Since 2004, a regimen of 6 months of treatment with oxaliplatin plus a fluoropyrimidine has been standard adjuvant therapy in patients with stage III colon cancer. However, since oxaliplatin is ...associated with cumulative neurotoxicity, a shorter duration of therapy could spare toxic effects and health expenditures.
We performed a prospective, preplanned, pooled analysis of six randomized, phase 3 trials that were conducted concurrently to evaluate the noninferiority of adjuvant therapy with either FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CAPOX (capecitabine and oxaliplatin) administered for 3 months, as compared with 6 months. The primary end point was the rate of disease-free survival at 3 years. Noninferiority of 3 months versus 6 months of therapy could be claimed if the upper limit of the two-sided 95% confidence interval of the hazard ratio did not exceed 1.12.
After 3263 events of disease recurrence or death had been reported in 12,834 patients, the noninferiority of 3 months of treatment versus 6 months was not confirmed in the overall study population (hazard ratio, 1.07; 95% confidence interval CI, 1.00 to 1.15). Noninferiority of the shorter regimen was seen for CAPOX (hazard ratio, 0.95; 95% CI, 0.85 to 1.06) but not for FOLFOX (hazard ratio, 1.16; 95% CI, 1.06 to 1.26). In an exploratory analysis of the combined regimens, among the patients with T1, T2, or T3 and N1 cancers, 3 months of therapy was noninferior to 6 months, with a 3-year rate of disease-free survival of 83.1% and 83.3%, respectively (hazard ratio, 1.01; 95% CI, 0.90 to 1.12). Among patients with cancers that were classified as T4, N2, or both, the disease-free survival rate for a 6-month duration of therapy was superior to that for a 3-month duration (64.4% vs. 62.7%) for the combined treatments (hazard ratio, 1.12; 95% CI, 1.03 to 1.23; P=0.01 for superiority).
Among patients with stage III colon cancer receiving adjuvant therapy with FOLFOX or CAPOX, noninferiority of 3 months of therapy, as compared with 6 months, was not confirmed in the overall population. However, in patients treated with CAPOX, 3 months of therapy was as effective as 6 months, particularly in the lower-risk subgroup. (Funded by the National Cancer Institute and others.).
We present a suite of large-eddy simulations (LES) of a wind farm operating in conventionally neutral boundary layers. A fixed 1.6 GW wind farm is considered for 40 different atmospheric ...stratification conditions to investigate effects on wind-farm efficiency and blockage, as well as related gravity-wave excitation. A tuned Rayleigh damping layer and a wave-free fringe-region method are used to avoid spurious excitation of gravity waves, and a domain-size study is included to evaluate and minimize effects of artificial domain blockage. A fully neutral reference case is also considered, to distinguish between a case with hydrodynamic blockage only, and cases that include hydrostatic blockage induced by the air column above the boundary layer and the excitation of gravity waves therein. We discuss in detail the dependence of gravity-wave excitation, flow fields and wind-farm blockage on capping-inversion height, strength and free-atmosphere lapse rate. In all cases, an unfavourable pressure gradient is present in front of the farm, and a favourable pressure gradient in the farm, with hydrostatic contributions arising from gravity waves at least an order of magnitude larger than hydrodynamic effects. Using respectively non-local and wake efficiencies $\eta _{nl}$ and $\eta _{w}$, we observe a strong negative correlation between the unfavourable upstream pressure rise and $\eta _{nl}$, and a strong positive correlation between the favourable pressure drop in the farm and $\eta _{w}$. Using a simplified linear gravity-wave model, we formulate a simple scaling for the ratio $(1-\eta _{nl})/\eta _{w}$, which matches reasonably well with the LES results.
