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.

The personalised oncology paradigm remains challenging to deliver despite technological advances in genomics-based identification of actionable variants combined with the increasing focus of drug development on these specific targets. To ensure we continue to build concerted momentum to improve outcomes across all cancer types, financial, technological and operational barriers need to be addressed. For example, complete integration and certification of the ‘molecular tumour board’ into ‘standard of care’ ensures a unified clinical decision pathway that both counteracts fragmentation and is the cornerstone of evidence-based delivery inside and outside of a research setting. Generally, integrated delivery has been restricted to specific (common) cancer types either within major cancer centres or small regional networks. Here, we focus on solutions in real-world integration of genomics, pathology, surgery, oncological treatments, data from clinical source systems and analysis of whole-body imaging as digital data that can facilitate cost-effectiveness analysis, clinical trial recruitment, and outcome assessment. This urgent imperative for cancer also extends across the early diagnosis and adjuvant treatment interventions, individualised cancer vaccines, immune cell therapies, personalised synthetic lethal therapeutics and cancer screening and prevention. Oncology care systems worldwide require proactive step-changes in solutions that include inter-operative digital working that can solve patient centred challenges to ensure inclusive, quality, sustainable, fair and cost-effective adoption and efficient delivery. Here we highlight workforce, technical, clinical, regulatory and economic challenges that prevent the implementation of precision oncology at scale, and offer a systematic roadmap of integrated solutions for standard of care based on minimal essential digital tools. These include unified decision support tools, quality control, data flows within an ethical and legal data framework, training and certification, monitoring and feedback. Bridging the technical, operational, regulatory and economic gaps demands the joint actions from public and industry stakeholders across national and global boundaries.

Interest group ideology is theoretically and empirically critical in the study of American politics, yet our measurement of this key concept is lacking both in scope and time. By leveraging network science and ideal point estimation, we provide a novel measure of ideology for amicus curiae briefs and organized interests with accompanying uncertainty estimates. Our Amicus Curiae Network scores cover more than 12,000 unique groups and more than 11,000 briefs across 95 years, providing the largest and longest measure of organized interest ideologies to date. Substantively, the scores reveal that: interests before the Court are ideologically polarized, despite variance in their coalition strategies; interests that donate to campaigns are more conservative and balanced than those that do not; and amicus curiae briefs were more common from liberal organizations until the 1980s, with ideological representation virtually balanced since then.

Background: Eye movements reveal neurodegenerative disease processes due to overlap between oculomotor circuitry and disease-affected areas. Characterizing oculomotor behaviour in context of cognitive function may enhance disease diagnosis and monitoring. We therefore aimed to quantify cognitive impairment in neurodegenerative disease using saccade behaviour and neuropsychology. Methods: The Ontario Neurodegenerative Disease Research Initiative recruited individuals with neurodegenerative disease: one of Alzheimer’s disease, mild cognitive impairment, amyotrophic lateral sclerosis, frontotemporal dementia, Parkinson’s disease, or cerebrovascular disease. Patients (n=450, age 40-87) and healthy controls (n=149, age 42-87) completed a randomly interleaved pro- and anti-saccade task (IPAST) while their eyes were tracked. We explored the relationships of saccade parameters (e.g. task errors, reaction times) to one another and to cognitive domain-specific neuropsychological test scores (e.g. executive function, memory). Results: Task performance worsened with cognitive impairment across multiple diseases. Subsets of saccade parameters were interrelated and also differentially related to neuropsychology-based cognitive domain scores (e.g. antisaccade errors and reaction time associated with executive function). Conclusions: IPAST detects global cognitive impairment across neurodegenerative diseases. Subsets of parameters associate with one another, suggesting disparate underlying circuitry, and with different cognitive domains. This may have implications for use of IPAST as a cognitive screening tool in neurodegenerative disease.

