Reconsidering laminate nonsymmetry

Nonsymmetric laminates are commonly precluded from composite design due to perceptions of reduced performance arising from in- and out-of-plane coupling. This coupling introduces warpage during cure—leading to raised stresses, together with diminished buckling and load carrying capacity. However, these reduced performance characteristics are rarely quantified and included in the design process; instead the symmetric-only paradigm remains pervasive at the cost of a significantly reduced design space. Warpage is largely driven by mismatch in the coefficients of thermal expansion between sublaminates located above and below the midplane and can be predicted by the classical laminate theory. Acknowledging that all symmetric laminates in multipart structures have build stresses from assembly, it is proposed that subsets of nonsymmetric laminates that translate to similar raised stress levels be considered for design. Challenging this symmetric-only design paradigm would permit greater design freedom and offer new routes to elastically tailor composite structures. Further analysis of structural performance is assessed in terms of reduced loading and buckling capacity

Adaptive stiffness in lattice metastructures through tensile-buckling inspired topology morphing

This paper explores the use of simultaneous tensile buckling of unit cells to induce a transformation in lattice topology. Under tension, unit cells undergo passive transformation from a rectangle-like to a triangle-/pentagon-like topology, with an associated change in the effective stiffness properties. This behaviour is investigated through finite element analysis and experiments, with analytical results providing insights into the observed behaviour. The analysis identifies (i) that the initial unit cell topology (rectangular) is dominated by membrane effects, (ii) the transformation phase is associated with negative stiffness, and (iii) once formed, the new topology (triangular/pentagonal) exhibits increased stiffness in both compression and tension. Finite element analysis confirms that the unit cell behaviour is also preserved in lattices. Under tension, the lattice undergoes a seven-fold increase in stiffness as it transitions from its initial to the new topology, with a regime of negative stiffness during this transformation accounting for approximately 82% of its total elastic deformation. This new approach to elastically tailor the nonlinear response of (meta-)materials/structures has the potential to contribute to the development of novel tensile energy absorbers

Acoustic detection of microbubble formation induced by enhanced optical breakdown of silver/dendrimer nanocomposites

We utilize a real-time acoustic technique, based on pulse-echo measurements to detect formation of microbubbles in an aqueous solution of a silver/dendrimer nanocomposite (DNC). Wave-field plots of successive recordings illustrate the generation and behavior of bubbles created by the optical breakdown process. A significant threshold reduction is achieved with DNC particles compared to its host dendrimer, enabling a diverse field of low-threshold breakdown applications. © 2003 American Institute of Physics.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/70570/2/APPLAB-82-6-994-1.pd

Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of bladder carcinoma

Abstract The standard of care for most patients with non-muscle-invasive bladder cancer (NMIBC) is immunotherapy with intravesical Bacillus Calmette-Guérin (BCG), which activates the immune system to recognize and destroy malignant cells and has demonstrated durable clinical benefit. Urologic best-practice guidelines and consensus reports have been developed and strengthened based on data on the timing, dose, and duration of therapy from randomized clinical trials, as well as by critical evaluation of criteria for progression. However, these reports have not penetrated the community, and many patients do not receive appropriate therapy. Additionally, several immune checkpoint inhibitors have recently been approved for treatment of metastatic disease. The approval of immune checkpoint blockade for patients with platinum-resistant or -ineligible metastatic bladder cancer has led to considerations of expanded use for both advanced and, potentially, localized disease. To address these issues and others surrounding the appropriate use of immunotherapy for the treatment of bladder cancer, the Society for Immunotherapy of Cancer (SITC) convened a Task Force of experts, including physicians, patient advocates, and nurses, to address issues related to patient selection, toxicity management, clinical endpoints, as well as the combination and sequencing of therapies. Following the standard approach established by the Society for other cancers, a systematic literature review and analysis of data, combined with consensus voting was used to generate guidelines. Here, we provide a consensus statement for the use of immunotherapy in patients with bladder cancer, with plans to update these recommendations as the field progresses

Mocetinostat for patients with previously treated, locally advanced/metastatic urothelial carcinoma and inactivating alterations of acetyltransferase genes

