Ovarian cancers are hallmarked by chromosomal instability. New therapies deliver improved patient outcomes in relevant phenotypes, however therapy resistance and poor long-term survival signal ...requirements for better patient preselection. An impaired DNA damage response (DDR) is a major chemosensitivity determinant. Comprising five pathways, DDR redundancy is complex and rarely studied alongside chemoresistance influence from mitochondrial dysfunction. We developed functional assays to monitor DDR and mitochondrial states and trialled this suite on patient explants.
We profiled DDR and mitochondrial signatures in cultures from 16 primary-setting ovarian cancer patients receiving platinum chemotherapy. Explant signature relationships to patient progression-free (PFS) and overall survival (OS) were assessed by multiple statistical and machine-learning methods.
DR dysregulation was wide-ranging. Defective HR (HRD) and NHEJ were near-mutually exclusive. HRD patients (44%) had increased SSB abrogation. HR competence was associated with perturbed mitochondria (78% vs 57% HRD) while every relapse patient harboured dysfunctional mitochondria. DDR signatures classified explant platinum cytotoxicity and mitochondrial dysregulation. Importantly, explant signatures classified patient PFS and OS.
Whilst individual pathway scores are mechanistically insufficient to describe resistance, holistic DDR and mitochondrial states accurately predict patient survival. Our assay suite demonstrates promise for translational chemosensitivity prediction.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
•Study evaluating postoperative course after TORS oropharyngeal resection.•Clinical trial patients receiving deescalated adjuvant therapy for HPV(+)OPSCC.•Patients had acceptable post-operative ...bleeding rates requiring intervention (4.6%)•There were very low rates of postoperative complication.
Dose de-escalation of adjuvant therapy (DART) in patients with HPV(+)OPSCC was investigated in two prospective Phase II and III clinical trials (MC1273 and MC1675). We report the 30-day morbidity and mortality associated with primary TORS resection in patients enrolled in these trials.
Patients with HPV(+)OPSCC, who underwent TORS resection between 2013 and 2020 were considered in this analysis. The severity of postoperative transoral bleeding was graded using both the Hinni Grade (HG) transoral surgery bleeding scale and the Common Terminology for Adverse Events (CTCAE) v5.0. Post-surgical complications within 30 days of surgery, as well as rates of tracheostomy, PEG and nasogastric tube placement.
219 patients were included. A total of 7 (3.2 %) patients had a tracheostomy placed at the time of surgery, and all were decannulated within 26 days (median: 5, range: 2–26). There were 33 (15.1 %) returns to the emergency department (ED) with 10 (4.6 %) patients requiring readmission. Using the HG scale, 10 (4.6 %) patients experienced ≥ Grade 3 bleeding with no Grade 5 or 6 bleeds. In contrast, using the CTCAE scale, 15 patients (6.8 %) experienced ≥ Grade 3 bleeding with no Grade 5 bleeds. There was one post-operative death in a patient withdrawn from the trial, and no deaths related to hemorrhage.
TORS for HPV(+)OPSCC in carefully selected patients at a high volume center was associated with low morbidity and mortality.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
ABSTRACT
Misalignments within protoplanetary discs are now commonly observed, and features such as shadows in scattered light images indicate departure from a co-planar geometry. VLT/SPHERE (Very ...Large Telescope/Spectro-Polarimetric High-contrast Exoplanet REsearch) observations of the disc around HD 143006 show a large-scale asymmetry and two narrow dark lanes that are indicative of shadowing. ALMA (Atacama Large Millimeter/submillimeter Array) observations also reveal the presence of rings and gaps in the disc, along with a bright arc at large radii. We present new hydrodynamic simulations of HD 143006, and show that a configuration with both a strongly inclined binary and an outer planetary companion is the most plausible to explain the observed morphological features. We compute synthetic observations from our simulations, and successfully reproduce both the narrow shadows and the brightness asymmetry seen in infrared scattered light. Additionally, we reproduce the large dust observed in the mm continuum, due to a 10 Jupiter-mass planet detected in the CO kinematics. Our simulations also show the formation of a circumplanetary disc, which is misaligned with respect to the outer disc. The narrow shadows cast by the inner disc and the planet-induced ‘kink’ in the disc kinematics are both expected to move on a time-scale of ∼5–10 yr, presenting a potentially observable test of our model. If confirmed, HD 143006 would be the first known example of a circumbinary planet on a strongly misaligned orbit.
