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The Sandia Fracture Challenges provide a forum for the mechanics community to assess its ability to predict ductile fracture through a blind, round-robin format where mechanicians are challenged to predict the deformation and failure of an arbitrary geometry given experimental calibration data. The Third Challenge (SFC3) required participants to predict fracture in an additively manufactured (AM) 316L stainless steel bar containing through holes and internal cavities that could not have been conventionally machined. The volunteer participants were provided extensive data including tension and notched tensions tests of 316L specimens built on the same build-plate as the Challenge geometry, micro-CT scans of the Challenge specimens and geometric measurements of the feature based on the scans, electron backscatter diffraction (EBSD) information on grain texture, and post-test fractography of the calibration specimens. Surprisingly, the global behavior of the SFC3 geometry specimens had modest variability despite being made of AM metal, with all of the SFC3 geometry specimens failing under the same failure mode. This is attributed to the large stress concentrations from the holes overwhelming the stochastic local influence of the AM voids and surface roughness. The teams were asked to predict a number of quantities of interest in the response based on global and local measures that were compared to experimental data, based partly on Digital Image Correlation (DIC) measurements of surface displacements and strains, including predictions of variability in the resulting fracture response, as the basis for assessment of the predictive capabilities of the modeling and simulation strategies. Twenty-one teams submitted predictions obtained from a variety of methods: the finite element method (FEM) or the mesh-free, peridynamic method; solvers with explicit time integration, implicit time integration, or quasi-statics; fracture methods including element deletion, peridynamics with bond damage, XFEM, damage (stiffness degradation), and adaptive remeshing. These predictions utilized many different material models: plasticity models including J2 plasticity or Hill yield with isotropic hardening, mixed Swift-Voce hardening, kinematic hardening, or custom hardening curves; fracture criteria including GTN model, Hosford-Coulomb, triaxiality-dependent strain, critical fracture energy, damage-based model, critical void volume fraction, and Johnson-Cook model; and damage evolution models including damage accumulation and evolution, crack band model, fracture energy, displacement value threshold, incremental stress triaxiality, Cocks-Ashby void growth, and void nucleation, growth, and coalescence. Teams used various combinations of calibration data from tensile specimens, the notched tensile specimens, and literature data. A detailed comparison of results based of these different methods is presented in this paper to suggest a set of best practices for modeling ductile fracture in situations like the SFC3 AM-material problem. All blind predictions identified the nominal crack path and initiation location correctly. The SFC3 participants generally fared better in their global predictions of deformation and failure than the participants in the previous Challenges, suggesting the relative maturity of the models used and adoption of best practices from previous Challenges. This paper provides detailed analyses of the results, including discussion of the utility of the provided data, challenges of the experimental-numerical comparison, defects in the AM material, and human factors.

PD-L1 and CTLA-4 immune checkpoints inhibit antitumour T-cell activity. Combination treatment with the anti-PD-L1 antibody durvalumab and the anti-CTLA-4 antibody tremelimumab might provide greater antitumour activity than either drug alone. We aimed to assess durvalumab plus tremelimumab in patients with advanced squamous or non-squamous non-small cell lung cancer (NSCLC). We did a multicentre, non-randomised, open-label, phase 1b study at five cancer centres in the USA. We enrolled immunotherapy-naive patients aged 18 years or older with confirmed locally advanced or metastatic NSCLC. We gave patients durvalumab in doses of 3 mg/kg, 10 mg/kg, 15 mg/kg, or 20 mg/kg every 4 weeks, or 10 mg/kg every 2 weeks, and tremelimumab in doses of 1 mg/kg, 3 mg/kg, or 10 mg/kg every 4 weeks for six doses then every 12 weeks for three doses. The primary endpoint of the dose-escalation phase was safety. Safety analyses were based on the as-treated population. The dose-expansion phase of the study is ongoing. This study is registered with ClinicalTrials.gov, number NCT02000947. Between Oct 28, 2013, and April 1, 2015, 102 patients were enrolled into the dose-escalation phase and received treatment. At the time of this analysis (June 1, 2015), median follow-up was 18·8 weeks (IQR 11–33). The maximum tolerated dose was exceeded in the cohort receiving durvalumab 20 mg/kg every 4 weeks plus tremelimumab 3 mg/kg, with two (30%) of six patients having a dose-limiting toxicity (one grade 3 increased aspartate aminotransferase and alanine aminotransferase and one grade 4 increased lipase). The most frequent treatment-related grade 3 and 4 adverse events were diarrhoea (11 [11%]), colitis (nine [9%]), and increased lipase (eight [8%]). Discontinuations attributable to treatment-related adverse events occurred in 29 (28%) of 102 patients. Treatment-related serious adverse events occurred in 37 (36%) of 102 patients. 22 patients died during the study, and three deaths were related to treatment. The treatment-related deaths were due to complications arising from myasthenia gravis (durvalumab 10 mg/kg every 4 weeks plus tremelimumab 1 mg/kg), pericardial effusion (durvalumab 20 mg/kg every 4 weeks plus tremelimumab 1 mg/kg), and neuromuscular disorder (durvalumab 20 mg/kg every 4 weeks plus tremelimumab 3 mg/kg). Evidence of clinical activity was noted both in patients with PD-L1-positive tumours and in those with PD-L1-negative tumours. Investigator-reported confirmed objective responses were achieved by six (23%, 95% CI 9–44) of 26 patients in the combined tremelimumab 1 mg/kg cohort, comprising two (22%, 95% CI 3–60) of nine patients with PD-L1-positive tumours and four (29%, 95% CI 8–58) of 14 patients with PD-L1-negative tumours, including those with no PD-L1 staining (four [40%, 95% CI 12–74] of ten patients). Durvalumab 20 mg/kg every 4 weeks plus tremelimumab 1 mg/kg showed a manageable tolerability profile, with antitumour activity irrespective of PD-L1 status, and was selected as the dose for phase 3 studies, which are ongoing. MedImmune.

