Neutron imaging of the deuterium-tritium tamping gas volume in an inertial confinement fusion hohlraum.

To benchmark the accuracy of the models and improve the predictive capability of future experiments, the National Ignition Facility requires measurements of the physical conditions inside inertial confinement fusion hohlraums. The ion temperature and bulk motion velocity of the gas-filled regions of the hohlraum can be obtained by replacing the helium tamping gas in the hohlraum with deuterium-tritium (DT) gas and measuring the Doppler broadening and Doppler shift of the neutron spectrum produced by nuclear reactions in the hohlraum. To understand the spatial distribution of the neutron production inside the hohlraum, we have developed a new penumbral neutron imager with a 12 mm diameter field of view using a simple tungsten alloy spindle. We performed the first experiment using this imager on a DT gas-filled hohlraum and successfully obtained the spatial distribution of neutron production in the hohlraum plasma. We will report on the design of the spindle, characterization of the detectors, and methodology of the image reconstruction.

Measurements of K-edge and L-edge extended x-ray absorption fine structure at the national ignition facility (invited).

High-energy-density laser facilities and advances in dynamic compression techniques have expanded access to material states in the Terapascal regime relevant to inertial confinement fusion, planetary science, and geophysics. However, experimentally determining the material temperature in these extreme conditions has remained a difficult challenge. Extended X-ray Absorption Fine Structure (EXAFS), referring to the modulations in x-ray absorption above an absorption edge from photoelectrons' interactions with neighboring atoms, has proven to be a versatile and robust technique for probing material temperature and density for mid-to-high Z elements under dynamic compression. The current platform at the National Ignition Facility has developed six configurations for EXAFS measurements between 7 and 18 keV for different absorption edges (Fe K, Co K, Cu K, Ta L3, Pb L3, and Zr K) using a curved-crystal spectrometer and a bright, continuum foil x-ray source. In this work, we describe the platform geometry, x-ray source performance, spectrometer resolution and throughput, design considerations, and data in ambient and dynamic-compression conditions.

Identifying, quantifying, and mitigating background with the time-resolved x-ray diffraction platform at the National Ignition Facility.

The time-resolved x-ray diffraction platform at the National Ignition Facility (NIF) fields electronic sensors closer to the exploding laser-driven target than any other NIF diagnostic in order to directly detect diffracted x rays from highly compressed materials. We document strategies to characterize and mitigate the unacceptably high background signals observed in this geometry. We specifically assess the possible effects of electromagnetic pulse, x-ray fluorescence, hot electrons, and sensor-specific non-x-ray artifacts. Significant background reduction is achieved by strategic shielding.

Time resolved x-ray diffraction using the flexible imaging diffraction diagnostic for laser experiments (FIDDLE) at the National Ignition Facility (NIF): Preliminary assessment of diffraction precision.

The Flexible Imaging Diffraction Diagnostic for Laser Experiments (FIDDLE) is a new diagnostic at the National Ignition Facility (NIF) designed to observe in situ solid-solid phase changes at high pressures using time resolved x-ray diffraction. FIDDLE currently incorporates five Icarus ultrafast x-ray imager sensors that take 2 ns snapshots and can be tuned to collect X-rays for tens of ns. The platform utilizes the laser power at NIF for both the laser drive and the generation of 10 keV X-rays for ∼10 ns using a Ge backlighter foil. We aim to use FIDDLE to observe diffraction at different times during compression to probe the kinetics of phase changes. Pb undergoes two solid-solid phase transitions during ramp compression: from face centered cubic (FCC) to hexagonal close packed (HCP) and HCP to body centered cubic (BCC). Results will be reported on some of the first shots using the FIDDLE diagnostic at NIF on ramp compressed Pb to a peak pressure of ∼110 GPa and a single undriven CeO2 calibration shot. A discussion of the uncertainties in the observed diffraction is included.

Developing time-resolved x-ray diffraction diagnostics at the National Ignition Facility (invited).

