Life extending control for rocket engines

The concept of life extending control is defined. A brief discussion of current fatigue life prediction methods is given and the need for an alternative life prediction model based on a continuous functional relationship is established. Two approaches to life extending control are considered: (1) the implicit approach which uses cyclic fatigue life prediction as a basis for control design; and (2) the continuous life prediction approach which requires a continuous damage law. Progress on an initial formulation of a continuous (in time) fatigue model is presented. Finally, nonlinear programming is used to develop initial results for life extension for a simplified rocket engine (model)

Combustion Dynamics Characteristics and Fuel Pressure Modulation Responses of a Three-Cup Third-Generation Swirl-Venturi Lean Direct Injection Combustion Concept

This paper presents the combustion dynamic data and fuel modulation response of a three-cup Lean Direct Injection combustor developed by Woodward, FST. The test was conducted at the NASA Glenn Research Center CE-5 flame tube test facility. The facility provided inlet air up to 922 K and pressure up to 19.0 bar. At the low-power configuration, the combustion noise was quiet. Large combustion pressure oscillations were observed with the High-power configuration at an off design condition, with low inlet air temperature and pressure conditions and a high equivalence ratio (about T3=600 K, P3 = 800 kPa, and ER =0.46). The noise amplitude was as high as 1.5 psi at around 220 Hz. As inlet air pressure and temperature increased, this combustion instability decreased. Fuel modulated signals were produced with the WASK fuel modulator located in the fuel line upstream of the center cup pilot fuel-air mixer. The amplitudes of the modulated signals detected in the combustor were low. Only less than 0.13% (0.06 psi) of the input energy was detected, and the signal amplitudes decreased as the modulated frequencies increased. Interaction between the modulated signals and the combustion noise varied with operating conditions. At a condition with low combustion noise around 150 hz, modulating a signal at around the same frequency would increase the combustion noise from 0.2 psi to as high as 0.6 psi, whereas at a condition with a high combustion instability around 250 hz, the modulated signal did not seem to have much effect on the combustion noise

Recuperación edilicia integral, restauración y puesta en valor arquitectónico de la Basílica de Guadalupe de la ciudad de Santa Fe

El presente trabajo refleja la combinación de una experiencia de obra, cimentada en investigaciones de campo, y corresponde a la intervención en un edificio con patología estructural severa.- La Basílica de Guadalupe ubicada en Santa Fe (ciudad), posee estilo neogótico bajo, construida en 1905, en mampostería de ladrillos desde las cimentaciones. Con una planimetría en forma de cruz de aproximadamente 2.200 m2 (nave central y dos laterales). Posee cubiertas combinadas de chapas sobre estructura de hierro y losas de bovedilla apoyadas en muros. La carga muerta estimada para transferir a las bases es aproximadamente de 8.600 toneladas.- Ante un cuadro de afectación severo, evidenciado en la manifestación de patologías típicas de fallas en la cadena de transferencia de cargas por asentamientos diferenciados, punzonamientos y pérdida de verticalidad en muros, mostrando deformaciones en pisos y fisuraciones en muros y cielorrasos al nivel de producirse el colapso parcial de un sector de cielorraso abovedado (en diciembre de 2004), fue necesario diseñar acciones correctivas para la recuperación de la condición de seguridad. Se elaboró como primera medida un diagnóstico de situación, evaluación estructural mediante. Para ello se llevaron a cabo una serie de instancias apuntando a determinar las causas del problema (etiología) y la magnitud de afectación. La evaluación contempló en general observación ocular, estudios de suelos y control de deformaciones diferido en el tiempo. Se pudo diagnosticar como causal básico del cuadro de afectación a la pérdida de capacidad portante por saturación del suelo de fundación con erosión de finos (limos, arcillas y coloides) por ingreso directo no contemplado de aguas filtrantes de los sistemas de desagües pluviales perimetrales del edificio en combinación fuertemente desfavorable con un emisario de la red pública pluvial que presentó fallas de estanqueidad. El control de deformaciones de mediciones sucesivas y periódicas en el tiempo permitió verificar la presencia de un proceso activo en la estructura con un patrón creciente con incremento de espesores de fisuras.- Con los resultados obtenidos, se diseñaron acciones correctivas: reconstrucción de la red pluvial interna, recalce de cimientos mediante la transferencia de cargas del plano de fundación hasta un estrato de mayor resistencia; y anclajes de muros afectados por fisuras. El recalce se realizó mediante la construcción de MP IRS (micropilotes con Inyección Repetitiva y Selectiva) y el refuerzo de muros incorporando tensores pasivos horizontales dentro del espesor de los mismos en tres niveles diferentes.- La ejecución de MP se realizó entre diciembre 2005 y julio 2007 (cambio de tecnología de ejecución mediante sobre la marcha); mientras que los tensores horizontales, se ejecutaron entre setiembre 2007 y abril 2008.- Paralelamente para monitorear la evolución y analizar la eficiencia de los refuerzos en forma global en la estructura, se diseñó e implementó un sistema referencial de control de asentamientos colocando escalas perimetrales exteriores, y de fisuras, con comparadores interiores (con mediciones efectuadas trimestralmente durante el primer año y semestralmente en el segundo).- Esta contribución se centró en aspectos relativos a las etapas de ejecución del micropilotaje por entender que allí es donde se puede brindar el aporte más interesante para este Congreso, dado que habitualmente se basa en técnicas que aplican pautas teóricas que requieren ajustes según las particularidades de cada caso. - Del monitoreo realizado se infiere un comportamiento que marca una clara tendencia general en los movimientos relativos decreciente asintóticamente, reflejo de la toma de carga de los micropilotes y la transferencia paulatina, con adecuamiento de la estructura edilicia a nuevas condiciones de cimentación y refuerzos. Alcanzada ésta y recompuesta la cadena de transferencia de cargas queda habilitada la factibilidad de iniciar la siguiente etapa de restauración y puesta en valor arquitectónico de la Basílica.-Tópico 5: Intervenciones en construcciones con patologías estructurales y aplicación de refuerzos

