Background: TERT promoter mutation (TPM) is an established biomarker in meningiomas associated with aberrant TERT expression and reduced progression-free survival (PFS). TERT expression, however, has also been observed even in tumours with wildtype TERT promoters (TP-WT). This study aimed to examine TERT expression and clinical outcomes in meningiomas. Methods: TERT expression, TPM status, and TERT promoter methylation of a multi-institutional cohort of meningiomas (n=1241) was assessed through nulk RNA sequencing (n=604), Sanger sequencing of the promoter (n=1095), and methylation profiling (n=1218). 380 Toronto meningiomas were used for discovery, and 861 external institution samples were compiled as a validation cohort. Results: Both TPMs and TERTpromoter methylation were associated with increased TERT expression and may represent independent mechanisms of TERT reactivation. TERT expression was detected in 30.4% of meningiomas that lacked TPMs, was associated with higher WHO grades, and corresponded to shorter PFS, independent of grade and even among TP-WT tumours. TERT expression was associated with a shorter PFS equivalent to those of TERT-negative meningiomas of one higher grade. Conclusions: Our findings highlight the prognostic significance of TERT expression in meningiomas, even in the absence of TPMs. Its presence may identify patients who may progress earlier and should be considered in risk stratification models.

We provide an assessment of the Infinity Two fusion pilot plant (FPP) baseline plasma physics design. Infinity Two is a four-field period, aspect ratio $A = 10$, quasi-isodynamic stellarator with improved confinement appealing to a max-$J$ approach, elevated plasma density and high magnetic fields ($ \langle B\rangle = 9$ T). Here $J$ denotes the second adiabatic invariant. At the envisioned operating point ($800$ MW deuterium-tritium (DT) fusion), the configuration has robust magnetic surfaces based on magnetohydrodynamic (MHD) equilibrium calculations and is stable to both local and global MHD instabilities. The configuration has excellent confinement properties with small neoclassical transport and low bootstrap current ($|I_{bootstrap}| \sim 2$ kA). Calculations of collisional alpha-particle confinement in a DT FPP scenario show small energy losses to the first wall (${\lt}1.5 \,\%$) and stable energetic particle/Alfvén eigenmodes at high ion density. Low turbulent transport is produced using a combination of density profile control consistent with pellet fueling and reduced stiffness to turbulent transport via three-dimensional shaping. Transport simulations with the T3D-GX-SFINCS code suite with self-consistent turbulent and neoclassical transport predict that the DT fusion power$P_{{fus}}=800$ MW operating point is attainable with high fusion gain ($Q=40$) at volume-averaged electron densities $n_e\approx 2 \times 10^{20}$ m$^{-3}$, below the Sudo density limit. Additional transport calculations show that an ignited ($Q=\infty$) solution is available at slightly higher density ($2.2 \times 10^{20}$ m$^{-3}$) with $P_{{fus}}=1.5$ GW. The magnetic configuration is defined by a magnetic coil set with sufficient room for an island divertor, shielding and blanket solutions with tritium breeding ratios (TBR) above unity. An optimistic estimate for the gas-cooled solid breeder designed helium-cooled pebble bed is TBR $\sim 1.3$. Infinity Two satisfies the physics requirements of a stellarator fusion pilot plant.

Background: Meningiomas are the most common intracranial tumor with surgery, dural margin treatment, and radiotherapy as cornerstones of therapy. Response to treatment continues to be highly heterogeneous even across tumors of the same grade. Methods: Using a cohort of 2490 meningiomas in addition to 100 cases from the prospective RTOG-0539 phase II clinical trial, we define molecular biomarkers of response across multiple different, recently defined molecular classifications and use propensity score matching to mimic a randomized controlled trial to evaluate the role of extent of resection, dural marginal resection, and adjuvant radiotherapy on clinical outcome. Results: Gross tumor resection led to improved progression-free-survival (PFS) across all molecular groups (MG) and improved overall survival in proliferative meningiomas (HR 0.52, 95%CI 0.30-0.93). Dural margin treatment (Simpson grade 1/2) improved PFS versus complete tumor removal alone (Simpson 3). MG reliably predicted response to radiotherapy, including in the RTOG-0539 cohort. A molecular model developed using clinical trial cases discriminated response to radiotherapy better than standard of care grading in multiple cohorts (ΔAUC 0.12, 95%CI 0.10-0.14). Conclusions: We elucidate biological and molecular classifications of meningioma that influence response to surgery and radiotherapy in addition to introducing a novel molecular-based prediction model of response to radiation to guide treatment decisions.

