High repetition-rate dual-channel X-ray spectrometer for high-intensity laser-plasma experiments.

We describe the development and demonstration of a high-repetition-rate-capable dual-channel (DC) x-ray spectrometer designed for high-intensity laser-plasma experiments (≥1×1021 W/cm2). The spectrometer, which operates at high repetition rates, is limited only by the refresh rate of targets and the camera's frame rate. It features two channels, each equipped with a flat highly oriented pyrolytic graphite (HOPG) crystal and a unique detector plane, allowing it to resolve two distinct x-ray bands: approximately 7-10 and 10-13 keV. Each detector plate carrier holds two slots for active (scintillators) or passive (imaging plates) x-ray detectors. We present the design and testing of the HR-DC-HOPG using both the COMET laser (10 J, 0.5 ps shot/4 min) at LLNL's Jupiter Laser Facility and the SCARLET laser (10 J, 30 fs shot/min) at Ohio State University. The results demonstrate the spectrometer's performance across various laser energies, target materials, pulse shapes, and detector types.

Tongue orthotopic xenografts to study fusion-negative rhabdomyosarcoma invasion and metastasis in live animals.

PAX3/7 fusion-negative rhabdomyosarcoma (FN-RMS) is a childhood mesodermal lineage malignancy with a poor prognosis for metastatic or relapsed cases. Limited understanding of advanced FN-RMS is partially attributed to the absence of sequential invasion and dissemination events and the challenge in studying cell behavior, using, for example, non-invasive intravital microscopy (IVM), in currently used xenograft models. Here, we developed an orthotopic tongue xenograft model of FN-RMS to study cell behavior and the molecular basis of invasion and metastasis using IVM. FN-RMS cells are retained in the tongue and invade locally into muscle mysial spaces and vascular lumen, with evidence of hematogenous dissemination to the lungs and lymphatic dissemination to lymph nodes. Using IVM of tongue xenografts reveals shifts in cellular phenotype, migration to blood and lymphatic vessels, and lymphatic intravasation. Insight from this model into tumor invasion and metastasis at the tissue, cellular, and subcellular level can guide new therapeutic avenues for advanced FN-RMS.

Laboratory realization of relativistic pair-plasma beams.

Relativistic electron-positron plasmas are ubiquitous in extreme astrophysical environments such as black-hole and neutron-star magnetospheres, where accretion-powered jets and pulsar winds are expected to be enriched with electron-positron pairs. Their role in the dynamics of such environments is in many cases believed to be fundamental, but their behavior differs significantly from typical electron-ion plasmas due to the matter-antimatter symmetry of the charged components. So far, our experimental inability to produce large yields of positrons in quasi-neutral beams has restricted the understanding of electron-positron pair plasmas to simple numerical and analytical studies, which are rather limited. We present the first experimental results confirming the generation of high-density, quasi-neutral, relativistic electron-positron pair beams using the 440 GeV/c beam at CERN's Super Proton Synchrotron (SPS) accelerator. Monte Carlo simulations agree well with the experimental data and show that the characteristic scales necessary for collective plasma behavior, such as the Debye length and the collisionless skin depth, are exceeded by the measured size of the produced pair beams. Our work opens up the possibility of directly probing the microphysics of pair plasmas beyond quasi-linear evolution into regimes that are challenging to simulate or measure via astronomical observations.

EuroGuiderm guideline on lichen sclerosus-introduction into lichen sclerosus.