Chromosome-level assemblies from diverse clades reveal limited structural and gene content variation in the genome of Candida glabrata

Background Candida glabrata is an opportunistic yeast pathogen thought to have a large genetic and phenotypic diversity and a highly plastic genome. However, the lack of chromosome-level genome assemblies representing this diversity limits our ability to accurately establish how chromosomal structure and gene content vary across strains. Results Here, we expanded publicly available assemblies by using long-read sequencing technologies in twelve diverse strains, obtaining a final set of twenty-one chromosome-level genomes spanning the known C. glabrata diversity. Using comparative approaches, we inferred variation in chromosome structure and determined the pan-genome, including an analysis of the adhesin gene repertoire. Our analysis uncovered four new adhesin orthogroups and inferred a rich ancestral adhesion repertoire, which was subsequently shaped through a still ongoing process of gene loss, gene duplication, and gene conversion. Conclusions C. glabrata has a largely stable pan-genome except for a highly variable subset of genes encoding cell wall-associated functions. Adhesin repertoire was established for each strain and showed variability among clades.TG group acknowledges support from the Spanish Ministry of Science and Innovation (MCIN) for grant PGC2018-099921-B-I00, cofounded by European Regional Development Fund (ERDF); from the Catalan Research Agency (AGAUR) SGR423; from the European Union’s Horizon 2020 research and innovation programme (ERC-2016-724173); from the Gordon and Betty Moore Foundation (Grant GBMF9742); from the “La Caixa” foundation (Grant LCF/PR/HR21/00737), and from the Instituto de Salud Carlos III (IMPACT Grant IMP/00019 and CIBERINFEC CB21/13/00061- ISCIII-SGEFI/ERDF). PWJG acknowledges support by grants SBPLY/19/180501/000114 and SBPLY/19/180501/000356 funded by the Regional government of Castilla-La Mancha and grants SAF2013-47570-P and PID2020-117983RB-I00 funded by MCIN/AEI/10.13039/501100011033 and by ERDF a way of making Europe.Peer ReviewedPostprint (author's final draft

Working towards a consensus on the oncological approach of breakthrough pain: A Delphi survey of Spanish experts

Purpose: There is a lack of standards for the diagnosis, assessment and management of breakthrough cancer pain (BTcP). La Fundación ECO (the Foundation for Excellence and Quality in Oncology) commissioned a study to establish a consensus and lay the foundations for the appropriate management of BTcP in oncology patients. Patients and methods: A modified Delphi survey comprising two rounds was used to gather and analyze data, which was conducted over the Internet. Each statement that reached a consensus with the respondents was defined as a median consensus score (MED) of =7, and agreement among panelists as an interquartile range (IQR) of =3. Results: In total, 69 medical oncologists responded, with a broad consensus that BTcP implied exacerbations of high-intensity pain, as opposed to moderate pain. Furthermore, they concurred that appropriate diagnostic equipment is needed, and that rapid-onset fentanyl formulations should be the preferred treatment for BTcP management. The panelists agreed that a lack of appropriate information and training to attend to patients, as well as limited patient visitation rights, were barriers to effective BTcP management. Regarding gaps in detected knowledge, the panelists were unsure of the measures necessary to assess the burden of the disease on the patient’s quality of life and associated medication costs. Alongside this, there was a lack of awareness of the technical specifics of the different formulations of rapid-onset fentanyl. Conclusion: These results represent the current status of BTcP management. They may inform recommendations and provide a framework for future research