The Intensity Interferometry technique consists of measuring the spatial coherence (visibility) of an object via its intensity fluctuations over a sufficient range of telescope separations (baselines). This allows us to study the size, shape and morphology of stars with an unprecedented resolution. Cherenkov telescopes have a set of characteristics that coincidentally allow for Intensity Interferometry observations: very large reflective surfaces, sensitivity to individual photons, temporal resolution of nanoseconds and the fact that they come in groups of several telescopes. In the recent years, the MAGIC Collaboration has developed a deadtime-free Intensity Interferometry setup for its two 17 m diameter Cherenkov telescopes that includes a 4-channel GPU-based real-time correlator, 410–430 nm filters and new ways of splitting its primary mirrors into submirrors using Active Mirror Control (AMC). With this setup, MAGIC can operate as a long-baseline optical interferometer in the baseline range 40–90 m, which translates into angular resolutions of 0.5-1 mas. Additionally, thanks to its AMC, it can simultaneously measure the zero-baseline correlation or, by splitting into submirrors, access shorter baselines under 17 m in multiple u-v plane orientations. The best candidates to observe with this technique are relatively small and bright stars, in other words, massive stars (O, B and A types). We will present the science cases that are currently being proposed for this setup, as well as the prospects for the future of the system and technique, like the possibility of large-scale implementation with CTA.

In this article, an ultra-wideband printed flexible monopole antenna is proposed for indoor wireless communications. A flexible Rogers RO3003 is used as a substrate, and its performance is estimated for a flat state and when subject to bending along the y-axis. A 2.45 and 5.8 GHz dual-band textile artificial magnetic conductor (AMC) surface consisting of a 4 × 4 unit-cell array was integrated into antenna design with optimum separation distance to extend its potential applications to wearable on-body communications. The specific absorption rate (SAR) levels were numerically investigated using the Hugo human voxel model at both frequencies to evaluate the on-body safety level. Detailed analysis is presented for antenna designs of flat and bent states in free space and on the human body. The proposed UWB flexible antenna has the size of 41 × 38 × 0.25 mm (0.33λ0 × 0.31λ0 × 0.002λ0 at 2.45 GHz). It was added at a distance of 3 mm above a textile AMC surface of 99 × 99 mm. The integrated model is fabricated and experimentally characterized. Measured data and numerical results show that the impedance matching and radiation characteristics are slightly affected by introducing the bending and human body loading. With these remarkable features, the integrated model can be utilized for wireless indoor and wearable applications.

Adverse life events precede the onset of functional neurological disorder (FND, also known as conversion disorder) more commonly than other neuropsychiatric conditions, but their aetiological role is unclear. We conducted a systematic review and quantitative analysis of the type, timing and number of life events preceding the onset of FND in adults, and a meta-analysis of the proportions of types of events in controlled studies. Fifty-one studies of different designs, covering 4247 patients, were eligible for inclusion. There was no clear majority of any type of preceding event. Family problems were the most common category of events, followed by relationship problems. Females were more likely to experience preceding family/relationship problems than males, who reported more work problems. Family problems were the commonest type of preceding event in studies in developing countries, whereas family and health problems were equally common in developed countries. Abuse was associated with early symptom onset, while patients with later onset were more likely to report family problems. The median number of events was one, and the events occurred closer to onset than in controls. Meta-analysis found that family, relationship and work events were all relatively more common in patients than pathological controls, as were events where symptoms might provide a solution to the stressor. In conclusion, although a range of events precede the onset of FND, they do not appear to do so uniformly. This may support a different aetiological role for stressors than in other disorders, although the support is indirect and the quality generally low.

High-energy and high-intensity lasers are essential for pushing the boundaries of science. Their development has allowed leaps forward in basic research areas, including laser–plasma interaction, high-energy density science, metrology, biology and medical technology. The Helmholtz International Beamline for Extreme Fields user consortium contributes and operates two high-peak-power optical lasers using the high energy density instrument at the European X-ray free electron laser (EuXFEL) facility. These lasers will be used to generate transient extreme states of density and temperature to be probed by the X-ray beam. This paper introduces the ReLaX laser, a short-pulse high-intensity Ti:Sa laser system, and discusses its characteristics as available for user experiments. It will also present the first experimental commissioning results validating its successful integration into the EuXFEL infrastructure and viability as a relativistic-intensity laser driver.