Background: Meningiomas have significant heterogeneity between patients, making prognostication challenging. For this study, we prospectively validate the prognostic capabilities of a DNA methylation-based predictor and multiomic molecular groups (MG) of meningiomas. Methods: DNA methylation profiles were generated using the Illumina EPICarray. MG were assigned as previously published. Performance of our methylation-based predictor and MG were compared with WHO grade using generalized boosted regression modeling by generating time-dependent receiver operating characteristic (ROC) curves and computing area under the ROC curves (AUCs) along with their 95% confidence interval using bootstrap resampling. Results: 295 meningiomas treated from 2018-2021 were included. Methylation-defined high-risk meningiomas had significantly poorer PFS and OS compared to low-risk cases (p<0.0001). Methylation risk increased with higher WHO grade and MG. Higher methylome risk (HR 4.89, 95%CI 2.02-11.82) and proliferative MG (HR 4.11, 95%CI 1.29-13.06) were associated with significantly worse PFS independent of WHO grade, extent of resection, and adjuvant RT. Both methylome-risk and MG classification predicted 3- and 5-year PFS and OS more accurately than WHO grade alone (ΔAUC=0.10-0.23). 42 cases were prescribed adjuvant RT prospectively although RT did not significantly improve PFS in high-risk cases (p=0.41). Conclusions: Molecular profiling outperforms conventional WHO grading for prognostication in an independent, prospectively collected cohort of meningiomas.

Precision Medicine is an emerging approach for disease treatment and prevention that takes into account individual variability in genes, environment, and lifestyle. Autoimmune diseases are those in which the body’s natural defense system loses discriminating power between its own cells and foreign cells, causing the body to mistakenly attack healthy tissues. These conditions are very heterogeneous in their presentation and therefore difficult to diagnose and treat. Achieving precision medicine in autoimmune diseases has been challenging due to the complex etiologies of these conditions, involving an interplay between genetic, epigenetic, and environmental factors. However, recent technological and computational advances in molecular profiling have helped identify patient subtypes and molecular pathways which can be used to improve diagnostics and therapeutics. This review discusses the current understanding of the disease mechanisms, heterogeneity, and pathogenic autoantigens in autoimmune diseases gained from genomic and transcriptomic studies and highlights how these findings can be applied to better understand disease heterogeneity in the context of disease diagnostics and therapeutics.

Among nursing home outbreaks of coronavirus disease 2019 (COVID-19) with ≥3 breakthrough infections when the predominant severe acute respiratory coronavirus virus 2 (SARS-CoV-2) variant circulating was the SARS-CoV-2 δ (delta) variant, fully vaccinated residents were 28% less likely to be infected than were unvaccinated residents. Once infected, they had approximately half the risk for all-cause hospitalization and all-cause death compared with unvaccinated infected residents.

Some physiological variables which could aid in assessing the welfare of beef cattle in feedlots were screened in this exploratory study. In two experiments, each of 42 days duration, the physiological responses of Bos taurus steers to three treatments were investigated: pasture (rotation between 1.5 hectare paddocks); a feedlot yard stocked at 12.0 m2 per head with a dry, firm pen surface; and a ‘high-density’ feedlot yard stocked at 6.0 m2 per head with a wet and muddy pen surface. Fourteen steers were used per group per experiment. Relative adrenal mass in both feedlot groups was 8-10% higher than in the pasture group, and this finding was supported by morphological measurements of the adrenal glands. Out of 17 immune variables examined, only serum IgA and the T-cell lymphocytes subpopulation WC+1 showed consistent differences between the feedlot and pasture groups. Interestingly, no differences were observed between the two feedlot treatments. It was concluded that although there may have been some disruption of epithelial/mucosal immunity, more support was required from other immune variables before it could be stated that the immune system was depressed and that pre-pathological states existed in the feedlot groups. However, measures of relative adrenal weight, adrenal index, serum IgA and WC1+ lymphocytes are good candidates for use in future welfare investigations of feedlot cattle.

