This work examined combustion modes in a fundamental, axisymmetric, supersonic combustor at flight equivalent Mach numbers ranging from 7.5 to 9.0. Ethylene was injected at a variety of mass flow ...rates to examine both scram-mode, jet wake stabilized and dual-mode combustion. At higher flight Mach number conditions, the fuelling rate required to transition from scram-mode to dual-mode combustion increased. Distributions of the OH radical were observed using planar laser-induced fluorescence (PLIF) in a cross-sectional plane immediately downstream of the combustor exit, and analyzed according to their variation in the radial and circumferential dimensions. It was observed that radial centroids of the ring-like OH PLIF signal for the scram-mode cases approached the centerline linearly with increasing equivalence ratio, but the dual-mode cases appeared to randomly fluctuate in the observed exhaust cross-section. The distributions of scram- and dual-mode cases were clustered in specific regions on plots of circumferential variation as a function of radial centroid, with a jet wake stabilized case appearing between the two clusters. These clusters may be used to help identify scram- and dual-mode combustion in future experiments.
•Fibrodysplasia ossificans progressiva (FOP) causes characteristic joint and skeletal dysmorphology throughout the body.•Individuals with FOP frequently develop early onset degenerative arthropathy ...of the spine and lower limbs.•Hip dysplasia, ankylosed vertebral and costovertebral joints, and fused proximal tibio-fibular joints are common in FOP.
Fibrodysplasia ossificans progressiva (FOP) is primarily a disease of progressive heterotopic ossification (HO) leading to impaired mobility throughout life. An additional diagnostic feature is a characteristic malformation of the great toes. The culpable gene for FOP,ACVR1 (activin A receptor type 1) has a clear effect on the induction of extra-skeletal bone formation. However, this bone morphogenetic protein (BMP) pathway receptor is expressed widely throughout skeletal development and has a seminal role in axial and appendicular chondrogenesis, prompting suspicion of widespread bone and joint defects in those with ACVR1 mutations.
We analyzed baseline whole body (minus skull) computed tomographic (CT) scans of 113 individuals with classic clinical features of FOP and the ACVR1 (R206H) mutation who were enrolled in a non-interventional natural history study ((NCT02322255)) for skeletal malformations, atypical morphology, intra-articular synovial osteochondromatosis, developmental arthropathy, and associated degenerative joint phenotypes. Individuals were evaluated in three age groups: 4–13; 14–25; and 25–56 years old, based on historical models of FOP disease progression.
We found widespread evidence of developmental arthropathy throughout the axial and appendicular skeleton in all age groups (61M, 52F; ages: 4–56 years). Asymmetric narrowing and subchondral sclerosis were present throughout the joints of the normotopic skeleton and osteophytes were common in the hips and knees of individuals who have FOP in all age groups. The costovertebral joints, intervertebral facet joints, and proximal tibio-fibular joints frequently showed partial or total intra-articular ankylosis, particularly after age 13. The hips of FOP subjects are frequently malformed and dysplastic. We also found evidence of degenerative joint phenotypes after age 13, particularly in the spine, sacro-iliac joints, and lower limbs.
The effects of ACVR1 mutation on the normotopic skeletons of individuals who have FOP extend beyond malformation of the great toes and include both morphological defects and developmental arthropathy. Associated degenerative joint disease occurring at multiple sites starts in adolescence and progresses throughout life. These phenotypes appear to be uncoupled from heterotopic bone formation, indicating a potential role for ACVR1 in the development and progression of degenerative joint disease.
FOP is a disease of not only progressive heterotopic ossification, but also widespread and extensive developmental arthropathy and associated degenerative joint disease. These findings have relevance for understanding the natural history of FOP and for designing and evaluating clinical trials with emerging therapeutics.
Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare genetic disorder of extraskeletal bone formation, but could appropriately be viewed as a seminal disorder of osteochondrogenesis. Many, if ...not most, of the musculoskeletal features of FOP are related to dysregulated chondrogenesis including abnormal articular cartilage formation, abnormal diarthrodial joint specification, growth plate dysplasia, osteochondroma formation, heterotopic endochondral ossification (HEO), and precocious arthropathy. In FOP, causative activating mutations of Activin receptor A type I (ACVR1), a bone morphogenetic protein (BMP) type I receptor, are responsible for the osteochondrodysplasia that impacts developmental phenotypes as well as postnatal features of this illustrative disorder. Here, we highlight the myriad developmental and postnatal effects on osteochondrogenesis that emanate directly from mutant ACVR1 and dysregulated bone morphogenetic protein (BMP) signaling in FOP.
•FOP is a genetic disease of heterotopic ossification that can be considered a disorder of osteochondrogenesis.•The activating mutations in ACVR1 that cause FOP also alter normal skeletal development.•Dysregulated ACVR1-mediated signaling in FOP causes a myriad of effects on developmental and postnatal osteochondrogenesis.
This paper numerically examines methods to modify the upstream wall of cavities within scramjet combustors. The prevailing geometrical features of cavities have remained unchanged since 1957, when ...the baseline cavity operated in subsonic flows. The rapid expansion experienced over the front wall (a rear-facing step) produces a low-pressure region and accompanying base drag, while the two-vortex structure has only the larger contributing to mixing. The current work examines four new cavity profiles, substituting the rear-facing step for ramps (inclined at 45 and 22.5 deg), or streamtracing it to aerodynamically conform with the primary vortex. Examined in Mach 8 combustor flows, unfuelled flow fields see complete removal of the secondary vortex. A 45 deg ramp angle ensured immediate boundary layer separation. While all cases exhibited reduced drag due to increased pressure loads upon the front wall, combining streamtracing with the ramped profiles provided drag reductions of 12%. Ethylene-fuelled cases exhibited drag reductions to 6.6% for the 45 deg ramp. The stronger single-vortex structure displayed universally improved mixing, with improvements to 16.8%. The 22.5 deg ramp suffered reduced mixing, owing to the shortened residence time experienced. Hence, a minimum front wall angle likely exists. Within lower Mach number flows, universal drag reductions for the unfuelled and fuelled cases were realised, while mixing was comparable amongst most cases. Aerodynamic contouring may hence become more necessary as flight speeds reach Mach 8.
The cavity flameholder has been widely used in scramjets to improve mixing and combustion rates. While many have investigated modifications to the cavity downstream-wall, few have investigated ...modifying the upstream-wall - a rear-facing step. The rapid expansion produces a low pressure region and base drag force, while only the larger of the induced twin vortices contributes substantially to mixing. In this paper, the upstream-wall of a scramjet combustor cavity was inclined, aiming to reduce cavity base drag and remove superfluous cavity vortex structures. Upstream-wall angles of 90°, 45° and 22.5° were examined, at cavity length-to-depth (L/D) ratios from 4 to 7. Cavity downstream-wall angles of 90° and 22.5° were examined for each configuration. Reflected shock tunnel experiments were conducted at Mach 7 enthalpy, scramjet combustor conditions. Experimental Schlieren imaging showed that reducing the upstream-wall angle did not significantly affect shear layer separation for L/D ratios of 4 and 5. At L/D ratios 6 and 7, however, reducing the upstream-wall angle saw the shear layer penetrating deeper into the cavity. Reynolds-averaged Navier-Stokes computations examined the internal flow structure and it was shown that reducing the upstream-wall angle to 45° retained the dominant mixing vortex in the cavity, with base drag reduced by 21% compared to the standard 90° upstream-wall case.