School-based studies, despite the large number of studies conducted, have reported inconclusive results on obesity prevention. The sample size is a major constraint in such studies by requiring large samples. This pooled analysis overcomes this problem by analysing 5926 students (mean age 11·5 years) from five randomised school-based interventions. These studies focused on encouraging students to change their drinking and eating habits, and physical activities over the one school year, with monthly 1-h sessions in the classroom; culinary class aimed at developing cooking skills to increase healthy eating and attempts to family engagement. Pooled intention-to-treat analysis using linear mixed models accounted for school clusters. Control and intervention groups were balanced at baseline. The overall result was a non-significant change in BMI after one school year of positive changes in behaviours associated with obesity. Estimated mean BMI changed from 19·02 to 19·22 kg/m2 in the control group and from 19·08 to 19·32 kg/m2 in the intervention group (P value of change over time = 0·09). Subgroup analyses among those overweight or with obesity at baseline also did not show differences between intervention and control groups. The percentage of fat measured by bioimpedance indicated a small reduction in the control compared with intervention (P = 0·05). This large pooled analysis showed no effect on obesity measures, although promising results were observed about modifying behaviours associated with obesity.

Lymphopenia is common in adults who have had a Fontan operation although its aetiology and clinical implications remain unknown. Previous work suggests an association between lymphopenia and both liver disease and splenomegaly. The objective of this study was to assess the prevalence of lymphopenia in adults with a Fontan circulation and evaluate its associations with risk factors and clinical outcomes. Using a retrospective cohort study design, we studied 73 adult Fontan patients (age 25.0 ± 8.4 years) who had a complete blood count and abdominal imaging performed. Patients with protein-losing enteropathy were excluded. Clinical data were extracted from hospital records. The mean white blood cell count was 6580 ± 220/ml with a mean lymphocyte count of 1223 ± 508/ml. Lymphopenia, defined as lymphocyte count <1000/ml, was present in 23 (32%) patients. Patients with lymphopenia had a lower total white blood cell count (5556 ± 2517 versus 7136 ± 1924/ml, p = 0.009) and a lower platelet count (162 ± 69 versus 208 ± 69 k/ml, p = 0.008). Lymphopenia was also associated with findings of portal hypertension, including splenomegaly (36 versus 14%, p = 0.04), varices (22 versus 6%, p = 0.04), and ascites (39 versus 14%, p = 0.02). Lymphopenia did not correlate with any cardiac imaging, haemodynamic or exercise testing variables. In conclusion, lymphopenia is common in adult Fontan patients and is associated with markers of portal hypertension. Larger studies are needed to better define the relationship between lymphopenia and clinical outcomes.

Foodborne salmonellosis causes approximately 1 million illnesses annually in the United States. In the summer of 2017, we investigated four multistate outbreaks of Salmonella infections associated with Maradol papayas imported from four Mexican farms. PulseNet initially identified a cluster of Salmonella Kiambu infections in June 2017, and early interviews identified papayas as an exposure of interest. Investigators from Maryland, Virginia and Food and Drug Administration (FDA) collected papayas for testing. Several strains of Salmonella were isolated from papayas sourced from Mexican Farm A, including Salmonella Agona, Gaminara, Kiambu, Thompson and Senftenberg. Traceback from two points of service associated with illness sub-clusters in two states identified Farm A as a common source of papayas, and three voluntary recalls of Farm A papayas were issued. FDA sampling isolated four additional Salmonella strains from papayas sourced from Mexican Farms B, C and D. In total, four outbreaks were identified, resulting in 244 cases with illness onset dates from 20 December 2016 to 20 September 2017. The sampling of papayas and the collaborative work of investigative partners were instrumental in identifying the source of these outbreaks and preventing additional illnesses. Evaluating epidemiological, laboratory and traceback evidence together during investigations is critical to solving and stopping outbreaks.