INTRODUCTION: Lichen sclerosus (LS) is an inflammatory skin disease affecting all ages. LS typically involves the anogenital site where it causes itching and soreness. It may lead to sexual and urinary dysfunction in females and males; however, it may be asymptomatic. First signs of LS are redness and oedema, typically followed by whitening of the genital skin; sometimes fissuring, scarring, shrinkage and fusion of structures may follow in its course. LS is associated with an increased risk of genital cancer. LS has a huge impact on the quality of life of affected patients, and it is important to raise more awareness of this not uncommon disease in order to diagnose and treat it early. OBJECTIVES: The guideline intends to provide guidance on the diagnostic of LS, highlight important aspects in the care of LS patients (part 1), generate recommendations and treatment algorithms (part 2) on topical, interventional and surgical therapy, based on the latest evidence, provide guidance in the management of LS patients during pregnancy, provide guidance for the follow-up of patients with LS and inform about new developments and potential research aspects. MATERIALS AND METHODS: The guideline was developed in accordance with the EuroGuiDerm Methods Manual v1.3 https://www.edf.one/de/home/Guidelines/EDF-EuroGuiDerm.html. The wording of the recommendations was standardized (as suggested by the GRADE Working Group). The guideline development group is comprised of 34 experts from 16 countries, including 5 patient representatives. RESULTS: Ultrapotent or potent topical corticosteroids in females and males, adults and children remain gold standard of care for genital LS; co-treatment with emollients is recommended. If standard treatment fails in males, a surgical intervention is recommended, complete circumcision may cure LS in males. UV light treatment is recommended for extragenital LS; however, there is limited scientific evidence. Topical calcineurin inhibitors are second line treatment. Laser treatment, using various wave lengths, is under investigation, and it can currently not be recommended for the treatment of LS. Treatment with biologics is only reported in single cases. CONCLUSIONS: LS has to be diagnosed and treated as early as possible in order to minimize sequelae like scarring and cancer development. Topical potent and ultrapotent corticosteroids are the gold standard of care; genital LS is often a lifelong disease and needs to be treated long-term.

EuroGuiderm guideline on lichen sclerosus-Treatment of lichen sclerosus.

INTRODUCTION: Lichen sclerosus (LS) is an inflammatory skin disease affecting all ages. LS typically involves the anogenital site where it causes itching and soreness; it may lead to sexual and urinary dysfunction in females and males; however, it may be asymptomatic. First signs of LS are usually a whitening of the genital skin, sometimes preceded by redness and oedema; fissuring, scarring, shrinkage and fusion of structures may follow in its course. LS is associated with an increased risk of genital cancer. LS has a huge impact on the quality of life of affected patients, and it is important to raise more awareness of this not uncommon disease in order to diagnose and treat it early. OBJECTIVES: The guideline intends to provide guidance on the diagnostic of LS (part 1), highlight important aspects in the care of LS patients, generate recommendations and treatment algorithms (part 2) on topical, interventional and surgical therapy, based on the latest evidence, provide guidance in the management of LS patients during pregnancy, provide guidance for the follow-up of patients with LS and inform about new developments and potential research aspects. MATERIALS AND METHODS: The guideline was developed in accordance with the EuroGuiDerm Methods Manual v1.3 https://www.edf.one/de/home/Guidelines/EDF-EuroGuiDerm.html. The wording of the recommendations was standardized (as suggested by the GRADE Working Group). The guideline development group is comprised of 34 experts from 16 countries, including 5 patient representatives. RESULTS: Ultrapotent or potent topical corticosteroids in females and males, adults and children remain gold standard of care for genital LS; co-treatment with emollients is recommended. If standard treatment fails in males, a surgical intervention is recommended, complete circumcision may cure LS in males. UV light treatment is recommended for extragenital LS; however, there is limited scientific evidence. Topical calcineurin inhibitors are second line treatment. Laser treatment, using various wave lengths, is under investigation, and it can currently not be recommended for the treatment of LS. Treatment with biologics is only reported in single cases. CONCLUSIONS: LS has to be diagnosed and treated as early as possible in order to minimize sequelae like scarring and cancer development. Topical potent and ultrapotent corticosteroids are the gold standard of care; genital LS is often a lifelong disease and needs to be treated long-term.

Fusion-negative rhabdomyosarcoma orthotopic tongue xenografts for study of invasion, intravasation and metastasis in live animals.

