Tripled yield in direct-drive laser fusion through statistical modelling.

Focusing laser light onto a very small target can produce the conditions for laboratory-scale nuclear fusion of hydrogen isotopes. The lack of accurate predictive models, which are essential for the design of high-performance laser-fusion experiments, is a major obstacle to achieving thermonuclear ignition. Here we report a statistical approach that was used to design and quantitatively predict the results of implosions of solid deuterium-tritium targets carried out with the 30-kilojoule OMEGA laser system, leading to tripling of the fusion yield to its highest value so far for direct-drive laser fusion. When scaled to the laser energies of the National Ignition Facility (1.9 megajoules), these targets are predicted to produce a fusion energy output of about 500 kilojoules-several times larger than the fusion yields currently achieved at that facility. This approach could guide the exploration of the vast parameter space of thermonuclear ignition conditions and enhance our understanding of laser-fusion physics.

Direct Measurements of DT Fuel Preheat from Hot Electrons in Direct-Drive Inertial Confinement Fusion.

Hot electrons generated by laser-plasma instabilities degrade the performance of laser-fusion implosions by preheating the DT fuel and reducing core compression. The hot-electron energy deposition in the DT fuel has been directly measured for the first time by comparing the hard x-ray signals between DT-layered and mass-equivalent ablator-only implosions. The electron energy deposition profile in the fuel is inferred through dedicated experiments using Cu-doped payloads of varying thickness. The measured preheat energy accurately explains the areal-density degradation observed in many OMEGA implosions. This technique can be used to assess the viability of the direct-drive approach to laser fusion with respect to the scaling of hot-electron preheat with laser energy.

Experimentally Inferred Fusion Yield Dependencies of OMEGA Inertial Confinement Fusion Implosions.

Statistical modeling of experimental and simulation databases has enabled the development of an accurate predictive capability for deuterium-tritium layered cryogenic implosions at the OMEGA laser [V. Gopalaswamy et al.,Nature 565, 581 (2019)10.1038/s41586-019-0877-0]. In this letter, a physics-based statistical mapping framework is described and used to uncover the dependencies of the fusion yield. This model is used to identify and quantify the degradation mechanisms of the fusion yield in direct-drive implosions on OMEGA. The yield is found to be reduced by the ratio of laser beam to target radius, the asymmetry in inferred ion temperatures from the ℓ=1 mode, the time span over which tritium fuel has decayed, and parameters related to the implosion hydrodynamic stability. When adjusted for tritium decay and ℓ=1 mode, the highest yield in OMEGA cryogenic implosions is predicted to exceed 2×10^{14} fusion reactions.

A randomised phase II trial of three dosing regimens of radium-223 in patients with bone metastatic castration-resistant prostate cancer.

BACKGROUND: Radium-223 prolongs overall survival and delays symptomatic skeletal events (SSEs) in patients with metastatic castration-resistant prostate cancer (mCRPC) and bone metastases. The approved radium-223 regimen is 55 kBq/kg every 4 weeks (q4w) for six cycles (standard dose). We investigated different radium-223 regimens in patients with mCRPC. PATIENTS AND METHODS: Patients were randomised 1 : 1 : 1 to radium-223 standard-dose, high-dose (88 kBq/kg q4w for six cycles) or extended-schedule arms (55 kBq/kg q4w for 12 cycles). The primary end point, SSE-free survival (SSE-FS), was compared in patients treated with a high- versus standard-dose regimen, or with a standard dose in an extended (>6 to 12 cycles) versus standard schedule (six cycles). RESULTS: A total of 391 patients were randomised; baseline characteristics were balanced between arms. On-treatment SSEs developed in 37/130 (28%), 42/130 (32%) and 48/131 (37%) patients in the standard-dose, high-dose and extended-schedule arms, respectively. There was no statistically significant difference in SSE-FS in the high- versus standard-dose arms [median 12.9 months versus 12.3 months; hazard ratio (HR) 1.06, 80% confidence interval (CI) 0.88-1.27, P = 0.70], and in the extended- versus standard-schedule arms (median 10.8 months versus 13.2 months; HR 1.26, 80% CI 0.94-1.69, P = 0.31). Overall survival in the three treatment arms was similar. As many as 370 (95%) patients received treatment (median of six cycles) in each arm. Grade ≥3 treatment-emergent adverse events (TEAEs) affected 34% of patients in the standard-dose, 48% in the high-dose and 53% in the extended-schedule arm, causing permanent discontinuation in 9%, 16% and 17% of patients, respectively. CONCLUSION: Radium-223 high-dose or extended-schedule regimens resulted in no change in SSE-FS or other efficacy end points and were associated with more grade ≥3 TEAEs. The extended-schedule regimen (beyond six doses) could not be implemented in a large proportion of patients due to disease progression. Therefore, the standard-dose schedule remains one of the standard therapies for patients with symptomatic mCRPC. TRIAL REGISTRATION: ClinicalTrials.govNCT02023697.