Early in the COVID-19 pandemic, the World Health Organization stressed the importance of daily clinical assessments of infected patients, yet current approaches frequently consider cross-sectional timepoints, cumulative summary measures, or time-to-event analyses. Statistical methods are available that make use of the rich information content of longitudinal assessments. We demonstrate the use of a multistate transition model to assess the dynamic nature of COVID-19-associated critical illness using daily evaluations of COVID-19 patients from 9 academic hospitals. We describe the accessibility and utility of methods that consider the clinical trajectory of critically ill COVID-19 patients.

Two introduced carnivores, the European red fox Vulpes vulpes and domestic cat Felis catus, have had extensive impacts on Australian biodiversity. In this study, we collate information on consumption of Australian birds by the fox, paralleling a recent study reporting on birds consumed by cats. We found records of consumption by foxes on 128 native bird species (18% of the non-vagrant bird fauna and 25% of those species within the fox’s range), a smaller tally than for cats (343 species, including 297 within the fox’s Australian range, a subset of that of the cat). Most (81%) bird species eaten by foxes are also eaten by cats, suggesting that predation impacts are compounded. As with consumption by cats, birds that nest or forage on the ground are most likely to be consumed by foxes. However, there is also some partitioning, with records of consumption by foxes but not cats for 25 bird species, indicating that impacts of the two predators may also be complementary. Bird species ≥3.4 kg were more likely to be eaten by foxes, and those <3.4 kg by cats. Our compilation provides an inventory and describes characteristics of Australian bird species known to be consumed by foxes, but we acknowledge that records of predation do not imply population-level impacts. Nonetheless, there is sufficient information from other studies to demonstrate that fox predation has significant impacts on the population viability of some Australian birds, especially larger birds, and those that nest or forage on the ground.

Background: Automated testing instruments (ATIs) are commonly used by clinical microbiology laboratories to perform antimicrobial susceptibility testing (AST), whereas public health laboratories may use established reference methods such as broth microdilution (BMD). We investigated discrepancies in carbapenem minimum inhibitory concentrations (MICs) among Enterobacteriaceae tested by clinical laboratory ATIs and by reference BMD at the CDC. Methods: During 2016–2018, we conducted laboratory- and population-based surveillance for carbapenem-resistant Enterobacteriaceae (CRE) through the CDC Emerging Infections Program (EIP) sites (10 sites by 2018). We defined an incident case as the first isolation of Enterobacter spp (E. cloacae complex or E. aerogenes), Escherichia coli, Klebsiella pneumoniae, K. oxytoca, or K. variicola resistant to doripenem, ertapenem, imipenem, or meropenem from normally sterile sites or urine identified from a resident of the EIP catchment area in a 30-day period. Cases had isolates that were determined to be carbapenem-resistant by clinical laboratory ATI MICs (MicroScan, BD Phoenix, or VITEK 2) or by other methods, using current Clinical and Laboratory Standards Institute (CLSI) criteria. A convenience sample of these isolates was tested by reference BMD at the CDC according to CLSI guidelines. Results: Overall, 1,787 isolates from 112 clinical laboratories were tested by BMD at the CDC. Of these, clinical laboratory ATI MIC results were available for 1,638 (91.7%); 855 (52.2%) from 71 clinical laboratories did not confirm as CRE at the CDC. Nonconfirming isolates were tested on either a MicroScan (235 of 462; 50.9%), BD Phoenix (249 of 411; 60.6%), or VITEK 2 (371 of 765; 48.5%). Lack of confirmation was most common among E. coli (62.2% of E. coli isolates tested) and Enterobacter spp (61.4% of Enterobacter isolates tested) (Fig. 1A), and among isolates testing resistant to ertapenem by the clinical laboratory ATI (52.1%, Fig. 1B). Of the 1,388 isolates resistant to ertapenem in the clinical laboratory, 1,006 (72.5%) were resistant only to ertapenem. Of the 855 nonconfirming isolates, 638 (74.6%) were resistant only to ertapenem based on clinical laboratory ATI MICs. Conclusions: Nonconfirming isolates were widespread across laboratories and ATIs. Lack of confirmation was most common among E. coli and Enterobacter spp. Among nonconfirming isolates, most were resistant only to ertapenem. These findings may suggest that ATIs overcall resistance to ertapenem or that isolate transport and storage conditions affect ertapenem resistance. Further investigation into this lack of confirmation is needed, and CRE case identification in public health surveillance may need to account for this phenomenon.