Abstract Background Despite the excellent total knee arthroplasty (TKA) results reported using traditional outcome measures, dissatisfaction rates of up to 30% are reported following surgery. ...Although several preoperative factors have been identified as possible predictors of satisfaction, there is conflicting evidence. Identification of dissatisfaction in the early postoperative assessment may therefore be an alternative consideration. Methods We examined the relationship between 12-month satisfaction, and early post-operative outcomes in a cohort of 486 TKA patients. Preoperative, and postoperative outcome measures at 3- and 12-months (Oxford knee score, pain score, SF12, and knee motion), were analysed and compared between patients who were satisfied and dissatisfied at 12-months following TKA. Mean scores, and postoperative change in scores were calculated. Postoperative outcomes were examined for correlation with satisfaction, and multivariate logistic regression models used to identify potential predictors of dissatisfaction. Results Overall satisfaction was 77.0%. No preoperative differences were observed between groups. Dissatisfaction was associated with worse postoperative status across all outcome measures ( p < 0.001), except the 3-month SF12-physical component ( p = 0.052). Dissatisfied patients demonstrated minimal further improvement or even worsening of outcome scores between 3- and 12-months postoperatively ( p < 0.02). Both the 3-month OKS (OR = 1.15, p < 0.001), and knee flexion (OR = 1.03, p = 0.009) were significant predictors of subsequent 12-month satisfaction. Conclusions Dissatisfaction following TKA is associated with worse outcomes as early as 3 months following surgery, with minimal further improvement subsequently achieved at 12-months. Early postoperative assessment following TKA should therefore be considered, including clinical assessment, to identify those patients at risk of dissatisfaction.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
35.
THE MATERHORN Fernando, H. J. S.; Pardyjak, E. R.; Di Sabatino, S. ...
Bulletin of the American Meteorological Society,
11/2015, Volume:
96, Issue:
11
Journal Article
Peer reviewed
Open access
Emerging application areas such as air pollution in megacities, wind energy, urban security, and operation of unmanned aerial vehicles have intensified scientific and societal interest in mountain ...meteorology. To address scientific needs and help improve the prediction of mountain weather, the U.S. Department of Defense has funded a research effort—the Mountain Terrain Atmospheric Modeling and Observations (MATERHORN) Program—that draws the expertise of a multidisciplinary, multiinstitutional, and multinational group of researchers. The program has four principal thrusts, encompassing modeling, experimental, technology, and parameterization components, directed at diagnosing model deficiencies and critical knowledge gaps, conducting experimental studies, and developing tools for model improvements. The access to the Granite Mountain Atmospheric Sciences Testbed of the U.S. Army Dugway Proving Ground, as well as to a suite of conventional and novel high-end airborne and surface measurement platforms, has provided an unprecedented opportunity to investigate phenomena of time scales from a few seconds to a few days, covering spatial extents of tens of kilometers down to millimeters. This article provides an overview of the MATERHORN and a glimpse at its initial findings. Orographic forcing creates a multitude of time-dependent submesoscale phenomena that contribute to the variability of mountain weather at mesoscale. The nexus of predictions by mesoscale model ensembles and observations are described, identifying opportunities for further improvements in mountain weather forecasting.