Family caregiver descriptions of stopping chemotherapy and end-of-life transitions.

PURPOSE: The purpose of this study was to describe family caregivers' perspectives of the final month of life of patients with advanced cancer, particularly whether and how chemotherapy was discontinued and the effect of clinical decision-making on family caregivers' perceptions of the patient's experience of care at the end of life (EOL). METHODS: Qualitative descriptive design using semi-structured interviews collected from 92 family caregivers of patients with end-stage cancer enrolled in a randomized clinical trial. We used a phased approach to data analysis including open coding, focused coding, and within and across analyses. RESULTS: We identified three patterns of transitions characterizing the shift away from active cancer treatment: (1) "We Pretty Much Knew," characterized by explicit discussions about EOL care, seemingly shared understanding about prognosis and seamless transitions from disease-oriented treatment to comfort-oriented care, (2) "Beating the Odds," characterized by explicit discussions about disease-directed treatment and EOL care options, but no shared understanding about prognosis and often chaotic transitions to EOL care, and (3) "Left to Die," characterized by no recall of EOL discussions with transitions to EOL occurring in crisis. CONCLUSIONS: As communication and palliative care interventions continue to develop to improve care for patients with advanced cancer, it is imperative that we take into account the different patterns of transition and their unique patient and caregiver needs near the end of life. Our findings reveal considerable, and potentially unwarranted, variation in transitions from active treatment to death.

Origins and Scaling of Hot-Electron Preheat in Ignition-Scale Direct-Drive Inertial Confinement Fusion Experiments.

Planar laser-plasma interaction (LPI) experiments at the National Ignition Facility (NIF) have allowed access for the first time to regimes of electron density scale length (∼500 to 700 µm), electron temperature (∼3 to 5 keV), and laser intensity (6 to 16×10^{14} W/cm^{2}) that are relevant to direct-drive inertial confinement fusion ignition. Unlike in shorter-scale-length plasmas on OMEGA, scattered-light data on the NIF show that the near-quarter-critical LPI physics is dominated by stimulated Raman scattering (SRS) rather than by two-plasmon decay (TPD). This difference in regime is explained based on absolute SRS and TPD threshold considerations. SRS sidescatter tangential to density contours and other SRS mechanisms are observed. The fraction of laser energy converted to hot electrons is ∼0.7% to 2.9%, consistent with observed levels of SRS. The intensity threshold for hot-electron production is assessed, and the use of a Si ablator slightly increases this threshold from ∼4×10^{14} to ∼6×10^{14} W/cm^{2}. These results have significant implications for mitigation of LPI hot-electron preheat in direct-drive ignition designs.

Hypotension during induction of anaesthesia is neither a reliable nor a useful quality measure for comparison of anaesthetists' performance.