As part of a program to measure phase transition timescales in materials under dynamic compression, we have designed new x-ray imaging diagnostics to record multiple x-ray diffraction measurements during a single laser-driven experiment. Our design places several ns-gated hybrid CMOS (hCMOS) sensors within a few cm of a laser-driven target. The sensors must be protected from an extremely harsh environment, including debris, electromagnetic pulses, and unconverted laser light. Another key challenge is reducing the x-ray background relative to the faint diffraction signal. Building on the success of our predecessor (Target Diffraction In Situ), we implemented a staged approach to platform development. First, we built a demonstration diagnostic (Gated Diffraction Development Diagnostic) with two hCMOS sensors to confirm we could adequately protect them from the harsh environment and also acquire acceptable diffraction data. This allowed the team to quickly assess the risks and address the most significant challenges. We also collected scientifically useful data during development. Leveraging what we learned, we recently developed a much more ambitious instrument (Flexible Imaging Diffraction Diagnostic for Laser Experiments) that can field up to eight hCMOS sensors in a flexible geometry and participate in back-to-back shots at the National Ignition Facility (NIF). The design also allows for future iterations, such as faster hCMOS sensors and an embedded x-ray streak camera. The enhanced capabilities of the new instrument required a much more complex design, and the unexpected issues encountered on the first few shots at NIF remind us that complexity has consequences. Our progress in addressing these challenges is described herein, as is our current focus on improving data quality by reducing x-ray background and quantifying the uncertainties of our diffraction measurements.

Inflammatory Giant Cell Carcinoma of the Lung: Clinicopathologic, Immunohistochemical, and Next-generation Sequencing Study of 14 Cases.

A distinctive histological variant of poorly differentiated, sarcomatoid, non-small cell lung carcinoma characterized by a discohesive population of giant tumor cells associated with prominent interstitial inflammatory cell infiltrates is described. The tumors occurred in 7 women and 7 men, 42 to 72 years of age (mean: 56 y). They predominantly affected the upper lobes and measured 1.3 to 9 cm in greatest diameter (mean: 4.6 cm). The tumor cells were characterized by large pleomorphic nuclei with prominent nucleoli, ample cytoplasm, and frequent abnormal mitoses, and were surrounded by a dense inflammatory cell infiltrate, often associated with emperipolesis. Immunohistochemical stains were positive in the tumor cells for cytokeratin AE1/AE3 and CK8/18 and negative for TTF1, napsin A, p40, and CK5/6. Next-generation sequencing was performed in all cases using the Oncomine Precision Assay; the most common abnormalities found included TP53 mutations (9 cases) and AKT1 amplification (8 cases), followed by KRAS mutations (4 cases) and MAP2K1/2 mutations (4 cases). Clinical follow-up was available in 13 patients. Three patients presented with metastases as the initial manifestation of disease; 8 patients died of their tumors from 6 months to 8 years (mean: 2.7 y); 3 patients were alive and well from 4 to 6 years; and 2 patients had metastases when last seen but were lost to follow-up thereafter. The importance of recognizing this distinctive and aggressive variant of non-small cell lung carcinoma lies in avoiding confusion with a sarcoma or other types of malignancy.

Electrical design of the flexible imaging diffraction diagnostic for laser experiments (FIDDLE) at the National Ignition Facility (NIF)-Requirements, design, and performance.

