals.

Emotional and social adaptation is a central challenge for women with recently diagnosed breast cancer [1]. Prevalence rates for anxiety and depressive disorders among a heterogeneous sample of cancer patients are estimated to range from 10 to 40% [2,3], and women with newly diagnosed breast cancer demonstrate comparable rates of affective distress [4]. As a result, breast reconstruction outcome studies routinely assess psychological variables and their influence on various patient-specific outcomes such as aesthetic satisfaction and functional status. While these studies typically include measures of preoperative depression and anxiety as possible predictors of clinical outcomes, relatively little attention has been paid to the identification of suicidal ideation (SI) in this cohort. This may seem surprising given evidence that depression is highly prevalent among cancer patients and, when increasingly severe, presents a primary risk for SI and intention [5]. While numerous studies describe the incidence of suicide among cancer patients in general [6], and women with breast cancer more specifically [7], there is sparse information on the prevalence of suicidal ideation among these populations. The assessment of SI in breast cancer patients presenting for reconstruction is in line with the American College of Surgeons (ACS) Commission on Cancer guidelines for distress screening of all cancer patients by 2015 [8]. We examined the prevalence of preoperative anxiety and depression among women enrolled in an ongoing prospective study of post-mastectomy breast reconstruction procedure outcomes. The prevalence of moderate-to-severe SI challenged the study team to devise an identification and response system to intervene with potential at-risk patients and triage them to appropriate mental health attention. We describe this system and propose its consideration for future surgical outcome studies where depression and SI are of reasonable concern.

Purpose We describe a case of bilateral anterior lenticonus in a patient with Alport syndrome treated with femtosecond laser-assisted cataract surgery (FLACS). Observations FLACS was performed without complication, and a desirable postoperative visual acuity was achieved. Conclusions and importance Femtosecond laser-assisted cataract surgery is an effective approach for managing patients with anterior lenticonus secondary to Alport syndrome.

Hepatocellular carcinoma (HCC) is one of the most common causes of cancer-related deaths worldwide and its incidence is rising. Percutaneous locoregional therapies, such as radiofrequency ablation and microwave ablation, are widely used as curative treatment options for patients with small HCC, but their effectiveness remains restricted because of the associated high rate of recurrence, occurring in about 70% of patients at five years. These thermal ablation techniques have the particularity to induce immunomodulation by destroying tumours, although this is not sufficient to raise an effective antitumour immune response. Ablative therapies combined with immunotherapies could act synergistically to enhance antitumour immunity. This review aims to understand the different immune changes triggered by radiofrequency ablation and microwave ablation as well as the interest in using immunotherapies in combination with thermal ablation techniques as a tool for complementary immunomodulation.