BACKGROUND: Identification of statistically reliable outcomes for comparison among anaesthetists is challenging. Time-weighted intraoperative mean arterial pressure <65 mm Hg (AUC 65 ) is associated with increased odds for myocardial damage. We explored retrospectively whether such hypotension before incision was statistically reliable for peer comparison. METHODS: We retrieved electronic data between 2006 and 2015 at a tertiary care, academic hospital in the USA for patients at risk for myocardial damage (inpatient after surgery, ASA physical status ≥III, ≥50 yr of age, and case duration ≥60 min). We determined the percentage of anaesthetists comparable based on caseload and case-mix. The AUC 65 was compared amongst anaesthetists supervising ≥100 cases involving at-risk patients during the last 12 months. RESULTS: Only 14.1% [95% confidence interval (CI) 13.6-14.5%] of cases involved patients who were 'at risk' during the 10 yr study period. A yearly average of 49 ( sd 6) anaesthetists supervised ≥100 cases of any type, of whom only 52% (95% CI 47.1-56.0%) supervised ≥100 cases involving at-risk patients. Thus, nearly half the anaesthetists would have been excluded from peer comparison. During the last 12 months, there were two outliers among 34 evaluable anaesthetists ( P <0.05, controlling for false discovery). However, their contribution to total hypotension amongst cases for all patients was small, because hypotension was widely distributed (e.g. 80% of hypotension attributable to 61.8% of anaesthetists, 95% CI 59.8-63.7%). There was no relationship between the AUC 65 and propofol induction dose. CONCLUSIONS: The AUC 65 of time-weighted pre-incision hypotension is not a suitable metric for comparing anaesthetists. There were few at-risk patients, half the anaesthetists were not evaluable because of their case-mix and caseload, and hypotension was widely distributed.

Publisher's Note: Demonstration of Fuel Hot-Spot Pressure in Excess of 50 Gbar for Direct-Drive, Layered Deuterium-Tritium Implosions on OMEGA [Phys. Rev. Lett. 117, 025001 (2016)].

This corrects the article DOI: 10.1103/PhysRevLett.117.025001.

Demonstration of Fuel Hot-Spot Pressure in Excess of 50 Gbar for Direct-Drive, Layered Deuterium-Tritium Implosions on OMEGA.

A record fuel hot-spot pressure P_{hs}=56±7 Gbar was inferred from x-ray and nuclear diagnostics for direct-drive inertial confinement fusion cryogenic, layered deuterium-tritium implosions on the 60-beam, 30-kJ, 351-nm OMEGA Laser System. When hydrodynamically scaled to the energy of the National Ignition Facility, these implosions achieved a Lawson parameter ∼60% of the value required for ignition [A. Bose et al., Phys. Rev. E 93, 011201(R) (2016)], similar to indirect-drive implosions [R. Betti et al., Phys. Rev. Lett. 114, 255003 (2015)], and nearly half of the direct-drive ignition-threshold pressure. Relative to symmetric, one-dimensional simulations, the inferred hot-spot pressure is approximately 40% lower. Three-dimensional simulations suggest that low-mode distortion of the hot spot seeded by laser-drive nonuniformity and target-positioning error reduces target performance.

Trans people's experiences with assisted reproduction services: a qualitative study.

