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On December 5, 2022, an indirect drive fusion implosion on the National Ignition Facility (NIF) achieved a target gain G_{target} of 1.5. This is the first laboratory demonstration of exceeding "scientific breakeven" (or G_{target}>1) where 2.05 MJ of 351 nm laser light produced 3.1 MJ of total fusion yield, a result which significantly exceeds the Lawson criterion for fusion ignition as reported in a previous NIF implosion [H. Abu-Shawareb et al. (Indirect Drive ICF Collaboration), Phys. Rev. Lett. 129, 075001 (2022)PRLTAO0031-900710.1103/PhysRevLett.129.075001]. This achievement is the culmination of more than five decades of research and gives proof that laboratory fusion, based on fundamental physics principles, is possible. This Letter reports on the target, laser, design, and experimental advancements that led to this result.

For more than half a century, researchers around the world have been engaged in attempts to achieve fusion ignition as a proof of principle of various fusion concepts. Following the Lawson criterion, an ignited plasma is one where the fusion heating power is high enough to overcome all the physical processes that cool the fusion plasma, creating a positive thermodynamic feedback loop with rapidly increasing temperature. In inertially confined fusion, ignition is a state where the fusion plasma can begin "burn propagation" into surrounding cold fuel, enabling the possibility of high energy gain. While "scientific breakeven" (i.e., unity target gain) has not yet been achieved (here target gain is 0.72, 1.37 MJ of fusion for 1.92 MJ of laser energy), this Letter reports the first controlled fusion experiment, using laser indirect drive, on the National Ignition Facility to produce capsule gain (here 5.8) and reach ignition by nine different formulations of the Lawson criterion.

Context: Cushing syndrome (CS) is associated with impaired health-related quality of life (HRQOL) even after surgical cure., Objective: To characterize patient and provider perspectives on recovery from CS, drivers of decreased HRQOL during recovery, and ways to improve HRQOL., Design: Cross-sectional observational survey., Participants: Patients (n = 341) had undergone surgery for CS and were members of the Cushing's Support and Research Foundation. Physicians (n = 54) were Pituitary Society physician members and academicians who treated patients with CS., Results: Compared with patients, physicians underestimated the time to complete recovery after surgery (12 months vs 18 months, P  = 0.0104). Time to recovery did not differ by CS etiology, but patients with adrenal etiologies of CS reported a longer duration of cortisol replacement medication compared with patients with Cushing disease (12 months vs 6 months, P  = 0.0025). Physicians overestimated the benefits of work (26.9% vs 65.3%, P  < 0.0001), exercise (40.9% vs 77.6%, P  = 0.0001), and activities (44.8% vs 75.5%, P  = 0.0016) as useful coping mechanisms in the postsurgical period. Most patients considered family/friends (83.4%) and rest (74.7%) to be helpful. All physicians endorsed educating patients on recovery, but 32.4% (95% CI, 27.3-38.0) of patients denied receiving sufficient information. Some patients did not feel prepared for the postsurgical experience (32.9%; 95% CI, 27.6-38.6) and considered physicians not familiar enough with CS (16.1%; 95% CI, 12.2-20.8)., Conclusion: Poor communication between physicians and CS patients may contribute to dissatisfaction with the postsurgical experience. Increased information on recovery, including helpful coping mechanisms, and improved provider-physician communication may improve HRQOL during recovery., (Published by Oxford University Press on behalf of the Endocrine Society 2021.)