Background:Systemic sclerosis-related interstitial lung disease (SSc-ILD) involves a combination of inflammation, fibrosis and vascular pathology that is typically assessed on CT imaging as a mixture of ground-glass opacification (GGO) and fibrotic changes. We hypothesized that proteins recovered from bronchoalveolar lavage (BAL) could be used to probe the underlying pathobiology associated with GGO and fibrotic changes.Objectives:(1) To assess the relationship between 68 unique BAL proteins measured in participants of Scleroderma Lung Study (SLS) I1and radiographic and physiologic measures of ILD; (2) To identify inter-correlations among specific proteins to enlighten our understanding of how specific biological pathways contribute to SSc-ILD.Methods:Bronchoscopy was performed on 144 of the 158 participants in SLS I with 103 BAL samples available for analysis. BAL was lyophilized, concentrated 10X and used in a multiplex protein analysis for 68 different cytokines, chemokines and other factors. Kendall tau correlations were performed to assess the relationship between individual proteins and baseline measures of pulmonary function and quantitative CT scores for fibrosis, GGO and total ILD. Those proteins found to correlate significantly with at least 2 clinical measures of ILD were entered into a cluster analysis with inter-correlations expressed as a heatmap.Results:Significant correlations were observed between fibrosis scores and several biologic pathways including pro-fibrotic factors (transforming growth factor beta [TGF-β], platelet-derived growth factor [PDGF]), proteins involved in tissue remodeling (Matrix metallopeptidase [MMP]-1,7,8,9; Hepatocyte growth factor [HGF]), and those involved in monocyte/macrophage migration and activation (Monocyte chemoattractant protein [MCP]-1,3; macrophage colony-stimulating factor [MCSF]). These same pathways correlated with the diffusing capacity for carbon monoxide (DLCO). In contrast, GGO scores correlated primarily with immune and inflammatory mediators (interleukin [IL]-5,8,13,15, IL-1 receptor antagonist and interferon gamma) with only limited overlap to proteins that related to fibrosis. Vascular endothelial growth factor (VEGF) levels were lower in patients with more extensive GGO, fibrosis and diffusion impairment, suggesting that vascular changes are a central feature of SSc-ILD. Specific proteins were highly correlated with one another in a pattern suggesting biologically-related networks (Figure) that might provide additional insight regarding disease pathogenesis.Conclusion:Combining a diverse analysis of BAL proteins with the rich dataset available from SSc-ILD patients participating in SLS I, the study findings suggest the involvement of distinct biologic pathways, inter-related networks, and specific biologic signatures associated with unique radiographic features of ILD. The relationship of these factors to other SSc disease features, patient outcomes and as predictors of treatment responses will be studied in future analyses.References:[1]Tashkin DP, et al. NEJM 2006.Figure.Correlation heatmap of BAL proteins associated with at least 2 clinical measures of ILD in SSc patients. Absolute correlations are depicted, and darker colors signify stronger correlations.Disclosure of Interests:Elizabeth Volkmann Grant/research support from: Forbius, Corbus Pharmaceuticals, Consultant of: Boehringer Ingelheim, Forbius, Speakers bureau: Boehringer Ingelheim, Donald Tashkin: None declared, Ning Li: None declared, Grace Kim: None declared, Jonathan Goldin: None declared, Airi Harui: None declared, Michael Roth Grant/research support from: Genentech/Roche

Rationale: The Scleroderma Lung Study II (SLS II) demonstrated significant improvements in pulmonary function and dyspnea at 24 months compared with baseline when patients with symptomatic scleroderma–related interstitial lung disease (SSc-ILD) were treated with either cyclophosphamide for 1 year (followed for another year on placebo) or mycophenolate mofetil for 2 years in a randomized, double-blind clinical trial. Physiologic and clinical outcomes of SLS II have been published previously. Objectives: The aim of the study was to assess changes from baseline in the extent of SSc-ILD on high-resolution computed tomography (HRCT) measured in the SLS II participants using quantitative image analysis after 2 years and to determine whether these HRCT changes were correlated with the changes in physiologic and clinical measures over the same time interval. Methods: Ninety-seven of the 142 randomized subjects (cyclophosphamide group, 47 subjects; mycophenolate mofetil group, 50 subjects) participating in SLS II underwent thoracic volumetric thin-section HRCT at both baseline and 24 months. Quantitative computer-aided diagnosis scores using volumetric HRCT scans were obtained using a previously developed computer-aided system. The scores were quantitative lung fibrosis, quantitative ground glass, quantitative honeycomb, and quantitative interstitial lung disease (QILD), the latter representing the sum of quantitative lung fibrosis, quantitative ground glass, and quantitative honeycomb. These scores were obtained both for the whole lung and for individual lobes. Paired t tests were used for the combined (pooled) cyclophosphamide and mycophenolate mofetil groups to compare 24-month changes from baseline in both the whole lung and the lobe of maximal involvement as determined at baseline (worst lobe). Results: At the end of the 24-month trial, QILD in the whole lung was significantly reduced by a mean of 2.51% in the pooled groups (adjusted 95% confidence interval, −4.00 to −1.03%; P = 0.001). There was no significant difference in the QILD score improvement between the cyclophosphamide (−2.66%) and mycophenolate (−2.38%) groups when assessed separately (P = 0.88). For the pooled group, the 24-month changes in QILD scores in the whole lung correlated significantly with other outcomes, including 24-month changes in forced vital capacity (ρ = −0.37), single-breath diffusing capacity of the lung for carbon monoxide (ρ = −0.22), and breathlessness as measured by the Transition Dyspnea Index (ρ = −0.26). Conclusions: Treatment of SSc-ILD with either cyclophosphamide for 1 year, followed by placebo for a second year, or mycophenolate for 2 years was associated with a significant reduction (improvement) in the extent of HRCT SSc-ILD assessed by computer-aided diagnosis scores, which correlated well with one or more other measures of treatment response. These findings demonstrate that actual changes in lung structure accompany improvements in physiologic and/or symptomatic measures in SSc-ILD.