STUDY QUESTION: What are the experiences of trans persons (i.e. those whose gender identity does not match the gender assigned to them at birth) who sought or accessed assisted reproduction (AR) services in Ontario, Canada, between 2007 and 2010? SUMMARY ANSWER: The majority of trans persons report negative experiences with AR service providers. WHAT IS KNOWN ALREADY: Apart from research examining desire to have children among trans people, most of the literature on this topic has debated the ethics of assisting trans persons to become parents. To-date, all of the published research concerning trans persons' experiences with AR services is solely from the perspective of service providers; no studies have examined the experiences of trans people themselves. STUDY DESIGN, SIZE, DURATION: Secondary qualitative research study of data from nine trans-identified people and their partners (total n = 11) collected as part of a community-based study of access to AR services for sexual and gender minority people between 2010 and 2012. PARTICIPANTS/MATERIALS, SETTING, METHODS: Trans-identified volunteers (and their partners, when applicable) who had used or attempted to access AR services since 2007 from across Ontario, Canada, participated in a 60-90 minute, semi-structured qualitative interview. Qualitative analysis was performed using a descriptive phenomenological approach. Emerging themes were continually checked against the data as part of an iterative process. MAIN RESULTS AND THE ROLE OF CHANCE: The data highlight barriers to accessing AR services for trans people. Participant recommendations for improving AR service provision to better meet the needs of this population are presented. These recommendations address the following areas: (i) AR service provider education and training; (ii) service provider and clinic practices and (iii) clinic environment. LIMITATIONS, REASONS FOR CAUTION: The majority of study participants were trans people who identified as men and who resided in major urban areas; those living in smaller communities may have different experiences that were not adequately captured in this analysis. WIDER IMPLICATIONS OF THE FINDINGS: While existing literature debates the ethics of assisting trans people to become parents through the use of AR, our study demonstrates that they are already accessing or attempting to access these services. This reality necessitates a shift toward exploring the ways in which AR services can be improved to better meet the needs of this population, from the perspectives of both service users and service providers. STUDY FUNDING/COMPETING INTERESTS: This project was supported by the Canadian Institutes of Health Research-Institute of Gender and Health, in partnership with the Assisted Human Reproduction Canada: Catalyst Grant: Psychosocial Issues Associated with Assisted Human Reproduction (FRN-103595). S.M. was supported by a Canada Graduate Scholarship from the Social Science and Humanities Research Council, as well as research funding from Osgoode Hall Law School, York University. S.J.-A. was supported by an Ontario Graduate Scholarship funded by the Province of Ontario and the University of Toronto. TRIAL REGISTRATION NUMBER: N/A.

Resolution of paraneoplastic immune thrombocytopenia following everolimus treatment for metastatic renal cell carcinoma.

Autoimmune thrombocytopenia is an uncommon but reported paraneoplastic manifestation of renal cell carcinoma (RCC). Treatment usually involves management of the underlying malignancy; however, steroids have shown a benefit in published case reports. Here, we describe a patient with profound thrombocytopenia secondary to metastatic RCC. It was refractory to steroid and intravenous immunoglobulin, but the platelet count improved markedly following initiation of everolimus. The possible explanation includes immunomodulation, tumour lysis or a combination of both effects. This is the first reported case of everolimus used in paraneoplastic thrombocytopenia from RCC. More studies are needed for further investigation of its potential use in secondary immune thrombocytopenia from RCC and perhaps other malignancies.

Anticancer activity of combination targeted therapy using cetuximab plus vemurafenib for refractory BRAF (V600E)-mutant metastatic colorectal carcinoma.

Mismatch-repair-deficient colorectal cancers often contain kinase-activating V600E BRAF mutations, but no clinical utility has yet been demonstrated in this setting for monotherapy using oral braf kinase inhibitors such as vemurafenib or dabrafenib. Recent studies have indicated that tumour resistance to braf inhibition is mediated by upregulated epidermal growth factor receptor (egfr) signalling, disruption of which is a routine treatment strategy in KRAS wild-type colorectal cancer. In this report, we describe the clinical course of a heavily pretreated patient who elected to receive off-label dual-targeted braf- and egfr-inhibitory therapy with good tolerance and apparent clinical benefit.

Demonstration of the improved rocket efficiency in direct-drive implosions using different ablator materials.

The success of direct-drive implosions depends critically on the ability to create high ablation pressures (∼100 Mbar) and accelerating the imploding shell to ignition-relevant velocities (>3.7×10(7 ) cm/s) using direct laser illumination. This Letter reports on an experimental study of the conversion of absorbed laser energy into kinetic energy of the shell (rocket efficiency) where different ablators were used to vary the ratio of the atomic number to the atomic mass. The implosion velocity of Be shells is increased by 20% compared to C and CH shells in direct-drive implosions when a constant initial target mass is maintained. These measurements are consistent with the predicted increase in the rocket efficiency of 28% for Be and 5% for C compared to a CH ablator.

Onset of hydrodynamic mix in high-velocity, highly compressed inertial confinement fusion implosions.

