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The SPARC tokamak is a critical next step towards commercial fusion energy. SPARC is designed as a high-field ($B_0 = 12.2$ T), compact ($R_0 = 1.85$ m, $a = 0.57$ m), superconducting, D-T tokamak with the goal of producing fusion gain $Q>2$ from a magnetically confined fusion plasma for the first time. Currently under design, SPARC will continue the high-field path of the Alcator series of tokamaks, utilizing new magnets based on rare earth barium copper oxide high-temperature superconductors to achieve high performance in a compact device. The goal of $Q>2$ is achievable with conservative physics assumptions ($H_{98,y2} = 0.7$) and, with the nominal assumption of $H_{98,y2} = 1$, SPARC is projected to attain $Q \\approx 11$ and $P_{\\textrm {fusion}} \\approx 140$ MW. SPARC will therefore constitute a unique platform for burning plasma physics research with high density ($\\langle n_{e} \\rangle \\approx 3 \\times 10^{20}\\ \\textrm {m}^{-3}$), high temperature ($\\langle T_e \\rangle \\approx 7$ keV) and high power density ($P_{\\textrm {fusion}}/V_{\\textrm {plasma}} \\approx 7\\ \\textrm {MW}\\,\\textrm {m}^{-3}$) relevant to fusion power plants. SPARC's place in the path to commercial fusion energy, its parameters and the current status of SPARC design work are presented. This work also describes the basis for global performance projections and summarizes some of the physics analysis that is presented in greater detail in the companion articles of this collection.

Potential loss of energetic ions including alphas and radio-frequency tail ions due to classical orbit effects and magnetohydrodynamic instabilities (MHD) are central physics issues in the design and experimental physics programme of the SPARC tokamak. The expected loss of fusion alpha power due to ripple-induced transport is computed for the SPARC tokamak design by the ASCOT and SPIRAL orbit-simulation codes, to assess the expected surface heating of plasma-facing components. We find good agreement between the ASCOT and SPIRAL simulation results not only in integrated quantities (fraction of alpha power loss) but also in the spatial, temporal and pitch-angle dependence of the losses. If the toroidal field (TF) coils are well-aligned, the SPARC edge ripple is small (0.15–0.30 %), the computed ripple-induced alpha power loss is small (${\\sim } 0.25\\,\\%$) and the corresponding peak surface power density is acceptable ($244\\ \\textrm{kW}\\ \\textrm {m}^{-2}$). However, the ripple and ripple-induced losses increase strongly if the TF coils are assumed to suffer increasing magnitudes of misalignment. Surface heat loads may become problematic if the TF coil misalignment approaches the centimetre level. Ripple-induced losses of the energetic ion tail driven by ion cyclotron range of frequency (ICRF) heating are not expected to generate significant wall or limiter heating in the nominal SPARC plasma scenario. Because the expected classical fast-ion losses are small, SPARC will be able to observe and study fast-ion redistribution due to MHD including sawteeth and Alfvén eigenmodes (AEs). SPARC's parameter space for AE physics even at moderate $Q$ is shown to reasonably overlap that of the demonstration power plant ARC (Sorbom et al., Fusion Engng Des., vol. 100, 2015, p. 378), and thus measurements of AE mode amplitude, spectrum and associated fast-ion transport in SPARC would provide relevant guidance about AE behaviour expected in ARC.

Recently-proposed tokamak concepts use magnetic fields up to 12 T, far higher than in conventional devices, to reduce size and cost. Theoretical and computational study of trends in plasma behavior with increasing field strength is critical to such proposed devices. This paper considers trends in Alfvén eigenmode (AE) stability. Energetic particles, including alphas from D-T fusion, can destabilize AEs, possibly causing loss of alpha heat and damage to the device. AEs are sensitive to device magnetic field via the field dependence of resonances, alpha particle beta, and alpha orbit width. We describe the origin and effect of these dependences analytically and by using recently-developed numerical techniques (Rodrigues et al. 2015 Nucl. Fusion 55 083003). The work suggests high-field machines where fusion-born alphas are sub-Alfvénic or nearly sub-Alfvénic may partially cut off AE resonances, reducing growth rates of AEs and the energy of alphas interacting with them. High-field burning plasma regimes have non-negligible alpha particle beta and AE drive, but faster slowing down time, provided by high electron density, and higher field strength reduces this drive relative to low-field machines with similar power densities. The toroidal mode number of the most unstable modes will tend to be higher in high magnetic field devices. The work suggests that high magnetic field devices have unique, and potentially advantageous, AE instability properties at both low and high densities.