The Flexible Imaging Diffraction Diagnostic for Laser Experiments (FIDDLE) is a newly developed diagnostic for imaging time resolved diffraction in experiments at the National Ignition Facility (NIF). It builds on the successes of its predecessor, the Gated Diffraction Development Diagnostic (G3D). The FIDDLE was designed to support eight Daedalus version 2 sensors (six more hCMOS sensors than any other hCMOS-based diagnostic in NIF to date) and an integrated streak camera. We will review the electrical requirements, design, and performance of the electrical subsystems that were created to support this large number of cameras in the FIDDLE. The analysis of the data that the FIDDLE is intended to collect relies heavily on the accurate and well-understood timing of each sensor. We report camera-to-camera timing jitter of less than 100 ps rms and sensor integration times of 2.2 ns FWHM in 2-2 timing mode. Additionally, diffraction experiments on the NIF produce electric fields (EMI) on the order of 1 kV/m, which have been observed to negatively impact the performance of some electrical components of the FIDDLE. We report on the results of testing hCMOS camera electronics in a similar EMI environment generated in an offline lab. We also summarize the use of a novel approach to using a vector network analyzer as an EMI leak detector to understand and reduce the negative impacts of EMI on the FIDDLE.

Correction: Overexpression of the VRK1 kinase, which is associated with breast cancer, induces a mesenchymal to epithelial transition in mammary epithelial cells.

[This corrects the article DOI: 10.1371/journal.pone.0203397.].

Insulinoma-Associated Protein-1 Expression in Lymphoepithelial Carcinoma of the Thymus: A Potential Pitfall for Diagnosis With Neuroendocrine Carcinomas of the Thymus.

CONTEXT.­: Insulinoma-associated protein-1 (INSM1) is a recently developed immunohistochemical marker claimed to be highly specific and sensitive for the diagnosis of neuroendocrine malignancies. Recent studies, however, have demonstrated that this marker can also be expressed in non-neuroendocrine neoplasms including squamous cell carcinoma of the thymus. OBJECTIVE.­: To examine INSM1 expression in lymphoepithelial thymic carcinomas. DESIGN.­: Thirty-four cases of lymphoepithelial carcinoma of the thymus were examined by immunohistochemistry or in situ hybridization for INSM1, synaptophysin, chromogranin, CD5, CD117, Epstein-Barr virus-encoded small ribonucleic acid (EBER), and Ki-67. Basic clinical information was abstracted from the medical record. RESULTS.­: The patients were 14 women and 20 men, aged 20 to 85 years. The tumors arose in the anterior mediastinum without any previous history or evidence of malignancy at other sites. Immunohistochemical staining showed moderate to strong positivity of the tumor cells for INSM1 in 65% of cases (22 of 34), focal weak positivity in 20% (7 of 34), and negative staining in 5 cases. Chromogranin staining was focally and weakly positive in 1 case, and synaptophysin showed only focal weak positivity in scattered tumor cells in 12 cases. No significant correlation could be identified between the pattern and intensity of staining for INSM1 and staining for CD5, CD117, and Ki-67. CONCLUSIONS.­: INSM1 positivity in lymphoepithelial carcinoma of the thymus may represent a pitfall for diagnosis, particularly in small biopsy samples. Awareness of this finding may be of importance to avoid misdiagnosis of neuroendocrine malignancy.

Non-small cell lung carcinoma with clear cell features: a clinicopathologic, immunohistochemical, and molecular study of 31 cases.

Non-small cell lung carcinoma with predominantly clear cell features is a rare histologic presentation of lung carcinoma. We have examined 31 cases of lung carcinomas showing extensive clear cell features. The patients were 10 women and 21 men aged 47-92 years (mean: 70 years). The tumors showed a predilection for the right upper and lower lobes and measured from 0.8 to 9.5 cm (mean: 4.2 cm). By immunohistochemistry, 9 cases were typed as adenocarcinoma, 19 cases as squamous cell carcinoma, and 3 showed a "null" phenotype with complete loss of markers for adenocarcinoma or squamous cell carcinoma. Most cases that typed as adenocarcinoma showed a solid growth pattern. A subset of the solid adenocarcinoma cases showed a distinctive "pseudosquamous" morphology. Next-generation sequencing was performed in 20 cases and showed a variety of molecular alterations. The most common abnormalities were found in the TP53 gene (9 cases), FGFR gene family (8 cases), KRAS (5 cases), AKT1 (5 cases), and BRAF (3 cases). Clinical follow-up was available in 21 patients; 16/21 patients died of their tumors from 6 months to 12 years after initial diagnosis (mean: 4.2 years, median: 1.5 years). Four patients were alive and well from 4 to 27 years (mean: 11.5 years, median: 7.5 years); all were pathologic stage 1 or 2. NSCLC with clear cell features can display aggressive behavior and needs to be distinguished from various other tumors of the lung that can show clear cell morphology. The identification of targetable molecular alterations in some of these tumors may be of value for therapeutic management.