Active study: undetected prevalence and clinical inertia in the treatment of breakthrough cancer pain (BTcP)

Aims To prove if there is clinical inertia in the identification and treatment of episodes of breakthrough cancer pain (BTcP), comparing actual results from clinical practice with clinical oncologists’ prior perception. Design Observational and descriptive study, using information collected by practising medical oncologists, at three moments: (a) questionnaire regarding their professional judgement of the handling of patients with BTcP in their practice, (b) cross-sectional clinical screening, to detect possible existing cases of BTcP in a representative sample of their patients, (c) retrospective self-audit of clinical case histories of patients diagnosed with BTcP to find out about how it has been handled. Participants and study period A random sample on a state level of 108 specialists in medical oncology. 540 patients who suffer some type of cancer pain on the designated study date for each specialist (July–December 2016). Results The global prevalence of BTcP in the study sample covered 91.3% of the patients who were suffering some type of cancer pain. Barely 2% of the doctors surveyed suspected figures around this mark. 40.9% of the cases had not been previously detected as BTcP by their doctors. Although 90% of the patients who had previously been diagnosed with BTcP received a specific analgesic treatment for the symptoms, 42% of those patients with known BTcP were not able to control their episodes of pain. Conclusions Clinical inertia is a serious problem in the handling of BTcP in medical oncology services, where it is the subject of a significantly low level of detection and treatment, despite the contrasting perception of specialists.pre-print339 K

Oncologist’s knowledge and implementation of guidelines for breakthrough cancer pain in Spain: CONOCE study

[Purpose]: Breakthrough cancer pain (BTcP) has been shown to be a prevalent and poor prognostic factor for oncologic patients, which remain under diagnosed and undertreated. In 2012, the Spanish Society of Medical Oncology (SEOM) published a clinical practice guideline (CPG) for the treatment of cancer pain which specifically addressed the management of BTcP.[Methods]: Fundación ECO designed a qualitative study using an Internet-based survey to investigate the attitudes toward, compliance with, and use of SEOM Guideline.[Results]: A total of 83 oncologists with a mean experience of 13 years responded. Overall, 82% were aware of different guidelines to manage BTcP. Notably, attitudes toward guidelines were highly positive and there was nearly unanimous agreement that CPG provided the best scientific evidence available (99%), on the minimum information to be gathered for the medical history (100%), on the need for a specific treatment for BTcP (100%), and fentanyl as the first-choice drug (99%). Interestingly, there were discrepancies between what oncologists agreed with and what they do in clinical practice. In fact, 87.6% declare full compliance with SEOM guideline, although adherence to registration of BTcP data in medical records ranged from 30.1 to 91.6% (mean 64.5%); therapeutic management compliance was higher ranging from 75.9 to 91.6%. Main barriers identified were time pressure together with vague statements and limited dissemination of the guidelines.[Conclusion]: Despite oncologist’s clinical practice is increasingly guided by GPC, it suffers from limited compliance, at least in part due to suboptimal statements. Improved dissemination and education are needed to enhance guideline implementation.This study was funded by Kyowa Kirin Farmacéutica S. L.U. through Fundación ECO

IND-Enabling Studies for a Clinical Trial to Genetically Program a Persistent Cancer-Targeted Immune System