Foodborne non-typhoidal salmonellosis causes approximately 1 million illnesses annually in the USA. In April 2015, we investigated a multistate outbreak of 65 Salmonella Paratyphi B variant L(+) tartrate(+) infections associated with frozen raw tuna imported from Indonesia, which was consumed raw in sushi. Forty-six (92%) of 50 case-patients interviewed ate sushi during the week before illness onset, and 44 (98%) of 45 who specified ate sushi containing raw tuna. Two outbreak strains were isolated from the samples of frozen raw tuna. Traceback identified a single importer as a common source of tuna consumed by case-patients; this importer issued three voluntary recalls of tuna sourced from one Indonesian processor. Four Salmonella Weltevreden infections were also linked to this outbreak. Whole-genome sequencing was useful in establishing a link between Salmonella isolated from ill people and tuna. This outbreak highlights the continuing foodborne illness risk associated with raw seafood consumption, the importance of processing seafood in a manner that minimises contamination with pathogenic microorganisms and the continuing need to ensure imported foods are safe to eat. People at higher risk for foodborne illness should not consume undercooked animal products, such as raw seafood.

Service utilisation by refugee families may be affected by the mismatch between Western individualistic service delivery approaches and the target communities’ more collectivist cultural patterns and practices. In addition to access barriers, utilisation of early childhood services by refugees can also be impacted upon by distrust of services, health and settlement issues, stigma, unfamiliarity with early childhood programmes, and fear of child protection and other legal systems. This low service utilisation sits in conflict with the need for early interventions for very young children, who are in the peak period of brain development. This article explores the implementation of a model to address these issues in early childhood work with refugee families and communities, with the intent to increase service uptake. Some strategies to address potential barriers will be described in the context of a community engagement model that includes consultation, relationship building, collaborative flexible service design and delivery, partnerships in community capacity building and cross-referral. Flexible, culturally appropriate interventions can enhance strengths based, non-pathologising and development-focused approach. A community engagement approach will, nevertheless, present challenges for service providers who must be willing to adapt their practices. Services and funding bodies need to recognise that this process is lengthy and resource intensive, but will ultimately lead to better service delivery and uptake, potentially leading to improvements in health, development and relational outcomes, for children and families from refugee backgrounds.

The genetic diversity of 39 clones of common reed originating from different geographical areas of Iran were evaluated using morphological and RAPD analyses. High level of morphological variation was observed among clones. The 16 primers used in this study amplified 149 scorable RAPD loci among which 123 were polymorphic (83.1%). A dendrogram was prepared on the basis of a similarity matrix of RAPD data using the unweighted pair-group method with arithmetic averages (UPGMA) algorithm and separated the 39 clones into four groups, which mainly were in accordance with geographical origins. The results of the morphological comparison mostly corresponded with the results of RAPD analysis. It is possible that these variations among clones will affect successful management of common reed using chemical or the other methods of control.

Hairy nightshade is a common weed in potato rotations in the western United States. As a close relative of potato, hairy nightshade can host numerous potato nematodes, diseases, and insect pests. Hairy nightshade hosts three common parasitic nematodes of potato, Columbia and northern root-knot nematodes, and stubby root nematode. Tubers of a potato breeding line with roots that are resistant to Columbia root-knot nematode—race 1, were damaged when grown in the presence of hairy nightshade. The weed provided an alternate host for the nematode, which then allowed the nematode to infect susceptible tubers. Stubby root nematodes transmit tobacco rattle virus (TRV), the causal agent for corky ringspot disease (CRS) of potato. CRS disease was maintained in soil when hairy nightshade was present in rotation crops of alfalfa or Scotch spearmint that otherwise eliminated the disease. Hairy nightshade also is a host of potato leaf roll virus (PLRV), which is transmitted by green peach aphids (GPA). GPA preferentially land and readily reproduce on hairy nightshade. Aphid transmission of PLRV from hairy nightshade to potato was four times greater than the virus transmission rate from potato to potato. Integrated management of these potato nematodes, diseases, and insect pests also should include strategies to control hairy nightshade in potato and rotation crops.

We report on a wide-range Density Functional Theory (DFT) investigation of the g-C3N4 photocatalysis systems combined with metals/nonmetals, especially those available in plants and involved in the natural photosynthesis process, such as K, Mg, Mn, Mo, Fe, Co, Cr, S and B. It is found that doping increases the range at which light absorption occurs to significantly large regions of the visible spectrum. These findings suggested that the g-C3N4 can be a promising system for the photosynthesis process.