Health systems are struggling to manage a fluctuating volume of critically ill patients with COVID-19 while continuing to provide basic surgical services and expand capacity to address operative cases delayed by the pandemic. As we move forward through the next phases of the pandemic, we will need a decision-making system that allows us to remain nimble as clinicians to meet our patient's needs while also working with a new framework of healthcare operations. Here, we present our quality improvement process for the adaptation and application of the Medically Necessary Time-Sensitive (MeNTS) toolto gynecologic surgical services beyond the initial COVID response and into recovery of surgical services; with analysis of the reliability of the modified-MeNTS tool in our multi-site safety net hospital network. This multicenter study evaluated the gynecology surgical case volume at three tertiary acute care safety net institutions within the LA County Department of Health Services: Harbor-UCLA (HUMC), Olive View Medical Center (OVMC), and Los Angeles County + University of Southern California (LAC+USC). We describe our modified-Delphi approach to adapt the MeNTS tool in a structured fashion and its application to gynecologic surgical services. Blinded reviewers engaged in a three-round iterative adaptation and final scoring utilizing the modified tool. The cohort consisted of 392 female consecutive gynecology patients across three Los Angeles County Hospitals awaiting scheduled procedures in the surgical queue.The majority of patients were Latina (74.7%) and premenopausal (67.1%). Over half (52.4%) of the patients had cardiovascular disease, while 13.0% had lung disease, and 13.8% had diabetes. The most common indications for surgery were abnormal uterine bleeding (33.2%), pelvic organ prolapse (19.6%) and presence of an adnexal mass (14.3%). Minimally invasive approaches via laparoscopy, robotic-assisted laparoscopy, or vaginal surgery was the predominant planned surgical route (54.8%). Modified-MeNTS scores assumed a normal distribution across all patients within our cohort (Median 33, Range 18-52). Overall, ICC across all three institutions demonstrated "good" interrater reliability (0.72). ICC within institutions at HUMC and OVMC were categorized as "good" interrater reliability, while LAC-USC interrater reliability was categorized as "excellent" (HUMC 0.73, OVMC 0.65, LAC+USC 0.77). The modified-MeNTS tool performed well across a range of patients and procedures with a normal distribution of scores and high reliability between raters. We propose that the modified-MeNTS framework be considered as it employs quantitative methods for decision-making rather than subjective assessments.

Hypoxia has been implicated in the metastasis of Ewing sarcoma (ES) by clinical observations and in vitro data, yet direct evidence for its pro-metastatic effect is lacking and the exact mechanisms of its action are unclear. Here, we report an animal model that allows for direct testing of the effects of tumor hypoxia on ES dissemination and investigation into the underlying pathways involved. This approach combines two well-established experimental strategies, orthotopic xenografting of ES cells and femoral artery ligation (FAL), which induces hindlimb ischemia. Human ES cells were injected into the gastrocnemius muscles of SCID/beige mice and the primary tumors were allowed to grow to a size of 250 mm 3 . At this stage either the tumors were excised (control group) or the animals were subjected to FAL to create tumor hypoxia, followed by tumor excision 3 days later. The efficiency of FAL was confirmed by a significant increase in binding of hypoxyprobe-1 in the tumor tissue, severe tumor necrosis and complete inhibition of primary tumor growth. Importantly, despite these direct effects of ischemia, an enhanced dissemination of tumor cells from the hypoxic tumors was observed. This experimental strategy enables comparative analysis of the metastatic properties of primary tumors of the same size, yet significantly different levels of hypoxia. It also provides a new platform to further assess the mechanistic basis for the hypoxia-induced alterations that occur during metastatic tumor progression in vivo. In addition, while this model was established using ES cells, we anticipate that this experimental strategy can be used to test the effect of hypoxia in other sarcomas, as well as tumors orthotopically implanted in sites with a well-defined blood supply route.

Ewing sarcoma (ES) develops in bones or soft tissues of children and adolescents. The presence of bone metastases is one of the most adverse prognostic factors, yet the mechanisms governing their formation remain unclear. As a transcriptional target of EWS-FLI1, the fusion protein driving ES transformation, neuropeptide Y (NPY) is highly expressed and released from ES tumors. Hypoxia up-regulates NPY and activates its pro-metastatic functions. To test the impact of NPY on ES metastatic pattern, ES cell lines, SK-ES1 and TC71, with high and low peptide release, respectively, were used in an orthotopic xenograft model. ES cells were injected into gastrocnemius muscles of SCID/beige mice, the primary tumors excised, and mice monitored for the presence of metastases. SK-ES1 xenografts resulted in thoracic extra-osseous metastases (67%) and dissemination to bone (50%) and brain (25%), while TC71 tumors metastasized to the lungs (70%). Bone dissemination in SK-ES1 xenografts associated with increased NPY expression in bone metastases and its accumulation in bone invasion areas. The genetic silencing of NPY in SK-ES1 cells reduced bone degradation. Our study supports the role for NPY in ES bone invasion and provides new models for identifying pathways driving ES metastases to specific niches and testing anti-metastatic therapeutics.