Background: We evaluated vorasidenib (VOR), a dual inhibitor of mIDH1/2, in patients with mIDH1/2 glioma (Phase 3; NCT04164901). Methods: Patients with residual/recurrent grade 2 mIDH1/2 oligodendroglioma or astrocytoma were enrolled (age ≥12; Karnofsky Performance Score ≥80; measurable non-enhancing disease; surgery as only prior treatment; not in immediate need of chemoradiotherapy). Patients were stratified by 1p19q status and baseline tumor size and randomized 1:1 to VOR 40 mg or placebo (PBO) daily in 28-day cycles. Endpoints included imaging-based progression-free survival (PFS), time to next intervention (TTNI), tumor growth rate (TGR), health-related quality of life (HRQoL), neurocognition and seizure activity. Results: 331 patients were randomized (VOR, 168; PBO, 163). The median age was 40.0 years. 172 and 159 patients had histologically confirmed oligodendroglioma and astrocytoma, respectively. Treatment with VOR significantly improved PFS and TTNI. Median PFS: VOR, 27.7 mos; PBO, 11.1 mos (P=0.000000067). Median TTNI: VOR, not reached; PBO, 17.8 mos (P=0.000000019). Treatment with VOR resulted in shrinkage of tumor volume. Post-treatment TGR: VOR, -2.5% (95% CI: -4.7, -0.2); PBO, 13.9% (95% CI: 11.1, 16.8). HRQoL and neurocognition were preserved and seizure control was maintained. VOR had a manageable safety profile. Conclusions: VOR was effective in mIDH1/2 diffuse glioma not in immediate need of chemoradiotherapy.

Thin spray-on liners (TSLs) have been found to be effective for structurally supporting the walls of mining tunnels and thus reducing the occurrence of rock bursts, an effect primarily due to the penetration of cracks by the liner. Surface tension effects are thus important. However, TSLs are also used to simply stabilize rock surfaces, for example, to prevent rock fall, and in this context crack penetration is desirable but not necessary, and the tensile and shearing strength and adhesive properties of the liner determine its effectiveness. We examine the effectiveness of nonpenetrating TSLs in a global lined tunnel and in a local rock support context. In the tunnel context, we examine the effect of the liner on the stress distribution in a tunnel subjected to a geological or mining event. We show that the liner has little effect on stresses in the surrounding rock and that tensile stresses in the rock surface are transmitted across the liner, so that failure is likely to be due to liner rupture or detachment from the surface. In the local rock support context, loose rock movements are shown to be better achieved using a liner with small Young’s modulus, but high rupture strength.

Maternal adversity and prenatal stress confer risk for child behavioral health problems. Few studies have examined this intergenerational process across multiple dimensions of stress; fewer have explored potential protective factors. Using a large, diverse sample of mother–child dyads, we examined associations between maternal childhood trauma, prenatal stressors, and offspring socioemotional-behavioral development, while also examining potential resilience-promoting factors. The Conditions Affecting Neurocognitive Development and Learning and Early Childhood (CANDLE) study prospectively followed 1503 mother–child dyads (65% Black, 32% White) from pregnancy. Exposures included maternal childhood trauma, socioeconomic risk, intimate partner violence, and geocode-linked neighborhood violent crime during pregnancy. Child socioemotional-behavioral functioning was measured via the Brief Infant Toddler Social Emotional Assessment (mean age = 1.1 years). Maternal social support and parenting knowledge during pregnancy were tested as potential moderators. Multiple linear regressions (N = 1127) revealed that maternal childhood trauma, socioeconomic risk, and intimate partner violence were independently, positively associated with child socioemotional-behavioral problems at age one in fully adjusted models. Maternal parenting knowledge moderated associations between both maternal childhood trauma and prenatal socioeconomic risk on child problems: greater knowledge was protective against the effects of socioeconomic risk and was promotive in the context of low maternal history of childhood trauma. Findings indicate that multiple dimensions of maternal stress and adversity are independently associated with child socioemotional-behavioral problems. Further, modifiable environmental factors, including knowledge regarding child development, can mitigate these risks. Both findings support the importance of parental screening and early intervention to promote child socioemotional-behavioral health.