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BFBNIB, DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Recent molecular-typing studies suggest cross-infection as one of the potential acquisition pathways for Pseudomonas aeruginosa in patients with cystic fibrosis (CF). In Australia, there is only ...limited evidence of unrelated patients sharing indistinguishable P. aeruginosa strains. We therefore examined the point-prevalence, distribution, diversity and clinical impact of P. aeruginosa strains in Australian CF patients nationally. 983 patients attending 18 Australian CF centres provided 2887 sputum P. aeruginosa isolates for genotyping by enterobacterial repetitive intergenic consensus-PCR assays with confirmation by multilocus sequence typing. Demographic and clinical details were recorded for each participant. Overall, 610 (62%) patients harboured at least one of 38 shared genotypes. Most shared strains were in small patient clusters from a limited number of centres. However, the two predominant genotypes, AUST-01 and AUST-02, were widely dispersed, being detected in 220 (22%) and 173 (18%) patients attending 17 and 16 centres, respectively. AUST-01 was associated with significantly greater treatment requirements than unique P. aeruginosa strains. Multiple clusters of shared P. aeruginosa strains are common in Australian CF centres. At least one of the predominant and widespread genotypes is associated with increased healthcare utilisation. Longitudinal studies are now needed to determine the infection control implications of these findings.
This study evaluated the influence of the thickness of disilicate ceramic on the light attenuation (mW/cm2), degree of conversion (DC, %), Knoop hardness (KH, N/mm2) and the elastic modulus (E, MPa) ...of four luting resins.
Three resin cements: RelyX Veneer (RV, 3M Oral Care, Monrovia, CA USA); Allcem Veneer APS (AC, FGM); Variolink Esthetic LC (VE, Ivoclar Vivadent, Schaan, Liechtenstein) and one flowable resin composite Tetric N-Flow (TF, Ivoclar Vivadent) were photocured for 20 seconds. The irradiance (mW/cm2) and emission spectrum (mW/cm2/nm) from a broad-spectrum LED light unit (Bluephase G2, Ivoclar Vivadent) were measured over the luting material (control) and through 0.3 mm, 0.7 mm, and 1.0 mm thick ceramic discs (e.max CAD, Ivoclar Vivadent).
The LED light delivered 26.1 J/cm2 to the surface and 6.2 J/cm2 through the 1.0 mm thick ceramic. The distribution of violet and blue light across the light tip of the light-curing unit (LCU) was relatively homogeneous, but there was less violet range. The irradiance and spectral radiant power decreased significantly as the ceramic thicknesses increased (p<0.001). The luting material type had significant effect on KH and E values (p<0.001). The RV had the greatest KH and E values, and VE had the lowest. Ceramic thickness had no significant effect on KH (p=0.213) and E (p=0.130). The KH (p=0.265) and E (p=0.165) were also not influenced by the location where these measurements were made across the specimens. No significant reduction of the DC was observed as the ceramic thickness increased (p=0.311).
Increasing the ceramic thickness exponentially reduced the irradiance. This reduction was more pronounced at the shorter wavelengths (violet) of light, with an 82% decrease for 1 mm-thick ceramic. Increasing the ceramic thickness did not affect the DC, irrespective of photoinitiators used in the tested resins. The position of the violet and blue LEDs within the body of the LCU did not influence KH or E in any of the resins tested. The KH and E of VE were significantly lower than the other 3 luting materials tested.
The aim of the British Association for Surgery of the Knee (BASK) Meniscal Consensus Project was to develop an evidence-based treatment guideline for patients with meniscal lesions of the knee.
A ...formal consensus process was undertaken applying nominal group, Delphi, and appropriateness methods. Consensus was first reached on the terminology relating to the definition, investigation, and classification of meniscal lesions. A series of simulated clinical scenarios was then created and the appropriateness of arthroscopic meniscal surgery or nonoperative treatment in each scenario was rated by the group. The process was informed throughout by the latest published, and previously unpublished, clinical and epidemiological evidence. Scenarios were then grouped together based upon the similarity of clinical features and ratings to form the guideline for treatment. Feedback on the draft guideline was sought from the entire membership of BASK before final revisions and approval by the consensus group.