Patients with squamous non-small-cell lung cancer that is refractory to multiple treatments have poor outcomes. We assessed the activity of nivolumab, a fully human IgG4 PD-1 immune checkpoint inhibitor antibody, for patients with advanced, refractory, squamous non-small-cell lung cancer. We did this phase 2, single-arm trial at 27 sites (academic, hospital, and private cancer centres) in France, Germany, Italy, and USA. Patients who had received two or more previous treatments received intravenous nivolumab (3 mg/kg) every 2 weeks until progression or unacceptable toxic effects. The primary endpoint was the proportion of patients with a confirmed objective response as assessed by an independent radiology review committee. We included all treated patients in the analyses. This study is registered with ClinicalTrials.gov, number NCT01721759. Between Nov 16, 2012, and July 22, 2013, we enrolled and treated 117 patients. 17 (14·5%, 95% CI 8·7–22·2) of 117 patients had an objective response as assessed by an independent radiology review committee. Median time to response was 3·3 months (IQR 2·2–4·8), and median duration of response was not reached (95% CI 8·31–not applicable); 13 (77%) of 17 of responses were ongoing at the time of analysis. 30 (26%) of 117 patients had stable disease (median duration 6·0 months, 95% CI 4·7–10·9). 20 (17%) of 117 patients reported grade 3–4 treatment-related adverse events, including: fatigue (five [4%] of 117 patients), pneumonitis (four [3%]), and diarrhoea (three [3%]). There were two treatment-associated deaths caused by pneumonia and ischaemic stroke that occurred in patients with multiple comorbidities in the setting of progressive disease. Nivolumab has clinically meaningful activity and a manageable safety profile in previously treated patients with advanced, refractory, squamous non-small cell lung cancer. These data support the assessment of nivolumab in randomised, controlled, phase 3 studies of first-line and second-line treatment. Bristol-Myers Squibb.

Aim The Hemiptera is the fifth‐largest insect order but among non‐native insect species is approximately tied with the Coleoptera as the most species‐rich insect order (Hemiptera comprise 20% more species than in world fauna). This over‐representation may result from high propagule pressure or from high species invasiveness. Here, we assess the reasons for over‐representation in this group by analysing geographical, temporal and taxonomic variation in numbers of historical invasions. Location Global. Method We assembled lists of historical Hemiptera invasions in 12 world regions, countries or islands (Australia, Chile, Europe, New Zealand, North America, South Africa, South Korea, Japan and the Galapagos, Hawaiian, Okinawa and Ogasawara Islands) and border interception data from nine countries (Australia, Canada, European Union, United Kingdom, Hawaii, Japan, New Zealand, South Korea, USA mainland and South Africa). Using these data, we identified hemipteran superfamilies that are historically over‐represented among established non‐native species, and superfamilies that are over‐represented among arrivals (proxied by interceptions). We also compared temporal patterns of establishments among hemipteran suborders and among regions. Results Across all regions, patterns of over‐ and under‐representation were similar. The Aphidoidea, Coccoidea, Aleyrodoidea, Cimicoidea and Phylloxeroida were over‐represented among non‐native species. These same superfamilies were not consistently over‐represented among intercepted species indicating that propagule pressure does not completely explain the tendency of some Hemiptera to be over‐represented among invasions. Asexual reproduction is common in most over‐represented superfamilies and this trait may be key to explaining high invasion success in these superfamilies. Conclusions We conclude that both propagule pressure and species invasiveness are drivers of high invasion success in the Sternorrhyncha suborder (aphids, scales, whiteflies) and this group plays a major role in the exceptional invasion success of Hemiptera in general. The high historical rates of invasion by Sternorrhyncha species provide justification for biosecurity measure focusing on exclusion of this group.