Introduction: It is unclear whether anticoagulant or antiplatelet medications increase the risk for intracranial bleeding in older adults after a fall. Our aim was to report the incidence of intracranial bleeding among older adults presenting to the emergency department (ED) with a fall, among patients taking anticoagulants, antiplatelet medications, both medications and neither medication. Methods: This was a systematic review and meta-analysis, PROSPERO reference CRD42019122626. Medline, EMBASE (via OVID 1946 - July 2019), Cochrane, Database of Abstracts of Reviews of Effects databases and the grey literature were searched for studies reporting on older adults who were evaluated after a fall. We included prospective studies conducted in the ED where more than 80% of the cohort were 65 years or older and had fallen. We contacted study authors for aggregate data on intracranial bleeding in patients prescribed anticoagulant medication, antiplatelet medication and neither medication. Incidences of intracranial bleeding were pooled using random effect models, and I2 index was used to assess heterogeneity. Results: From 7,240 publication titles, 10 studies met inclusion criteria. The authors of 8 of these 10 studies provided data (on 9,489 patients). All studies scored low or moderate risk of bias. The pooled incidence of intracranial bleeding among patients taking an anticoagulant medication was 5.1% (n = 5,016, 95% Confidence Interval (CI): 4.1 to 6.3%) I2 = 42%, a single antiplatelet 6.4% (n = 2,148, 95% CI: 5.4 to 7.6%) I2 = 75%, both anticoagulant and antiplatelet medications 5.9% (n = 212, 95% CI: 1.3 to 13.5%) I2 = 72%, and neither of these medications 4.8% (n = 1,927, 95% CI: 3.5 to 6.2%) I2 = 50%. A sensitivity analysis restricted to patients who had a head CT in the ED reported incidences of 6.1% (n = 3,561, 95% CI: 3 to 8.3%), 8.4% (n = 1,781, 95% CI: 5.5 to 11.8%), 6.7% (n = 206, 95% CI 1.5 to 15.2%) and 6.6% (n = 1,310, 95% CI: 5.0 to 8.4%) respectively. Conclusion: The incidence of fall-related intracranial bleeding in older ED patients was similar among patients who take anticoagulant medication, antiplatelet medication, both and neither medication, although there was heterogeneity between study findings.

In support of the disposal system safety case for a geological disposal facility (GDF) there is a requirement to consider 'what-if' hypothetical scenarios for post-closure nuclear criticality. Although all such scenarios are considered very unlikely, one 'what-if' scenario is the mobilization of fissile material from a number of waste packages and its slow accumulation within the GDF or the immediate surroundings. Should sufficient fissile material accumulate a quasi-steady-state (QSS) transient criticality event could result. A computer model has been developed to understand the evolution and consequences of such an event.

Since a postulated QSS criticality could persist for many millennia, building confidence in the modelling approach is difficult. However, the Oklo natural reactors in Africa operated for similar durations around two billion years ago, providing a natural analogue for comparison. This paper describes the modelling approach, its application to hypothetical criticality events for a GDF, and how the model can be compared to Oklo. The model results are found to be in agreement with the observational evidence from Oklo, building confidence in the use of the QSS model to simulate postulated post-closure criticality events in GDFs.

The Environment Agency Guidance on Requirements for Authorisation (GRA) of a geological disposal facility (GDF) requires a demonstration that "the possibility of a local accumulation of fissile material such as to produce a neutron chain reaction is not a significant concern." A neutron chain reaction that is just self-sustaining is also known as critical.

Waste packages can be designed to ensure that criticality is impossible during the transport and operational phases of a GDF, and for a significant period post-closure. Over longer times, however, packages may degrade, and groundwater flows could lead to a localized accumulation of fissile material. Hence, even though the initial distribution of materials would need to change substantially, criticality cannot be ruled out completely.

This paper describes how an accumulation of fissile material could, hypothetically, lead to a critical configuration; how such a system could evolve; what the local consequences could be; and how the engineered and geological barriers could be affected. The conclusion from studies to date is that, even for large (and very unlikely) fissile accumulations, the consequences of a post-closure criticality event are not a significant concern.