This paper examines the scram/dual-mode combustion limits of hydrocabon fuels within a Mach 8, scramjet combustor. Flight-equivalent flows were delivered to the axisymmetric, cavity combustor via a ...reflected shock tunnel. Two scramjet fuels were examined: ethylene and a surrogate mixture representing endothermically cracked n-dodecane. Combustion modes were examined via static pressure sensors and through both chemiluminescence imaging, and planar laser induced fluorescence (PLIF) of the OH combustion radical in the combustor exhaust plume. Ethylene-fuelled experiments developed scram-mode combustion under reduced fuelling conditions, experiencing shock wave dominated flowfields. OH PLIF diagnostics indicated such combustion modes developed a ring-like structure of combustion products, primarily axisymmetrically adjacent to the combustor wall. Increased fuelling anchored combustion downstream of the fuel injector, while further increases instigated dual-mode combustion. In this mode, subsonic combustion regions combine with the supersonic coreflow to permit the transfer of information upstream with substantially increased pressure encountered. Optical diagnostics indicate broadly asymmetric, unsteady combustion features. The surrogate mixture representing endothermically cracked n-dodecane experienced rapid onset from no-combustion (optically confirmed) to fully developed dual-mode combustion at critical fuelling rates. OH PLIF signals and chemiluminescence of this fuel were weaker than comparable ethylene cases, indicating potential differences in combustion pathways.
Chest compression-only bystander cardiopulmonary resuscitation (CPR) may be as effective as conventional CPR with rescue breathing for out-of-hospital cardiac arrest.
To investigate the survival of ...patients with out-of-hospital cardiac arrest using compression-only CPR (COCPR) compared with conventional CPR.
A 5-year prospective observational cohort study of survival in patients at least 18 years old with out-of-hospital cardiac arrest between January 1, 2005, and December 31, 2009, in Arizona. The relationship between layperson bystander CPR and survival to hospital discharge was evaluated using multivariable logistic regression.
Survival to hospital discharge.
Among 5272 adults with out-of-hospital cardiac arrest of cardiac etiology not observed by responding emergency medical personnel, 779 were excluded because bystander CPR was provided by a health care professional or the arrest occurred in a medical facility. A total of 4415 met all inclusion criteria for analysis, including 2900 who received no bystander CPR, 666 who received conventional CPR, and 849 who received COCPR. Rates of survival to hospital discharge were 5.2% (95% confidence interval CI, 4.4%-6.0%) for the no bystander CPR group, 7.8% (95% CI, 5.8%-9.8%) for conventional CPR, and 13.3% (95% CI, 11.0%-15.6%) for COCPR. The adjusted odds ratio (AOR) for survival for conventional CPR vs no CPR was 0.99 (95% CI, 0.69-1.43), for COCPR vs no CPR, 1.59 (95% CI, 1.18-2.13), and for COCPR vs conventional CPR, 1.60 (95% CI, 1.08-2.35). From 2005 to 2009, lay rescuer CPR increased from 28.2% (95% CI, 24.6%-31.8%) to 39.9% (95% CI, 36.8%-42.9%; P < .001); the proportion of CPR that was COCPR increased from 19.6% (95% CI, 13.6%-25.7%) to 75.9% (95% CI, 71.7%-80.1%; P < .001). Overall survival increased from 3.7% (95% CI, 2.2%-5.2%) to 9.8% (95% CI, 8.0%-11.6%; P < .001).
Among patients with out-of-hospital cardiac arrest, layperson compression-only CPR was associated with increased survival compared with conventional CPR and no bystander CPR in this setting with public endorsement of chest compression-only CPR.
Responses of Arctic lakes to climate change are complex and heterogeneous at regional to local scales, but there are few studies comparing multiple sites within the same landscape. We studied ...sediment cores recovered from seven lake sites located within the forest-tundra biome of northern Manitoba, Canada. We first used sediment core pollen from the seven sites to reconstruct July temperatures and total annual precipitation for the past 7500 years based on the modern analog technique. Lake responses and peatland expansion were analyzed based on changes in the concentration and quality of organic matter, biogenic silica (bSi), Sphagnum spores, and published peat core basal dates. Changes in sediment organic matter and bSi were concentrated prior to 4500 cal. Yr BP. From 7500 to 3100 cal. Yr BP, July temperatures rose by ~3°C, and total annual precipitation fell by 200 mm; there was little change in temperature or precipitation after 3100 cal. Yr BP. Sphagnum spore concentrations exceeded 0.5% at all of the sites at 7500 cal. Yr BP indicating the early presence of peatlands. Spores increased markedly after 4500 cal. Yr BP in agreement with timing of peat basal dates, but the magnitude and timing of changes varied widely among sites likely reflecting local differences in hydrology or topography. The use of hierarchical generalized additive models provided a unified regional pattern of Holocene climate for northern Manitoba, even though lake responses to climate and peatland expansion differed greatly.