Funding: None

Disclosures: None

There is a requirement in some beef markets to slaughter bulls at under 16 months of age. This requires high levels of concentrate feeding. Increasing the slaughter age of bulls to 19 months facilitates the inclusion of a grazing period, thereby decreasing the cost of production. Recent data indicate few quality differences in longissimus thoracis (LT) muscle from conventionally reared 16-month bulls and 19-month-old bulls that had a grazing period prior to finishing on concentrates. The aim of the present study was to expand this observation to additional commercially important muscles/cuts. The production systems selected were concentrates offered ad libitum and slaughter at under 16 months of age (16-C) or at 19 months of age (19-CC) to examine the effect of age per se, and the cheaper alternative for 19-month bulls described above (19-GC). The results indicate that muscles from 19-CC were more red, had more intramuscular fat and higher cook loss than those from 16-C. No differences in muscle objective texture or sensory texture and acceptability were found between treatments. The expected differences in composition and quality between the muscles were generally consistent across the production systems examined. Therefore, for the type of animal and range of ages investigated, the effect of the production system on LT quality was generally representative of the effect on the other muscles analysed. In addition, the data do not support the under 16- month age restriction, based on meat acceptability, in commercial suckler bull production.

Between 2010 and 2019 the international health care organization Partners In Health (PIH) and its sister organization Zanmi Lasante (ZL) mounted a long-term response to the 2010 Haiti earthquake, focused on mental health. Over that time, implementing a Theory of Change developed in 2012, the organization successfully developed a comprehensive, sustained community mental health system in Haiti's Central Plateau and Artibonite departments, directly serving a catchment area of 1.5 million people through multiple diagnosis-specific care pathways. The resulting ZL mental health system delivered 28 184 patient visits and served 6305 discrete patients at ZL facilities between January 2016 and September 2019. The experience of developing a system of mental health services in Haiti that currently provides ongoing care to thousands of people serves as a case study in major challenges involved in global mental health delivery. The essential components of the effort to develop and sustain this community mental health system are summarized.

Pilot briefings, in their traditional form, drown pilots in a sea of information. Rather than unfocused swathes of air traffic management (ATM) information, pilots require only the information for their specific flight, preferably with an emphasis on the most important information. In this paper, we introduce the notion of ATM information cubes – in analogy to the well-established concept of Online analytical processing (OLAP) cubes in data warehousing. We propose a framework with merge and abstraction operations for the combination and summarization of the information in ATM information cubes to obtain management summaries of relevant information. To this end, we adopt the concept of semantic data container – a package of data items with a semantic description of the contents. The semantic descriptions then serve to hierarchically organise semantic containers along the dimensions of an ATM information cube. Leveraging this hierarchical organisation, a merge operation combines ATM information from individual semantic containers and collects the data items into composite containers. An abstraction operation summarises the data items within a semantic container, replacing individual data items with more abstract data items with summary information.