Non-Small Cell Lung Carcinoma With Clear Cell Features and FGFR3::TACC3 Gene Rearrangement : Clinicopathologic and Next Generation Sequencing Study of 7 Cases.

Seven cases of primary lung tumors characterized histologically by clear cell morphology and a distinctive FGFR3::TACC3 gene rearrangement are described. The tumors arose in 4 women and 3 men, aged 47 to 81 years (mean=68). They occurred in peripheral locations, predominantly subpleural, and ranged in size from 1.4 to 6.5 cm (mean=4.1 cm). All tumors showed a solid growth pattern with abundant central areas of necrosis and marked nuclear pleomorphism. The tumors demonstrated clear cell histology, with large cohesive tumor cells displaying atypical nuclei and abundant clear cytoplasm. Immunohistochemical stains identified a squamous phenotype in 5 cases and an adenocarcinoma phenotype in 2 cases. One case was a squamous cell carcinoma with focal glandular component, and one of the squamous cell carcinomas showed focal sarcomatoid changes. Next generation sequencing identified FGFR3::TACC3 gene rearrangements in all 7 cases. One case demonstrated a concurrent activating FGFR3 mutation and a second case demonstrated concurrent FGFR3 amplification. Two cases harbored a concurrent KRAS G12D mutation. One case harbored both KRAS and EGFR mutations, and 1 case had a concurrent TP53 mutation. Non-small cell lung carcinoma harboring FGFR3::TACC3 gene rearrangements is extremely rare, and this rearrangement may potentially be enriched in tumors that demonstrate clear cell histology. Identification of FGFR3::TACC3 in patients with lung carcinomas with clear cell features may be of importance as they could potentially be candidates for therapy with tyrosine kinase inhibitors.

Molecular pathology as basis for timely cancer diagnosis and therapy.

Precision and personalized therapeutics have witnessed significant advancements in technology, revolutionizing the capabilities of laboratories to generate vast amounts of genetic data. Coupled with computational resources for analysis and interpretation, and integrated with various other types of data, including genomic data, electronic medical health (EMH) data, and clinical knowledge, these advancements support optimized health decisions. Among these technologies, next-generation sequencing (NGS) stands out as a transformative tool in the field of cancer treatment, playing a crucial role in precision oncology. NGS-based workflows are employed across a range of applications, including gene panels, exome sequencing, and whole-genome sequencing, supporting comprehensive analysis of the entire cancer genome, including mutations, copy number variations, gene expression profiles, and epigenetic modifications. By utilizing the power of NGS, these workflows contribute to enhancing our understanding of disease mechanisms, diagnosis confirmation, identifying therapeutic targets, and guiding personalized treatment decisions. This manuscript explores the diverse applications of NGS in cancer treatment, highlighting its significance in guiding diagnosis and treatment decisions, identifying therapeutic targets, monitoring disease progression, and improving patient outcomes.

National Diagnostic Working Group (NDWG) for inertial confinement fusion (ICF)/high-energy density (HED) science: The whole exceeds the sum of its parts.

The National Diagnostic Working Group (NDWG) has led the effort to fully exploit the major inertial confinement fusion/high-energy density facilities in the US with the best available diagnostics. These diagnostics provide key data used to falsify early theories for ignition and suggest new theories, recently leading to an experiment that exceeds the Lawson condition required for ignition. The factors contributing to the success of the NDWG, collaboration and scope evolution, and the methods of accomplishment of the NDWG are discussed in this Review. Examples of collaborations in neutron and gamma spectroscopy, x-ray and neutron imaging, x-ray spectroscopy, and deep-ultraviolet Thomson scattering are given. An abbreviated history of the multi-decade collaborations and the present semiformal management framework is given together with the latest National Diagnostic Plan.