Deuterium-tritium inertial confinement fusion implosion experiments on the National Ignition Facility have demonstrated yields ranging from 0.8 to 7×10(14), and record fuel areal densities of 0.7 to 1.3 g/cm2. These implosions use hohlraums irradiated with shaped laser pulses of 1.5-1.9 MJ energy. The laser peak power and duration at peak power were varied, as were the capsule ablator dopant concentrations and shell thicknesses. We quantify the level of hydrodynamic instability mix of the ablator into the hot spot from the measured elevated absolute x-ray emission of the hot spot. We observe that DT neutron yield and ion temperature decrease abruptly as the hot spot mix mass increases above several hundred ng. The comparison with radiation-hydrodynamic modeling indicates that low mode asymmetries and increased ablator surface perturbations may be responsible for the current performance.

Hot-spot mix in ignition-scale inertial confinement fusion targets.

Mixing of plastic ablator material, doped with Cu and Ge dopants, deep into the hot spot of ignition-scale inertial confinement fusion implosions by hydrodynamic instabilities is diagnosed with x-ray spectroscopy on the National Ignition Facility. The amount of hot-spot mix mass is determined from the absolute brightness of the emergent Cu and Ge K-shell emission. The Cu and Ge dopants placed at different radial locations in the plastic ablator show the ablation-front hydrodynamic instability is primarily responsible for hot-spot mix. Low neutron yields and hot-spot mix mass between 34(-13,+50) ng and 4000(-2970,+17 160) ng are observed.

Laser-direct-drive fusion target design with a high-Z gradient-density pusher shell.

Laser-direct-drive fusion target designs with solid deuterium-tritium (DT) fuel, a high-Z gradient-density pusher shell (GDPS), and a Au-coated foam layer have been investigated through both 1D and 2D radiation-hydrodynamic simulations. Compared with conventional low-Z ablators and DT-push-on-DT targets, these GDPS targets possess certain advantages of being instability-resistant implosions that can be high adiabat (α≥8) and low hot-spot and pusher-shell convergence (CR_{hs}≈22 and CR_{PS}≈17), and have a low implosion velocity (v_{imp}<3×10^{7}cm/s). Using symmetric drive with laser energies of 1.9 to 2.5MJ, 1D lilac simulations of these GDPS implosions can result in neutron yields corresponding to ≳50-MJ energy, even with reduced laser absorption due to the cross-beam energy transfer (CBET) effect. Two-dimensional draco simulations show that these GDPS targets can still ignite and deliver neutron yields from 4 to ∼10MJ even if CBET is present, while traditional DT-push-on-DT targets normally fail due to the CBET-induced reduction of ablation pressure. If CBET is mitigated, these GDPS targets are expected to produce neutron yields of >20MJ at a driven laser energy of ∼2MJ. The key factors behind the robust ignition and moderate energy gain of such GDPS implosions are as follows: (1) The high initial density of the high-Z pusher shell can be placed at a very high adiabat while the DT fuel is maintained at a relatively low-entropy state; therefore, such implosions can still provide enough compression ρR>1g/cm^{2} for sufficient confinement; (2) the high-Z layer significantly reduces heat-conduction loss from the hot spot since thermal conductivity scales as ∼1/Z; and (3) possible radiation trapping may offer an additional advantage for reducing energy loss from such high-Z targets.

Phase II study of single-agent bosutinib, a Src/Abl tyrosine kinase inhibitor, in patients with locally advanced or metastatic breast cancer pretreated with chemotherapy.