Ordering of ferroelectric polarization
and its trajectory in response to an electric field
are essential for the operation of non-volatile memories
, transducers
and electro-optic devices
. However, ...for voltage control of capacitance and frequency agility in telecommunication devices, domain walls have long been thought to be a hindrance because they lead to high dielectric loss and hysteresis in the device response to an applied electric field
. To avoid these effects, tunable dielectrics are often operated under piezoelectric resonance conditions, relying on operation well above the ferroelectric Curie temperature
, where tunability is compromised. Therefore, there is an unavoidable trade-off between the requirements of high tunability and low loss in tunable dielectric devices, which leads to severe limitations on their figure of merit. Here we show that domain structure can in fact be exploited to obtain ultralow loss and exceptional frequency selectivity without piezoelectric resonance. We use intrinsically tunable materials with properties that are defined not only by their chemical composition, but also by the proximity and accessibility of thermodynamically predicted strain-induced, ferroelectric domain-wall variants
. The resulting gigahertz microwave tunability and dielectric loss are better than those of the best film devices by one to two orders of magnitude and comparable to those of bulk single crystals. The measured quality factors exceed the theoretically predicted zero-field intrinsic limit owing to domain-wall fluctuations, rather than field-induced piezoelectric oscillations, which are usually associated with resonance. Resonant frequency tuning across the entire L, S and C microwave bands (1-8 gigahertz) is achieved in an individual device-a range about 100 times larger than that of the best intrinsically tunable material. These results point to a rich phase space of possible nanometre-scale domain structures that can be used to surmount current limitations, and demonstrate a promising strategy for obtaining ultrahigh frequency agility and low-loss microwave devices.
Complex turbine wake interactions play an important role in overall energy extraction in large wind farms. Current control strategies optimize individual turbine power, and lead to significant energy ...losses in wind farms compared with lone-standing wind turbines. In recent work, an optimal coordinated control framework was introduced (Goit & Meyers 2015 J. Fluid Mech. 768, 5-50 (doi:10.1017/jfm.2015.70)). Here, we further elaborate on this framework, quantify the influence of optimization parameters and introduce new simulation results for which gains in power production of up to 21% are observed.
This article is part of the themed issue ‘Wind energy in complex terrains’.
Recent studies have demonstrated that large secondary motions are excited by surface roughness with dominant spanwise length scales of the order of the flow's outer length scale. Inspired by this, we ...explore the effect of spanwise heterogeneous surface temperature in weakly to strongly stratified closed channel flow (at $Ri_\tau =120$, 960; $Re_\tau = 180$, 550) with direct numerical simulations. The configuration consists of equally sized strips of high and low temperature at the lower and upper boundaries, while an overall stable stratification is induced by imposing an average temperature difference between the top and bottom. We consider the influence of the width of the strips (${\rm \pi} /8 \leq \lambda /h \leq 4{\rm \pi} $), Reynolds number, stability and upper boundary condition on the mean flow structure, skin friction and heat transfer. Results indicate that secondary flows are excited, with alternating high- and low-momentum pathways and vortices, similar to the patterns induced by spanwise heterogeneous surface roughness. We find that the impact of the surface heterogeneity on the outer layer depends strongly on the spanwise heterogeneity length scale of the surface temperature. Comparison to stable channel flow with uniform temperature reveals that the heterogeneous surface temperature increases the global friction coefficient and reduces the global Nusselt number in most cases. However, for the high-Reynolds cases with $\lambda /h \geq {\rm \pi} /2$, we find a reduction of the friction coefficient. At stronger stability, the vertical extent of the vortices is reduced and the impact of the heterogeneous temperature on momentum and heat transfer is smaller.
Cancer risk is determined by a complex interplay of environmental and heritable factors. Polygenic risk scores (PRS) provide a personalized genetic susceptibility profile that may be leveraged for ...disease prediction. Using data from the UK Biobank (413,753 individuals; 22,755 incident cancer cases), we quantify the added predictive value of integrating cancer-specific PRS with family history and modifiable risk factors for 16 cancers. We show that incorporating PRS measurably improves prediction accuracy for most cancers, but the magnitude of this improvement varies substantially. We also demonstrate that stratifying on levels of PRS identifies significantly divergent 5-year risk trajectories after accounting for family history and modifiable risk factors. At the population level, the top 20% of the PRS distribution accounts for 4.0% to 30.3% of incident cancer cases, exceeding the impact of many lifestyle-related factors. In summary, this study illustrates the potential for improving cancer risk assessment by integrating genetic risk scores.