The pepper weevil, Anthonomus eugenii Cano (Coleoptera: Curculionidae), is the most important pest of pepper (Capsicum Linnaeus; Solanaceae) crops in North America. Native to Mexico, the southern United States of America, and Central America, it is intercepted in Canada when peppers are imported to supplement domestic production. Given the proximity of greenhouse and field production to packing facilities, this pest poses a serious risk to the cultivation of peppers in Canada. Once established, it is difficult to control because immature stages of the weevil are protected within the pepper fruit. As such, chemical control targeting these life stages is not effective, and other strategies, including biological control, may prove useful. To explore the potential for biological control options to manage the pepper weevil in areas at risk in Canada, natural enemy surveys were conducted in southern Ontario following the reports of transient, localised field populations in 2016. Parasitoids belonging to three Hymenoptera families including Pteromalidae (Jaliscoa hunteri Crawford, Pteromalus anthonomi Ashmead), Eupelmidae (Eupelmus pulchriceps Cameron), and Braconidae (Nealiolus Mason species, Bracon Fabricius species) were reared from infested field-collected pepper fruits. Together, these new natural enemy records could facilitate the exploration and development of novel agents for the biological control of the pepper weevil.

A geological disposal facility (GDF) will include fissile materials that could, under certain conditions, lead to criticality. Demonstration of criticality safety therefore forms an important part of a GDF's safety case.

Containment provided by the waste package will contributeto criticality safety during package transport and the GDF operational phase. The GDF multiple-barrier system will ensure that criticality is prevented for some time after facility closure. However, on longer post-closure timescales, conditions in the GDF will evolve and it is necessary todemonstrate: an understanding of the conditions under which criticality could occur; the likelihood of such conditions occurring; and the consequences of criticality should it occur.

Work has addressed disposal of all of the UK's higher-activity wastes in three illustrative geologies.This paper, however, focuses on presenting results to support safe disposal of spent fuel, plutonium and highlyenriched uranium in higher-strength rock.

The results support a safety case assertion that post-closure criticality is of low likelihood and, if it was to occur, the consequenceswould be tolerable.

We examined the prospective associations of objective and subjective measures of stress during pregnancy with infant stress reactivity and regulation, an early-life predictor of psychopathology. In a racially and ethnically diverse low-income sample of 151 mother–infant dyads, maternal reports of stressful life events (SLE) and perceived stress (PS) were collected serially over gestation and the early postpartum period. Infant reactivity and regulation at 6 months of age was assessed via maternal report of temperament (negativity, surgency, and regulation) and infant parasympathetic nervous system physiology (respiratory sinus arrhythmia [RSA]) during the Still Face Paradigm. Regression models predicting infant temperament showed higher maternal prenatal PS predicted lower surgency and self-regulation but not negativity. Regression models predicting infant physiology showed higher numbers of SLE during gestation predicted greater RSA reactivity and weaker recovery. Tests of interactions revealed SLE predicted RSA reactivity only at moderate to high levels of PS. Thus, findings suggest objective and subjective measures of maternal prenatal stress uniquely predict infant behavior and physiology, adjusting for key pre- and postnatal covariates, and advance the limited evidence for such prenatal programming within high-risk populations. Assessing multiple levels of maternal stress and offspring stress reactivity and regulation provides a richer picture of intergenerational transmission of adversity.

The presence of numerical noise in engineering design optimisation problems inhibits the use of many gradient-based optimisation methods. This numerical noise may result in the inaccurate calculation of gradients which in turn slows or prevents convergence during optimisation, or it may promote convergence to spurious local optima. The problems created by numerical noise are particularly acute in aircraft design applications where a single aerodynamic or structural analysis of a realistic aircraft configuration may require tens of CPU hours on a supercomputer. The computational expense of the analyses coupled with the convergence difficulties created by numerical noise are significant obstacles to performing aircraft multidisciplinary design optimisation. To address these issues, a procedure has been developed to create noise-free algebraic models of subsonic and supersonic aerodynamic performance quantities, for use in the optimisation of high-speed civil transport (HSCT) aircraft configurations. This procedure employs methods from statistical design of experiments theory and response surface modelling to create the noise-free algebraic models. Results from a sample HSCT design problem involving ten variables are presented to demonstrate the utility of this method.

Neighboring tidewater glaciers often exhibit asynchronous dynamic behavior, despite relatively uniform regional atmospheric and oceanic forcings. This variability may be controlled by a combination of local factors, including glacier and fjord geometry, fjord heat content and circulation, and glacier surface melt. In order to characterize and understand contrasts in adjacent tidewater glacier and fjord dynamics, we made coincident ice-ocean-atmosphere observations at high temporal resolution (minutes to weeks) within a 10 000 km2 area near Uummannaq, Greenland. Water column velocity, temperature and salinity measurements reveal systematic differences in neighboring fjords that imply contrasting circulation patterns. The observed ocean velocity and hydrography, combined with numerical modeling, suggest that subglacial discharge plays a major role in setting fjord conditions. In addition, satellite remote sensing of seasonal ice flow speed and terminus position reveal both speedup and slow-down in response to melt, as well as differences in calving style among the neighboring glaciers. Glacier force budgets and modeling also point toward subglacial discharge as a key factor in glacier behavior. For the studied region, individual glacier and fjord geometry modulate subglacial discharge, which leads to contrasts in both fjord and glacier dynamics.