The ARC pilot plant conceptual design study has been extended beyond its initial scope [B. N. Sorbom et al., FED 100 (2015) 378] to explore options for managing ~525 MW of fusion power generated in a compact, high field (B_0 = 9.2 T) tokamak that is approximately the size of JET (R_0 = 3.3 m). Taking advantage of ARC's novel design - demountable high temperature superconductor toroidal field (TF) magnets, poloidal magnetic field coils located inside the TF, and vacuum vessel (VV) immersed in molten salt FLiBe blanket - this follow-on study has identified innovative and potentially robust power exhaust management solutions.

Multidrug-resistant tuberculosis threatens to reverse recent reductions in global tuberculosis incidence. Although children younger than 15 years constitute more than 25% of the worldwide population, the global incidence of multidrug-resistant tuberculosis disease in children has never been quantified. We aimed to estimate the regional and global annual incidence of multidrug-resistant tuberculosis in children. We developed two models: one to estimate the setting-specific risk of multidrug-resistant tuberculosis among child cases of tuberculosis, and a second to estimate the setting-specific incidence of tuberculosis disease in children. The model for risk of multidrug-resistant tuberculosis among children with tuberculosis needed a systematic literature review. We multiplied the setting-specific estimates of multidrug-resistant tuberculosis risk and tuberculosis incidence to estimate regional and global incidence of multidrug-resistant tuberculosis disease in children in 2010. We identified 3403 papers, of which 97 studies met inclusion criteria for the systematic review of risk of multidrug-resistant tuberculosis. 31 studies reported the risk of multidrug-resistant tuberculosis in both children and treatment-naive adults with tuberculosis and were used for evaluation of the linear association between multidrug-resistant disease risk in these two patient groups. We identified that the setting-specific risk of multidrug-resistant tuberculosis was nearly identical in children and treatment-naive adults with tuberculosis, consistent with the assertion that multidrug-resistant disease in both groups reflects the local risk of transmitted multidrug-resistant tuberculosis. After application of these calculated risks, we estimated that around 999 792 (95% CI 937 877–1 055 414) children developed tuberculosis disease in 2010, of whom 31 948 (25 594–38 663) had multidrug-resistant disease. Our estimates underscore that many cases of tuberculosis and multidrug-resistant tuberculosis disease are not being detected in children. Future estimates can be refined as more and better tuberculosis data and new diagnostic instruments become available. US National Institutes of Health, the Helmut Wolfgang Schumann Fellowship in Preventive Medicine at Harvard Medical School, the Norman E Zinberg Fellowship at Harvard Medical School, and the Doris and Howard Hiatt Residency in Global Health Equity and Internal Medicine at the Brigham and Women's Hospital.

Background Glaucoma is characterized by the progressive dysfunction and loss of retinal ganglion cells. Recent work in animal models suggests that a critical neuroinflammatory event damages retinal ganglion cell axons in the optic nerve head during ocular hypertensive injury. We previously demonstrated that monocyte-like cells enter the optic nerve head in an ocular hypertensive mouse model of glaucoma (DBA/2 J), but their roles, if any, in mediating axon damage remain unclear. Methods To understand the function of these infiltrating monocyte-like cells, we used RNA-sequencing to profile their transcriptomes. Based on their pro-inflammatory molecular signatures, we hypothesized and confirmed that monocyte-platelet interactions occur in glaucomatous tissue. Furthermore, to test monocyte function we used two approaches to inhibit their entry into the optic nerve head: (1) treatment with DS-SILY, a peptidoglycan that acts as a barrier to platelet adhesion to the vessel wall and to monocytes, and (2) genetic targeting of Itgam (CD11b, an immune cell receptor that enables immune cell extravasation). Results Monocyte specific RNA-sequencing identified novel neuroinflammatory pathways early in glaucoma pathogenesis. Targeting these processes pharmacologically (DS-SILY) or genetically ( Itgam / CD11b knockout) reduced monocyte entry and provided neuroprotection in DBA/2 J eyes. Conclusions These data demonstrate a key role of monocyte-like cell extravasation in glaucoma and demonstrate that modulating neuroinflammatory processes can significantly lessen optic nerve injury.