Alexandre Kojève developed an idiosyncratic and widely influential reading of G.W.F. Hegel in a seminar in Paris from 1933 to 1939. Kojève read Hegel as having discovered that truth was the product of history, and that history was the product of the human desire and struggle for recognition. Kojève emphasized that once this desire was satisfied, history, properly so-called, was over. He claimed that for all essential purposes this human desire had been satisfied in the modern period, and thus that we had experienced (and Hegel had come to know) the end of history. The notes from this seminar were published in 1947 and continued to have an important impact on French philosophy throughout the post-war period.

Recent estimates suggest an annual incidence of greater than 125,000 femoral neck fractures. Surgical treatment is indicated for the majority of these fractures, which are estimated to double by the year 2050. Most displaced femoral neck fractures in elderly patients are treated with arthroplasty secondary to high complication rates associated with internal fixation. Traditional implants used for internal fixation, typically in elderly patients with stable fracture morphology and younger patients regardless of morphology, include the sliding hip screw (SHS), with or without a supplemental anti-rotation screw, and multiple cancellous lag screws. Complications have been reported with both of these fixation techniques, especially as they apply to treating displaced femoral neck fractures in the elderly. Yet, complications of nonunion, loss of fixation and osteonecrosis, among others, still frequently occur in stable patterns of femoral neck fracture treated with internal fixation. Accordingly, additional implants have been designed recently to improve outcomes and avoid such complications in this population. The Targon Femoral Neck Plate (Aesculap, Tuttlinger, Germany) has been used in Europe for the treatment of both displaced and nondisplaced femoral neck fractures by combining a side plate and multiple cancellous lag screws. Multiple studies have shown superior rates of both nonunion and osteonecrosis when compared to the SHS and multiple cancellous screws in both displaced and nondisplaced femoral neck fractures. This article details the design rationale, surgical technique and early postoperative results of a new hybrid implant used for the treatment of both displaced and nondisplaced femoral neck fractures.