A large measles outbreak occurred in South Wales in 2012/2013. The outbreak has been attributed to low take-up of measles-mumps-rubella (MMR) immunization in the early 2000s. To understand better the factors that led to this outbreak we present the findings of a case-control study carried out in the outbreak area in 2001 to investigate parents' decision on whether to accept MMR. Parents who decided not to take-up MMR at the time were more likely to be older and better educated, more likely to report being influenced by newspapers [adjusted odds ratio (aOR) 3·07, 95% confidence interval (CI) 1·62–5·80], television (aOR 3·30, 95% CI 1·70–6·43), the internet (aOR 7·23, 3·26–16·06) and vaccine pressure groups (aOR 5·20, 95% CI 2·22–12·16), and less likely to be influenced by a health visitor (aOR 0·30, 95% CI 0·16–0·57). In this area of Wales, daily English-language regional newspapers, UK news programmes and the internet appeared to have a powerful negative influence. We consider the relevance of these findings to the epidemiology of the outbreak and the subsequent public health response.

Field collections of over-wintering and summer adults and nymphs of Lygus lineolaris (Palisot de Beauvois) (Hemiptera: Miridae), Lygus borealis (Kelton), and Lygus elisus Van Duzee were made weekly in five fields in Saskatchewan in 1998 and 1999. The crops sampled were alfalfa, Medicago sativa L. (Leguminosae), canola, Brassica napus L. (Cruciferae), and mustard, Sinapis alba L. (Cruciferae), at Vonda, and alfalfa and canola at Saskatoon. In alfalfa, the most abundant Lygus spp. found in May and June were over-wintering adult L. lineolaris and (or) L. borealis; the predominant species in mid-June to early July was L. borealis; and the population from mid-July to late August was dominated by L. lineolaris. In canola, adult populations of Lygus spp. were not found until mid-June. The predominant species, L. lineolaris, probably over-wintering adults, was first detected in canola at the early bud stage in late June to early July; high numbers of L. lineolaris adults occurred in canola in mid-August. Populations of Lygus spp. in organic mustard were negligible. Dissections of field-collected Lygus spp. nymphs revealed parasitism in up to 70% of the midsummer population in alfalfa. In contrast, less than 1% of the late-season Lygus spp. population, primarily L. lineolaris in canola and L. lineolaris and L. borealis in alfalfa, was parasitized.

Hypovitaminosis D may be associated with diabetes, hypertension and CHD. However, because studies examining the associations of all three chronic conditions with circulating 25-hydroxyvitamin D (25(OH)D) and 1,25-dihydroxyvitamin D (1,25(OH)2D) are limited, we examined these associations in the US Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial (n 2465). Caucasian PLCO participants selected as controls in previous nested case–control studies of 25(OH)D and 1,25(OH)2D were included in this analysis. Diabetes, CHD and hypertension prevalence, risk factors for these conditions and intake of vitamin D and Ca were collected from a baseline questionnaire. Results indicated that serum levels of 25(OH)D were low ( < 50 nmol/l) in 29 % and very low ( < 37 nmol/l) in 11 % of subjects. The prevalence of diabetes, hypertension and CHD was 7, 30 and 10 %, respectively. After adjustment for confounding by sex, geographical location, educational level, smoking history, BMI, physical activity, total dietary energy and vitamin D and Ca intake, only diabetes was significantly associated with lower 25(OH)D and 1,25(OH)2D levels. Caucasians who had 25(OH)D ≥ 80 nmol/l were half as likely to have diabetes (OR 0·5 (95 % CI 0·3, 0·9)) compared with those who had 25(OH)D < 37 nmol/l. Those in the highest quartile of 1,25(OH)2D ( ≥ 103 pmol/l) were less than half as likely to have diabetes (OR 0·3 (95 % CI 0·1, 0·7)) than those in the lowest quartile ( < 72 pmol/l). In conclusion, the independent associations of 25(OH)D and 1,25(OH)2D with diabetes prevalence in a large population are new findings, and thus warrant confirmation in larger, prospective studies.