During the past five to ten years, a broad partnership of institutions under NOPP sponsorship has collaborated in developing and demonstrating the performance and application of eddy-resolving, real-time global- and basin-scale ocean prediction systems using the HYbrid Coordinate Ocean Model (HYCOM). The partnership represents a broad spectrum of the oceanographic community, bringing together academia, federal agencies, and industry/commercial entities, and spanning modeling, data assimilation, data management and serving, observational capabilities, and application of HYCOM prediction system outputs. In addition to providing real-time, eddy-resolving global- and basin-scale ocean prediction systems for the US Navy and NOAA, this project also offered an outstanding opportunity for NOAA-Navy collaboration and cooperation, ranging from research to the operational level. This paper provides an overview of the global HYCOM ocean prediction system and highlights some of its achievements. An important outcome of this effort is the capability of the global system to provide boundary conditions to even higher-resolution regional and coastal models.

Inhibitors of poly-ADP-ribose polymerase 1 (PARPi) are highly effective in killing cells deficient in homologous recombination (HR); thus, PARPi have been clinically utilized to successfully treat BRCA2-mutant tumors. However, positive response to PARPi is not universal, even among patients with HR-deficiency. Here, we present the results of genome-wide CRISPR knockout and activation screens which reveal genetic determinants of PARPi response in wildtype or BRCA2-knockout cells. Strikingly, we report that depletion of the ubiquitin ligase HUWE1, or the histone acetyltransferase KAT5, top hits from our screens, robustly reverses the PARPi sensitivity caused by BRCA2-deficiency. We identify distinct mechanisms of resistance, in which HUWE1 loss increases RAD51 levels to partially restore HR, whereas KAT5 depletion rewires double strand break repair by promoting 53BP1 binding to double-strand breaks. Our work provides a comprehensive set of putative biomarkers that advance understanding of PARPi response, and identifies novel pathways of PARPi resistance in BRCA2-deficient cells. Mutations in the homologous recombination proteins BRCA1 and BRCA2 can sensitize cells to treatment with inhibitors of poly-ADP-ribose polymerase 1 (PARPi), but resistance to the treatment can occur. Here the authors by genome-wide CRISPR knockout and activation screens reveal novel pathways of PARPi resistance in BRCA2-deficient cells.

Importance Most unwanted sexual contact victimization (USCV) research utilizes predominantly white, cisgender, heterosexual college student samples. Estimates of USCV prevalence and demographic variation can determine the need for dedicated funding and culturally relevant campus services for students in high-risk groups. Objective To estimate the national prevalence and demographic variation in self-reported USCV within the first three months of college. Design Data are from the Sexual Assault Prevention for Undergrads (SAPU) (2020–2021) dataset. SAPU is an online intervention program administered to students on more than 600 college campuses in the United States ( N =  250,359). Group differences were assessed by race/ethnicity, gender identity, and sexual identity, and then stratified by gender to assess within-gender group differences. Setting The SAPU dataset includes public and private institutions and 2-year and 4-year colleges with varying sizes of enrollment. Participants The sample is demographically diverse, and consists of newly matriculated U.S. college students, most of whom complete the SAPU program within the first three months of enrollment. Main outcomes and measures The primary outcome measure is self-reported USCV within the first three months of college enrollment, analyzed for subgroup differences. We hypothesized that USCV would be higher among students from racial/ethnic, gender, and sexual minority populations. Results Nearly 8% of transgender men reported USCV, followed by 7.4% of transgender women, 7.4% of genderqueer/gender non-conforming students, 4.5% of women, and 1.5% of men. Several subgroups reported exceedingly high rates of USCV, including Black students who identified as transgender women (35.7%) and American Indian/Alaska Native/Native Hawaiian/Pacific Islander students who identified as trans men (55.6%) or genderqueer/gender non-conforming (41.7%). Conclusions and relevance Universal and targeted (selective and indicated) intervention programs are needed to lessen USCV, particularly among gender minority students who also identify as Black, Indigenous, other person of color, or as a sexual minority.