Discogenic back pain is a common condition without approved intervertebral disc (IVD) repair therapies. Cell delivery using injectable biomaterial carriers offers promise to restore disc height and ...biomechanical function, while providing a functional niche for delivered cells to repair degenerated tissues. This systematic review advances the injectable IVD cell delivery biomaterials field by characterising its current state and identifying themes of promising strategies. Preferred Reporting Items for Systematic Reviews and Meta- Analyses (PRISMA) guidelines were used to screen the literature and 183 manuscripts met the inclusion criteria. Cellular and biomaterial inputs, and biological and biomechanical outcomes were extracted from each study. Most identified studies targeted nucleus pulposus (NP) repair. No consensus exists on cell type or biomaterial carrier, yet most common strategies used mesenchymal stem cell (MSC) delivery with interpenetrating network/co-polymeric (IPN/CoP) biomaterials composed of natural biomaterials. All studies reported biological outcomes with about half the studies reporting biomechanical outcomes. Since the IVD is a load-bearing tissue, studies reporting compressive and shear moduli were analysed and two major themes were found. First, a competitive balance, or 'seesaw' effect, between biomechanical and biological performance was observed. Formulations with higher moduli had inferior cellular performance, and vice versa. Second, several low-modulus biomaterials had favourable biological performance and matured throughout culture duration with enhanced extracellular matrix synthesis and biomechanical moduli. Findings identify an opportunity to develop next-generation biomaterials that provide high initial biomechanical competence to stabilise and repair damaged IVDs with a capacity to promote cell function for long-term healing.
Objectives
Additive manufacturing (AM) technologies can be used to fabricate 3D‐printed interim dental restorations. The aim of this review is to report the manufacturing workflow, its chemical ...composition, and the mechanical properties that may support their clinical application.
Overview
These new 3D‐printing provisional materials are typically composed of monomers based on acrylic esters or filled hybrid material. The most commonly used AM methods to manufacture dental provisional restorations are stereolithography (SLA) and material jetting (MJ) technologies. To the knowledge of the authors, there is no published article that analyzes the chemical composition of these new 3D‐printing materials. Because of protocol disparities, technology selected, and parameters of the printers and material used, it is notably difficult to compare mechanical properties results obtained in different studies.
Conclusions
Although there is a growing demand for these high‐tech restorations, additional information regarding the chemical composition and mechanical properties of these new provisional printed materials is required.
Clinical Significance
Additive manufacturing technologies are a current option to fabricate provisional dental restorations; however, there is very limited information regarding its chemical composition and mechanical properties that may support their clinical application.
Deciphering the shared genetic basis of distinct cancers has the potential to elucidate carcinogenic mechanisms and inform broadly applicable risk assessment efforts. Here, we undertake genome-wide ...association studies (GWAS) and comprehensive evaluations of heritability and pleiotropy across 18 cancer types in two large, population-based cohorts: the UK Biobank (408,786 European ancestry individuals; 48,961 cancer cases) and the Kaiser Permanente Genetic Epidemiology Research on Adult Health and Aging cohorts (66,526 European ancestry individuals; 16,001 cancer cases). The GWAS detect 21 genome-wide significant associations independent of previously reported results. Investigations of pleiotropy identify 12 cancer pairs exhibiting either positive or negative genetic correlations; 25 pleiotropic loci; and 100 independent pleiotropic variants, many of which are regulatory elements and/or influence cross-tissue gene expression. Our findings demonstrate widespread pleiotropy and offer further insight into the complex genetic architecture of cross-cancer susceptibility.
Religiosity is a protective factor against many health problems, including alcohol use disorders (AUD). Studies suggest that religiosity has greater buffering effects on mental health problems among ...US Blacks and Hispanics than Whites. However, whether race/ethnic differences exist in the associations of religiosity, alcohol consumption and AUD is unclear.
Using 2004-2005 NESARC data (analytic n = 21 965), we examined the relationship of public religiosity (i.e. frequency of service attendance, religious social group size), and intrinsic religiosity (i.e. importance of religious/spiritual beliefs) to frequency of alcohol use and DSM-IV AUD in non-Hispanic (NH) Blacks, Hispanics and NH Whites, and whether associations differed by self-identified race/ethnicity.
Only public religiosity was related to AUD. Frequency of religious service attendance was inversely associated with AUD (NH Whites β: -0.103, p 0.05) or Hispanics (β: -0.002, p > 0.05).
US adults reporting greater public religiosity were at lower risk for AUD. Public religiosity may be particularly important among NH Blacks, while intrinsic religiosity may be particularly important among NH Whites, and among Hispanics who frequently attend religious services. Findings may be explained by variation in drinking-related norms observed among these groups generally, and in the context of specific religious institutions.
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