The Cancer Genome Atlas consortium analyzed 293 lower-grade gliomas obtained from adult patients. The integration of genomic and clinical data shows that genetic status correlates better with biology and survival than does histologic status. Diffuse low-grade and intermediate-grade gliomas (World Health Organization [WHO] grades II and III, hereafter called lower-grade gliomas) (see the Glossary) are infiltrative neoplasms that arise most often in the cerebral hemispheres of adults and include astrocytomas, oligodendrogliomas, and oligoastrocytomas. 1 , 2 Because of their highly invasive nature, complete neurosurgical resection is impossible, and the presence of residual tumor results in recurrence and malignant progression, albeit at highly variable intervals. A subset of these gliomas will progress to glioblastoma (WHO grade IV gliomas) within months, whereas others remain stable for years. Similarly, survival ranges widely, from 1 to 15 years, and some . . .

Adequate resources are required to rapidly diagnose and treat pediatric musculoskeletal infection (MSKI). The workload MSKI consults contribute to pediatric orthopaedic services is unknown as prior epidemiologic studies are variable and negative work-ups are not included in national discharge databases. The hypothesis was tested that MSKI consults constitute a substantial volume of total consultations for pediatric orthopaedic services across the United States. Eighteen institutions from the Children's ORthopaedic Trauma and Infection Consortium for Evidence-based Study (CORTICES) group retrospectively reviewed a minimum of 1 year of hospital data, reporting the total number of surgeons, total consultations, and MSKI-related consultations. Consultations were classified by the location of consultation (emergency department or inpatient). Culture positivity rate and pathogens were also reported. 87,449 total orthopaedic consultations and 7,814 MSKI-related consultations performed by 229 pediatric orthopaedic surgeons were reviewed. There was an average of 13 orthopaedic surgeons per site each performing an average of 154 consultations per year. On average, 9% of consultations were MSKI related and 37% of these consults yielded positive cultures. Finally, a weak inverse monotonic relationship was noted between percent culture positivity and percent of total orthopedic consults for MSKI. At large, academic pediatric tertiary care centers, pediatric orthopaedic services consult on an average of ~3,000 'rule-out' MSKI cases annually. These patients account for nearly 1 in 10 orthopaedic consultations, of which 1 in 3 are culture positive. Considering that 2 in 3 consultations were culture negative, estimating resources required for pediatric orthopaedic consult services to work up and treat children based on culture positive administrative discharge data underestimates clinical need. Finally, ascertainment bias must be considered when comparing differences in culture rates from different institution's pediatric orthopaedics services, given the variability in when orthopaedic physicians become involved in a MSKI workup.

We examined fifth-year seedling response to soil disturbance and vegetation control at 42 experimental locations representing 25 replicated studies within the North American Long-Term Soil Productivity (LTSP) program. These studies share a common experimental design while encompassing a wide range of climate, site conditions, and forest types. Whole-tree harvest had limited effects on planted seedling performance compared with the effects of stem-only harvest (the control); slight increases in survival were usually offset by decreases in growth. Forest-floor removal improved seedling survival and increased growth in Mediterranean climates, but reduced growth on productive, nutrient-limited, warm-humid sites. Soil compaction with intact forest floors usually benefited conifer survival and growth, regardless of climate or species. Compaction combined with forest-floor removal generally increased survival, had limited effects on individual tree growth, and increased stand growth in Mediterranean climates. Vegetation control benefited seedling growth in all treatments, particularly on more productive sites, but did not affect survival or alter the relative impact of organic matter removal and compaction on growth. Organic matter removal increased aspen coppice densities and, as with compaction, reduced aspen growth.

Managing lead in the complex plumbing systems of school buildings can be a challenge, but proper guidance, careful planning, and collaboration increase the likelihood of achieving this worthy goal.