BackgroundThe authors evaluated mocetinostat (a class I/IV histone deacetylase inhibitor) in patients with urothelial carcinoma harboring inactivating mutations or deletions in CREB binding protein [CREBBP] and/or E1A binding protein p300 [EP300] histone acetyltransferase genes in a singleâ arm, openâ label phase 2 study.MethodsEligible patients with platinumâ treated, advanced/metastatic disease received oral mocetinostat (at a dose of 70 mg 3 times per week [TIW] escalating to 90 mg TIW) in 28â day cycles in a 3â stage study (ClinicalTrials.gov identifier NCT02236195). The primary endpoint was the objective response rate.ResultsGenomic testing was feasible in 155 of 175 patients (89%). Qualifying tumor mutations were CREBBP (15%), EP300 (8%), and both CREBBP and EP300 (1%). A total of 17 patients were enrolled into stage 1 (the intentâ toâ treat population); no patients were enrolled in subsequent stages. One partial response was observed (11% [1 of 9 patients; the population that was evaluable for efficacy comprised 9 of the 15 planned patients]); activity was deemed insufficient to progress to stage 2 (null hypothesis: objective response rate of â ¤15%). All patients experienced â ¥1 adverse event, most commonly nausea (13 of 17 patients; 77%) and fatigue (12 of 17 patients; 71%). The median duration of treatment was 46 days; treatment interruptions (14 of 17 patients; 82%) and dose reductions (5 of 17 patients; 29%) were common. Mocetinostat exposure was lower than anticipated (doseâ normalized maximum serum concentration [Cmax] after TIW dosing of 0.2 ng/mL/mg).ConclusionsTo the authorsâ knowledge, the current study represents the first clinical trial using genomicâ based selection to identify patients with urothelial cancer who are likely to benefit from selective histone deacetylase inhibition. Mocetinostat was associated with significant toxicities that impacted drug exposure and may have contributed to modest clinical activity in these pretreated patients. The efficacy observed was considered insufficient to warrant further investigation of mocetinostat as a single agent in this setting.After the genomicâ based selection of patients with urothelial cancer with inactivating mutations/deletions in the histone acetyltransferase genes CREBBP and/or EP300, singleâ agent mocetinostat appears to be associated with significant toxicities that limit drug exposure. This may have contributed to the limited activity noted in the current phase 2 study (response rate of 11%) among heavily pretreated patients with platinumâ refractory disease.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/147860/1/cncr31817_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/147860/2/cncr31817.pd

Combining Enzalutamide with Abiraterone, Prednisone, and Androgen Deprivation Therapy in the STAMPEDE Trial

There are compelling reasons to study the addition of both enzalutamide and abiraterone, in combination, to standard-of-care for hormone-naïve prostate cancer. Through a protocol amendment, this will be assessed in the STAMPEDE trial, with overall survival as primary outcome measure. © 2014 European Association of Urology

Hundreds of variants clustered in genomic loci and biological pathways affect human height

Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P < 0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.

Post-release reforms for short prison sentences: re-legitimising and widening the net of punishment

Transforming Rehabilitation (TR) promised a ‘revolution’ in the way offenders are managed, providing a renewed focus on short sentence prisoners. The TR reforms extends mandatory post-release supervision and tailored through-the-gate resettlement provisions to a group that has predominately faced a ‘history of neglect’ yet often present with the most acute needs within the criminal justice system. However, existing literature underlines that serving short sentences lack ‘utility’ and can be counter-productive to facilitating effective rehabilitation. This article explores the purposes of providing post release supervision for short sentences, firstly exploring a previous attempt to reform short sentences; (the now defunct) ‘Custody Plus’ within the 2003 Criminal Justice Act and then the Offender Rehabilitation Act 2014 within the TR reforms. This article contends that both post release reforms have sought to re-affirm and re-legitimise prison as the dominant form of punishment in society- or what Carlen refers to as ‘carceral clawback’. This article will also use Cohen’s analysis on social control to establish that post release supervision will serve to ‘widen the net’ extend the period of punishment and oversight and will only reinforce a form of enforced ‘state obligated rehabilitation’ that will undermine efforts made to resettle short sentence prisoners

A Multilevel Approach to Relating Subjective Workload to Performance After Shifts in Task Demand

Objective: The aim of this laboratory experiment was to demonstrate how taking a longitudinal, multilevel approach can be used to examine the dynamic relationship between subjective workload and performance over a given period of activity involving shifts in task demand.Yeshttps://us.sagepub.com/en-us/nam/manuscript-submission-guideline