Despite improvements in chemotherapy that have increased the 5-year survival rates of pediatric ALL to close to 90%, 15-20% of patients may relapse with a very poor prognosis. Pediatric ALL patients, particularly those in relapse can harbor a specific point mutation (E1099K) in NSD2 (nuclear receptor binding SET domain protein 2) gene, also known as MMSET or WHSC1, which encodes a histone methyl transferase specific for H3K36me2. To understand the biology of mutant NSD2, we used CRISPR-Cas9 gene editing to disrupt the NSD2E1099K mutant allele in B-ALL cell lines (RCH-ACV and SEM) and T-ALL cell line (RPMI-8402) or insert the E1099K mutation into the NSD2WT T-ALL cell line (CEM) and B-ALL cell line (697). Cell lines in which the NSD2E1099K mutant allele is present display increased global levels of H3K36me2 and decreased H3K27me3. NSD2E1099Kcells demonstrate enhanced cell growth, colony formation and migration. NSD2E1099K mutant cell lines assayed by RNA-Seq exhibit an aberrant gene signature, mostly representing gene activation, with activation of signaling pathways, genes implicated in the epithelial mesenchymal transition and prominent expression of neural genes not generally found in hematopoietic tissues. Accordingly, NSD2E1099K cell lines showed prominent tropism to the central neural system in xenografts. To understand why this NSD2 mutations are identified prominently in children who relapse early from therapy for ALL, we performed high-throughput screening in our isogenic cell lines with the National Center for Advancing Translation Science (NCATS) Pharmaceutical Collection and other annotated chemical libraries and found that NSD2E1099K cells are resistant to glucocorticoids (GC) but not to other chemotherapeutic agents used to treat ALL such as vincristine, doxorubicin, cyclophosphamide, methotrexate, and 6-mercaptopurine. Accordingly, patient-derived-xenograft ALL cells with NSD2E1099K mutation were resistant to GC treatment. Reversion of NSD2E1099K mutation to NSD2WT restored GC sensitivity to both B- and T-ALL cell lines, which was accompanied by cell cycle arrest in G1 and induced-apoptosis. Furthermore, knock-in of the NSD2E1099K mutation conferred GC resistance to ALL cell lines by triggering cell cycle progression, proliferation and anti-apoptotic processes. Mice with NSD2E1099K xenografts were completely resistant to GC treatment while treatment of mice injected with isogenic NSD2WT cells led to significant tumor reduction and survival benefit. To illustrate these biological phenotypes and understand the molecular mechanism of GC resistance driven by NSD2E1099Kmutation, we investigated the GC-induced transcriptome, GC receptor (GR) binding sites and related epigenetic changes in isogenic ALL cell lines in response to GC treatment. RNA-Seq showed that GC transcriptional response was almost completely blocked in NSD2E1099K cells, especially in T-ALL cell lines, correlating with their lack of biological response. GC treatment activated apoptotic pathways and downregulated cell cycle and DNA repair pathways only in NSD2WT cells. The critical pro-apoptotic regulators BIM and BMF failed to be activated by GC in NSD2E1099K cells but were prominently activated when the NSD2 mutation was removed. Chromatin immunoprecipitation sequencing (ChIP-Seq) showed that, the NSD2E1099K mutation blocked the ability of GR and CTCF to bind most GC response elements (GREs) such as those within BIM and BMF. While GR binding in NSD2WT cells was accompanied by increased H3K27 acetylation and gene expression, this failed to occur in NSD2 mutant cells. Furthermore, we found that GR RNA and protein levels were repressed in ALL cells expressing NSD2E1099K and GC failed to induce GR expression in these cells. Paradoxically, while H3K27me3 levels were generally decreased in NSD2E1099K cells, we saw increased levels of H3K27me3 at the GRE within the GR gene body where GR itself and CTCF normally bind, suggesting a novel role for the polycomb repressive complex 2 and EZH2 inhibitors for this form of GC resistance. In conclusion, these studies demonstrate that NSD2E1099K mutation may play an important role in treatment failure of pediatric ALL relapse by interfering with the GR expression and its ability to bind and activate key target genes. Gene editing screens are being performed to understand how to overcome this resistance. Disclosures No relevant conflicts of interest to declare.

We thank the J-PARC staff for superb accelerator performance. We thank the CERN NA61/SHINE Collaboration for providing valuable particle production data. We acknowledge the support of MEXT, Japan; NSERC (Grant No. SAPPJ-2014-00031), NRC and CFI, Canada; CEA and CNRS/IN2P3, France; DFG, Germany; INFN, Italy; National Science Centre (NCN) and Ministry of Science and Higher Education, Poland; RSF, RFBR, and Ministry of Education and Science, Russia; MINECO and European Regional Development Fund, Spain; SNSF and SERI, Switzerland; STFC, UK; and DOE, U.S. We also thank CERN for the UA1/NOMAD magnet, DESY for the HERA-B magnet mover system, NII for SINET4, the WestGrid and SciNet consortia in Compute Canada, and GridPP in the United Kingdom. In addition, participation of individual researchers and institutions has been further supported by funds from ERC (FP7), H2020 Grant No. RISE-GA644294-JENNIFER, European Union; JSPS, Japan; Royal Society, United Kingdom; and the Alfred P. Sloan Foundation and the DOE Early Career program, U.S.