A total of 45 simulated clinical scenarios were refined to five common clinical presentations and six corresponding treatment recommendations. The final guideline stratifies patients based upon a new, standardized classification of symptoms, signs, radiological findings, duration of symptoms, and previous treatment.
The 2018 BASK Arthroscopic Meniscal Surgery Treatment Guidance will facilitate the consistent identification and treatment of patients with meniscal lesions. It is hoped that this guidance will be adopted nationally by surgeons and help inform healthcare commissioning guidance. Validation in clinical practice is now required and several areas of uncertainty in relation to treatment should be a priority for future high-quality prospective studies. Cite this article:
2019;101-B:652-659.
Prescribed burning is used to reduce the occurrence, extent and severity of uncontrolled fires in many flammable landscapes. However, epidemiologic evidence of the human health impacts of landscape ...fire smoke emissions is shaping fire management practice through increasingly stringent environmental regulation and public health policy. An unresolved question, critical for sustainable fire management, concerns the comparative human health effects of smoke from wild and prescribed fires. Here we review current knowledge of the health effects of landscape fire emissions and consider the similarities and differences in smoke from wild and prescribed fires with respect to the typical combustion conditions and fuel properties, the quality and magnitude of air pollution emissions, and the potential for dispersion to large populations. We further examine the interactions between these considerations, and how they may shape the longer term smoke regimes to which populations are exposed. We identify numerous knowledge gaps and propose a conceptual framework that describes pathways to better understanding of the health trade-offs of prescribed and wildfire smoke regimes.
Context.
Sheath regions ahead of coronal mass ejections (CMEs) are large-scale heliospheric structures that form gradually with CME expansion and propagation from the Sun. Turbulent and compressed ...sheaths could contribute to the acceleration of charged particles in the corona and in interplanetary space, but the relation of their internal structure to the particle energization process is still a relatively little studied subject. In particular, the role of sheaths in accelerating particles when the shock Mach number is low is a significant open research problem.
Aims.
This work seeks to provide new insights on the internal structure of CME-driven sheaths with regard to energetic particle enhancements. A good opportunity to achieve this aim was provided by multi-point, in-situ observations of a sheath region made by radially aligned spacecraft at 0.8 and ∼1 AU (Solar Orbiter, the L1 spacecraft Wind and ACE, and BepiColombo) on April 19−21, 2020. The sheath was preceded by a weak and slowly propagating fast-mode shock.
Methods.
We apply a range of analysis techniques to in situ magnetic field, plasma and particle observations. The study focuses on smaller scale sheath structures and magnetic field fluctuations that coincide with energetic ion enhancements.
Results.
Energetic ion enhancements were identified in the sheath, but at different locations within the sheath structure at Solar Orbiter and L1. Magnetic fluctuation amplitudes at inertial-range scales increased in the sheath relative to the solar wind upstream of the shock, as is typically observed. However, when normalised to the local mean field, fluctuation amplitudes did not increase significantly; magnetic compressibility of fluctuation also did not increase within the sheath. Various substructures were found to be embedded within the sheath at the different spacecraft, including multiple heliospheric current sheet (HCS) crossings and a small-scale flux rope. At L1, the ion flux enhancement was associated with the HCS crossings, while at Solar Orbiter, the ion enhancement occurred within a compressed, small-scale flux rope.
Conclusions.
Several internal smaller-scale substructures and clear difference in their occurrence and properties between the used spacecraft was identified within the analyzed CME-driven sheath. These substructures are favourable locations for the energization of charged particles in interplanetary space. In particular, substructures that are swept from the upstream solar wind and compressed into the sheath can act as effective acceleration sites. A possible acceleration mechanism is betatron acceleration associated with a small-scale flux rope and warped HCS compressed in the sheath, while the contribution of shock acceleration to the latter cannot be excluded.
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