Extended X-ray absorption fine structure of dynamically-compressed copper up to 1 terapascal.

Large laser facilities have recently enabled material characterization at the pressures of Earth and Super-Earth cores. However, the temperature of the compressed materials has been largely unknown, or solely relied on models and simulations, due to lack of diagnostics under these challenging conditions. Here, we report on temperature, density, pressure, and local structure of copper determined from extended x-ray absorption fine structure and velocimetry up to 1 Terapascal. These results nearly double the highest pressure at which extended x-ray absorption fine structure has been reported in any material. In this work, the copper temperature is unexpectedly found to be much higher than predicted when adjacent to diamond layer(s), demonstrating the important influence of the sample environment on the thermal state of materials; this effect may introduce additional temperature uncertainties in some previous experiments using diamond and provides new guidance for future experimental design.

Evaluation of a workplace suicide prevention program in the Australian manufacturing industry: protocol for a cluster-randomised trial of MATES in manufacturing.

Males are at higher risk of death by suicide than females in Australia, and among men, blue-collar males are at higher risk compared to other working males. In response, MATES in Construction developed a workplace suicide prevention program for the construction sector in 2007 that has been widely implemented in Australia. In the current project, this program is being adapted and trialled in the manufacturing sector. The common aims of MATES programs are to improve suicide prevention literacy, help-seeking intentions, and helping behaviours. The program will be evaluated using a cluster randomised-controlled trial design with waitlist controls across up to 12 manufacturing worksites in Australia. We hypothesise that after 8 months of the MATES in Manufacturing program, there will be significantly greater improvements in help-seeking intentions (primary outcome) compared to waitlist controls. The project is led by Deakin University in collaboration with the University of Melbourne, and in partnership with MATES in Construction and a joint labour-management Steering Group.Trial registration: The trial was registered retrospectively with the Australian New Zealand Clinical Trials Registry on 25 January 2022 (ACTRN12622000122752).Protocol version: 2.0, November 2022.

A 2-4 keV multilayer mirrored channel for the NIF Dante system.

During inertial confinement fusion experiments at the National Ignition Facility (NIF), a capsule filled with deuterium and tritium (DT) gas, surrounded by a DT ice layer and a high-density carbon ablator, is driven to the temperature and densities required to initiate fusion. In the indirect method, 2 MJ of NIF laser light heats the inside of a gold hohlraum to a radiation temperature of 300 eV; thermal x rays from the hohlraum interior couple to the capsule and create a central hotspot at tens of millions degrees Kelvin and a density of 100-200 g/cm3. During the laser interaction with the gold wall, m-band x rays are produced at ∼2.5 keV; these can penetrate into the capsule and preheat the ablator and DT fuel. Preheat can impact instability growth rates in the ablation front and at the fuel-ablator interface. Monitoring the hohlraum x-ray spectrum throughout the implosion is, therefore, critical; for this purpose, a Multilayer Mirror (MLM) with flat response in the 2-4 keV range has been installed in the NIF 37° Dante calorimeter. Precision engineering and x-ray calibration of components mean the channel will report 2-4 keV spectral power with an uncertainty of ±8.7%.

Protocol for a randomised controlled trial evaluating the effectiveness of a CBT-based smartphone application for improving mental health outcomes in adolescents: the MobiliseMe study.