BACKGROUND: This phase II study evaluated single-agent bosutinib in pretreated patients with locally advanced or metastatic breast cancer. PATIENTS AND METHODS: Patients received oral bosutinib 400 mg/day. The primary end point was the progression-free survival (PFS) rate at 16 weeks. Secondary end points included objective response rate, clinical benefit rate, 2-year overall survival rate, safety, and changes in levels of bone resorption/formation biomarkers. RESULTS: Seventy-three patients were enrolled and treated. Median time from diagnosis of metastatic disease to initiation of bosutinib treatment was 24.5 months. For the intent-to-treat population, the PFS rate at 16 weeks was 39.6%. Unexpectedly, all responding patients (n = 4) were hormone receptor positive. The clinical benefit rate was 27.4%. The 2-year overall survival rate was 26.4%. The main toxic effects were diarrhea (66%), nausea (55%), and vomiting (47%). Grade 3-4 laboratory aminotransferase elevations occurred in 14 (19%) patients. Myelosuppression was minimal. No consistent changes in the levels of bone resorption/formation biomarkers were seen. CONCLUSIONS: Bosutinib showed promising efficacy in prolonging time to progression in chemotherapy-pretreated patients with locally advanced or metastatic breast cancer. Bosutinib was generally well tolerated, with a safety profile different from that of the Src/Abl tyrosine kinase inhibitor dasatinib in a similar patient population.

Protocol paper: Multi-site, cluster-randomized clinical trial for optimizing functional outcomes of older cancer survivors after chemotherapy.

BACKGROUND: Cancer survivors over the age of 65 have unique needs due to the higher prevalence of functional and cognitive impairment, comorbidities, geriatric syndromes, and greater need for social support after chemotherapy. In this study, we will evaluate whether a Geriatric Evaluation and Management-Survivorship (GEMS) intervention improves functional outcomes important to older cancer survivors following chemotherapy. METHODS: A cluster-randomized trial will be conducted in approximately 30 community oncology practices affiliated with the University of Rochester Cancer Center (URCC) National Cancer Institute Community Oncology Research Program (NCORP) Research Base. Participating sites will be randomized to the GEMS intervention, which includes Advanced Practice Practitioner (APP)-directed geriatric evaluation and management (GEM), and Survivorship Health Education (SHE) that is combined with Exercise for Cancer Patients (EXCAP©®), or usual care. Cancer survivors will be recruited from community oncology practices (of participating oncology physicians and APPs) after the enrolled clinicians have consented and completed a baseline survey. We will enroll 780 cancer survivors aged 65 years and older who have completed curative-intent chemotherapy for a solid tumor malignancy within four weeks of study enrollment. Cancer survivors will be asked to choose one caregiver to also participate for a total up to 780 caregivers. The primary aim is to compare the effectiveness of GEMS for improving patient-reported physical function at six months. The secondary aim is to compare effectiveness of GEMS for improving patient-reported cognitive function at six months. Tertiary aims include comparing the effectiveness of GEMS for improving: 1) Patient-reported physical function at twelve months; 2) objectively assessed physical function at six and twelve months; and 3) patient-reported cognitive function at twelve months and objectively assessed cognitive function at six and twelve months. Exploratory health care aims include: 1) Survivor satisfaction with care, 2) APP communication with primary care physicians (PCPs), 3) completion of referral appointments, and 4) hospitalizations at six and twelve months. Exploratory caregiver aims include: 1) Caregiver distress; 2) caregiver quality of life; 3) caregiver burden; and 4) satisfaction with patient care at six and twelve months. DISCUSSION: If successful, GEMS would be an option for a standardized APP-led survivorship care intervention. TRIAL REGISTRATION: ClinicalTrials.govNCT05006482, registered on August 9, 2021.

Hot-electron preheat and mitigation in polar-direct-drive experiments at the National Ignition Facility.

Target preheat by superthermal electrons from laser-plasma instabilities is a major obstacle to achieving thermonuclear ignition via direct-drive inertial confinement fusion at the National Ignition Facility (NIF). Polar-direct-drive surrogate plastic implosion experiments were performed on the NIF to quantify preheat levels at an ignition-relevant scale and develop mitigation strategies. The experiments were used to infer the hot-electron temperature, energy fraction, and divergence, and to directly measure the spatial hot-electron energy deposition profile inside the imploding shell. Silicon layers buried in the ablator are shown to mitigate the growth of laser-plasma instabilities and reduce preheat, providing a promising path forward for ignition designs at an on-target intensity of about 10^{15}W/cm^{2}.