BackgroundAs single agents, durvalumab (MEDI4736), a human IgG1 anti-PD-L1 antibody, and tremelimumab, a human IgG2 anti-CTLA-4 antibody, have shown acceptable safety profiles and antitumor activity. Similar to other anti-PD-L1/anti-PD-1 monotherapies, durvalumab has shown greater objective tumor response rates in PD-L1-positive patients compared with PD-L1-negative patients. Anti-CTLA4 therapies activate T-cells and may increase immune infiltrate and PD-L1 expression in tumor cells and tumor infiltrating immune cells. Thus, combination therapy with durvalumab and tremelimumab could be active in NSCLC regardless of baseline PD-L1 expression.MethodsThis is a phase 1, open-label, dose-escalation/expansion study (NCT02000947) of D+T in patients with Stage III/IV NSCLC (any number of prior lines of therapy; immunotherapy-naïve). The primary endpoint is safety and tolerability; secondary endpoints include investigator-reported RECIST v1.1 response. PD-L1 expression was tested retrospectively using an immunohistochemical assay (Ventana).ResultsAs of 1 June 2015, 102 patients received treatment in the dose escalation phase; combinations of durvalumab [3 mg/kg (D3) to 20 mg/kg (D20) every 2 (q2w) or 4 weeks (q4w)] and tremelimumab [1 mg/kg (T1) to 3 mg/kg (T3)] q4w, plus a D15 + T10 combination, were explored. Across all cohorts, 80% and 42% of patients had ≥1 treatment-related AE (any Grade and Grade 3/4, respectively); 28% discontinued treatment due to a related AE. A greater frequency of AEs, without a corresponding increase in tumor response, was seen with increasing T dose. In the combined T1 cohort (D10–D20), 73% and 30% of patients had ≥1 related AE (any Grade and Grade 3/4, respectively); 16% discontinued treatment due to a related AE. There were 3 treatment-related deaths (myasthenia gravis, T1; pericardial effusion, T1; neuromuscular disorder, T3).84 patients (73 EGFR/ALK wild-type; 77 non-squamous; 48 with ≥2 prior lines of therapy) were evaluable for response (Table 1). The overall response rate (confirmed+unconfirmed) was 25%. Higher response rates were observed in those with 1 vs ≥2 prior therapies. Response rates do not appear dependent on PD-L1 status: 35% (PD-L1-positive), 22% (PD-L1-negative, <25% tumor cell staining) and 33% (PD-L1-negative, 0% tumor cell staining). Similar findings were observed for the combined T1 cohort. D+T also showed good durability of response similar to that seen for monotherapy.Response rates (Confirmed/unconfirmed with ≥16 weeks follow-up)Overall populationEGFR/ALK wild-type populationAll cohortsCombined cohort: D10–20 q4w or q2w + T1All cohortsCombined cohort: D10–20 q4w or q2w + T1n/N (%)95% CIn/N (%)95% CIn/N (%)95% CIn/N (%)95% CIAll patients21/84 (25)16–3611/39 (28)15–4521/73 (29)19–4111/34 (32)17–51PD-L1+ (≥25%)7/20 (35)15–593/9 (33)8–707/17 (41)18–673/9 (33)8–70PD-L1- (<25%)11/49 (22)12–376/23 (26)10–4811/45 (24)13–406/19 (32)13–57PD-L1- (0%)9/27 (33)17–546/12 (50)21–799/26 (35)17–566/11 (55)23–83All 2L patients15/32 (47)29–657/16 (44)20–7015/31 (48)30–677/15 (47)21–73PD-L1+ (≥25%)6/8 (75)35–972/3 (67)9–996/8 (75)35–972/3 (67)9–99PD-L1- (<25%)7/18 (39)17–644/11 (36)11–697/17 (41)18–674/10 (40)12–74PD-L1- (0%)6/8 (75)35–974/5 (80)28–1006/8 (75)35–974/5 (80)28–1002L, second line: 1 prior line of therapy, receiving D+T in second lineConclusionsD+T at selected phase 3 dose (D20, T1) has a manageable tolerability profile and anti-tumor activity in NSCLC. Unlike anti- PD-1/PD-L1 monotherapies, the combination of D+T appears to be active regardless of PD-L1 status, including even in patients with no tumor cell membrane PD-L1 staining, a setting where patients would not be expected to derive significant benefit from anti-PD-1/PD-L1 monotherapy over current standard of care [1, 2].