BACKGROUND: Depression is a leading cause of disability in adolescents, however few receive evidence-based treatment. Despite having the potential to overcome barriers to treatment uptake and adherence, there are very few CBT-based smartphone apps for adolescents. To address this gap, we developed ClearlyMe®, a self-guided CBT smartphone app for adolescent depression and anxiety. ClearlyMe® consists of 37 brief lessons containing core CBT elements, accessed either individually or as part of a 'collection'. Here, we describe the protocol for a randomised controlled trial aiming to evaluate the effect of ClearlyMe® on depressive symptoms and secondary outcomes, including engagement, anxiety and wellbeing, when delivered with and without guided support compared to an attention matched control. METHODS: We aim to recruit 489 adolescents aged 12-17 years with mild to moderately-severe depressive symptoms. Participants will be screened for inclusion, complete the baseline assessment and are then randomly allocated to receive ClearlyMe® (self-directed use), ClearlyMe® with guided SMS support (guided use) or digital psychoeducation (attention-matched control). Depressive symptoms and secondary outcomes will be assessed at 6-weeks (primary endpoint) and 4-months post-baseline (secondary endpoint). Engagement, conceptualised as uptake, adherence and completion, will also be assessed 6-weeks post-baseline. Mixed-effects linear modelling will be used to conduct intention-to-treat analyses to determine whether reductions in depressive symptoms and secondary outcomes are greater for conditions receiving ClearlyMe® relative to control at 6-weeks and 4-months post-baseline and greater for intervention adherers relative to non-adherers. To minimise risk, participants will be encouraged to use the Get Help section of the app and can also opt to receive a call from the team clinical psychologist at baseline, and at the 6-week and 4-month post-baseline assessments when reporting suicidal ideation. DISCUSSION: This is the first clinical trial examining a CBT smartphone app specifically designed for adolescent depression. It will provide empirical evidence on the effects of ClearlyMe® on depressive symptoms when used with and without guided support. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ACTRN12622000131752). UNIVERSAL TRIAL NUMBER: U1111-1271-8519.

A combined MeV-neutron and x-ray source for the National Ignition Facility.

In support of future radiation-effects testing, a combined environment source has been developed for the National Ignition Facility (NIF), utilizing both NIF's long-pulse beams, and the Advanced Radiographic Capability (ARC) short pulse lasers. First, ARC was used to illuminate a gold foil at high-intensity, generating a significant x-ray signal >1 MeV. This was followed by NIF 10 ns later to implode an exploding pusher target filled with fusionable gas for neutron generation. The neutron and x-ray bursts were incident onto a retrievable, close-standoff diagnostic snout. With separate control over both neutron and x-ray emission, the platform allows for tailored photon and neutron fluences and timing on a recoverable test sample. The platform exceeded its initial fluence goals, demonstrating a neutron fluence of 2.3 ×1013 n/cm2 and an x-ray dose of 7 krad.

The effectiveness of an Australian community suicide prevention networks program in preventing suicide: a controlled longitudinal study.

BACKGROUND: Suicide is a major issue affecting communities around the world. Community-based suicide prevention approaches can tailor activities at a local level and are recognised as a key component of national suicide prevention strategies. Despite this, research exploring their effects on completed suicides is rare. This study examined the effect of a national program of community suicide prevention networks on suicide rates in catchment areas across Australia. METHODS: Australian suicide data from the National Coronial Information System for 2001-2017 were mapped to geographic catchment areas of community suicide prevention networks and matched control areas with similar characteristics. The effect of network establishment on suicide rates was evaluated using longitudinal models including fixed effects for site type (network or control), time, season, and intervention (network establishment), with site included as a random intercept. RESULTS: Sixty suicide prevention networks were included, servicing areas with a population of 3.5 million. Networks varied in when they were established, ranging from 2007 to 2016. Across the time-period, suicide rates per 100,000 per quarter averaged 3.73 (SD = 5.35). A significant reduction in the suicide rate of 7.0% was found after establishment of networks (IRR = 0.93, 95% CI 0.87 to 0.99, p = .025). CONCLUSION: This study found evidence of an average reduction in suicide rates following the establishment of suicide prevention networks in Australian communities. These findings support the effectiveness of empowering local communities to take action to prevent suicide.