The development of joints in the mammalian skeleton depends on the precise regulation of multiple interacting signaling pathways including the bone morphogenetic protein (BMP) pathway, a key ...regulator of joint development, digit patterning, skeletal growth, and chondrogenesis. Mutations in the BMP receptor ACVR1 cause the rare genetic disease fibrodysplasia ossificans progressiva (FOP) in which extensive and progressive extra-skeletal bone forms in soft connective tissues after birth. These mutations, which enhance BMP-pSmad1/5 pathway activity to induce ectopic bone, also affect skeletal development. FOP can be diagnosed at birth by symmetric, characteristic malformations of the great toes (first digits) that are associated with decreased joint mobility, shortened digit length, and absent, fused, and/or malformed phalanges. To elucidate the role of ACVR1-mediated BMP signaling in digit skeletal development, we used an Acvr1R206H/+;Prrx1-Cre knock-in mouse model that mimics the first digit phenotype of human FOP. We have determined that the effects of increased Acvr1-mediated signaling by the Acvr1R206H mutation are not limited to the first digit but alter BMP signaling, Gdf5+ joint progenitor cell localization, and joint development in a manner that differently affects individual digits during embryogenesis. The Acvr1R206H mutation leads to delayed and disrupted joint specification and cleavage in the digits and alters the development of cartilage and endochondral ossification at sites of joint morphogenesis. These findings demonstrate an important role for ACVR1-mediated BMP signaling in the regulation of joint and skeletal formation, show a direct link between failure to restrict BMP signaling in the digit joint interzone and failure of joint cleavage at the presumptive interzone, and implicate impaired, digit-specific joint development as the proximal cause of digit malformation in FOP.
•The BMP type I receptor Acvr1 is a key regulator of digit and joint formation in early development.•Dysregulated BMP signaling caused by Acvr1 R206H disrupts joint development and growth plate organization in multiple murine digits.•Acvr1-R206H dysregulates spatial restriction of BMP pathway signaling and Gdf5 expression during skeletal development.
While typically analysed through ground-based impulse facilities, scramjets experience significant heating loads in flight, raising engine wall temperatures and the fuel used to cool them beyond ...standard laboratory conditions. Hence, the present work numerically compares an access-to-space scramjet's performance at both these conditions. The Mach 12 Rectangular-to-Elliptical Shape-Transitioning scramjet flow path is examined via three-dimensional and chemically reacting Reynolds-averaged Navier-Stokes solutions. Flight operation is modelled through 800 K and 1800 K inlet and combustor walls respectively, while fuel is injected at both inlet- and combustor-based stations at 1000 K stagnation temperature. Room temperature walls and fuel plena model shock tunnel conditions. Mixing and combustion performance indicates that while flight conditions promote rapid mixing, high combustor temperatures inhibit the completion of reaction pathways, with reactant dissociation reducing chemical heat release by 16%. However, the heated walls in flight ensured 28% less energy was absorbed by the walls. While inlet fuel injection promotes robust burning of combustor-injected fuel, premature ignition upon the inlet in flight suggests these injectors should be moved further downstream. Coupled with counteracting differences in heat release and loss to the walls, the optimal engine design for flight may differ considerably from that which gives the best performance in the tunnel.
•Scramjets experience heating loads in flight, raising engine wall temperatures.•Operation under both shock tunnel and flight conditions is compared numerically.•Inlet fuel injection promotes mixing, but triggers premature ignition in flight.•Reduced combustion heat release and loss to the walls is encountered in flight.•Optimal flight engine design may differ greatly from optimal shock tunnel design.
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