PURPOSE: To improve persistence of adoptively transferred T-cell receptor (TCR)-engineered T cells and durable clinical responses, we designed a clinical trial to transplant genetically-modified hematopoietic stem cells (HSCs) together with adoptive cell transfer of T cells both engineered to express an NY-ESO-1 TCR. Here, we report the preclinical studies performed to enable an investigational new drug (IND) application. EXPERIMENTAL DESIGN: HSCs transduced with a lentiviral vector expressing NY-ESO-1 TCR and the PET reporter/suicide gene HSV1-sr39TK and T cells transduced with a retroviral vector expressing NY-ESO-1 TCR were coadministered to myelodepleted HLA-A2/Kb mice within a formal Good Laboratory Practice (GLP)-compliant study to demonstrate safety, persistence, and HSC differentiation into all blood lineages. Non-GLP experiments included assessment of transgene immunogenicity and in vitro viral insertion safety studies. Furthermore, Good Manufacturing Practice (GMP)-compliant cell production qualification runs were performed to establish the manufacturing protocols for clinical use. RESULTS: TCR genetically modified and ex vivo-cultured HSCs differentiated into all blood subsets in vivo after HSC transplantation, and coadministration of TCR-transduced T cells did not result in increased toxicity. The expression of NY-ESO-1 TCR and sr39TK transgenes did not have a detrimental effect on gene-modified HSC's differentiation to all blood cell lineages. There was no evidence of genotoxicity induced by the lentiviral vector. GMP batches of clinical-grade transgenic cells produced during qualification runs had adequate stability and functionality. CONCLUSIONS: Coadministration of HSCs and T cells expressing an NY-ESO-1 TCR is safe in preclinical models. The results presented in this article led to the FDA approval of IND 17471

The association of HLA-DQB1, -DQA1 and -DPB1 alleles with anti- glomerular basement membrane (GBM) disease in Chinese patients

<p>Abstract</p> <p>Background</p> <p>Human leukocyte antigen (HLA) alleles are associated with many autoimmune diseases, including anti-glomerular basement membrane (GBM) disease. In our previous study, it was demonstrated that HLA-DRB1*1501 was strongly associated with anti-GBM disease in Chinese. However, the association of anti-GBM disease and other HLA class II genes, including HLA-DQB1, -DQA1,-DPB1 alleles, has rarely been investigated in Asian, especially Chinese patients. The present study further analyzed the association between anti-GBM disease and HLA-DQB1, -DQA1, and -DPB1 genes. Apart from this, we tried to locate the potential risk amino acid residues of anti-GBM disease.</p> <p>Methods</p> <p>This study included 44 Chinese patients with anti-GBM disease and 200 healthy controls. The clinical and pathological data of the patients were collected and analyzed. Typing of HLA-DQB1, -DQA1 and -DPB1 alleles were performed by bi-directional sequencing of exon 2 using the SeCoreTM Sequencing Kits.</p> <p>Results</p> <p>Compared with normal controls, the prevalence of HLA-DPB1*0401 was significantly lower in patients with anti-GBM disease (3/88 vs. 74/400, p = 4.4 × 10^-4, pc = 0.039). Comparing with normal controls, the combination of presence of DRB1*1501 and absence of DPB1*0401 was significantly prominent among anti-GBM patients (p = 2.0 × 10^-12, pc = 1.7 × 10^-10).</p> <p>Conclusions</p> <p>HLA-DPB1*0401 might be a protective allele to anti-GBM disease in Chinese patients. The combined presence of DRB1*1501 and absence of DPB1*0401 might have an even higher risk to anti-GBM disease than HLA-DRB1*1501 alone.</p

Isolation and characterization of NY-ESO-1–specific T cell receptors restricted on various MHC molecules

Tumor-specific T cell receptor (TCR) gene transfer enables specific and potent immune targeting of tumor antigens. Due to the prevalence of the HLA-A2 MHC class I supertype in most human populations, the majority of TCR gene therapy trials targeting public antigens have employed HLA-A2–restricted TCRs, limiting this approach to those patients expressing this allele. For these patients, TCR gene therapy trials have resulted in both tantalizing successes and lethal adverse events, underscoring the need for careful selection of antigenic targets. Broad and safe application of public antigen-targeted TCR gene therapies will require (i) selecting public antigens that are highly tumor-specific and (ii) targeting multiple epitopes derived from these antigens by obtaining an assortment of TCRs restricted by multiple common MHC alleles. The canonical cancer-testis antigen, NY-ESO-1, is not expressed in normal tissues but is aberrantly expressed across a broad array of cancer types. It has also been targeted with A2-restricted TCR gene therapy without adverse events or notable side effects. To enable the targeting of NY-ESO-1 in a broader array of HLA haplotypes, we isolated TCRs specific for NY-ESO-1 epitopes presented by four MHC molecules: HLA-A2, -B07, -B18, and -C03. Using these TCRs, we pilot an approach to extend TCR gene therapies targeting NY-ESO-1 to patient populations beyond those expressing HLA-A2