PAX3/7 Fusion-negative rhabdomyosarcoma (FN-RMS) is a childhood mesodermal lineage malignancy with a poor prognosis for metastatic or relapsed cases. Towards achieving a more complete understanding of advanced FN-RMS, we developed an orthotopic tongue xenograft model for studies of molecular basis of FN-RMS invasion and metastasis. The behavior of FN-RMS cells injected into murine tongue was examined using in vivo bioluminescence imaging, non-invasive intravital microscopy (IVM), and histopathology and compared to the prevailing hindlimb intramuscular and subcutaneous xenografts. FN-RMS cells were retained in the tongue and invaded locally into muscle mysial spaces and vascular lumen. While evidence of hematogenous dissemination to the lungs occurred in tongue and intramuscular xenografts, evidence of local invasion and lymphatic dissemination to lymph nodes only occurred in tongue xenografts. IVM and RNA-seq of tongue xenografts reveal shifts in cellular phenotype and differentiation state in tongue xenografts. IVM also shows homing to blood and lymphatic vessels, lymphatic intravasation, and dynamic membrane protrusions. Based on these findings, the tongue orthotopic xenograft of FN-RMS is a valuable model for tumor progression studies at the tissue, cellular and subcellular levels providing insight into kinetics and molecular bases of tumor invasion and metastasis and, hence, new therapeutic avenues for advanced FN-RMS.

Flexible tape-drive target system for secondary high-intensity laser-driven sources.

We present the development of a flexible tape-drive target system to generate and control secondary high-intensity laser-plasma sources. Its adjustable design permits the generation of relativistic MeV particles and x rays at high-intensity (i.e., ≥1 × 1018 W cm-2) laser facilities, at high repetition rates (>1 Hz). The compact and robust structure shows good mechanical stability and a high target placement accuracy (<4 µm RMS). Its compact and flexible design allows for mounting in both the horizontal and vertical planes, which makes it practical for use in cluttered laser-plasma experimental setups. The design permits ∼170° of access on the laser-driver side and 120° of diagnostic access at the rear. A range of adapted apertures have been designed and tested to be easily implemented to the targetry system. The design and performance testing of the tape-drive system in the context of two experiments performed at the COMET laser facility at the Lawrence Livermore National Laboratory and at the Advanced Lasers and Extreme Photonics (ALEPH) facility at Colorado State University are discussed. Experimental data showing that the designed prototype is also able to both generate and focus high-intensity laser-driven protons at high repetition rates are also presented.

A Randomised Clinical Feasibility Trial of a Breast Immobilisation Device: The SuPPORT 4 All Bra.

AIMS: Despite the breast being a mobile organ, there is currently no standard suitable immobilisation device to optimise radiotherapy for women with larger breasts treated after a wide local excision. The SuPPORT 4 All (S4A) bra was co-designed with patients and radiotherapy professionals. The purpose of this study was to test the feasibility of using the S4A bra in the existing breast cancer radiotherapy pathway. MATERIALS AND METHODS: A randomised feasibility trial was conducted in a single institution; the primary feasibility endpoint was the recruitment of 50 participants. Efficacy endpoints were also tested, including assessment of skin reactions, dose to organs at risk and patient comfort. Fifty women were randomised to receive either standard radiotherapy with no immobilisation (control) or radiotherapy with the S4A bra (intervention). A separate planning study was undertaken on the cases randomised to receive the S4A bra. Participants in the intervention arm (S4A bra) underwent two planning computed tomography scans, one with the bra on and one without the bra; allowing direct comparison of organs at risk data for S4A bra versus no bra. RESULTS: All women who started radiotherapy wearing the S4A bra completed treatment with the bra; patient comfort did not change across the 3 weeks of treatment. Positional accuracy using the bra was comparable with existing published accuracy for methods without immobilisation. The mean ipsilateral lung doses showed some improvement when positioning with the S4A bra was compared with the no bra set-up (3.72 Gy versus 4.85 Gy for right-sided cases, 3.23 Gy versus 3.62 Gy for left-sided cases). CONCLUSIONS: The S4A bra is feasible to use in the radiotherapy pathway with good patient adherence. The S4A bra has potential to reduce dose to organs at risk (specifically ipsilateral lung dose) while maintaining good breast tissue coverage, and improved patient dignity, warranting further investigation on a larger scale.

Survival analysis of germination data in response to temperature for Ornithopus species and other temperate pasture legumes.

Cool temperatures can limit productivity of temperate grazing systems as poor pasture growth rates in winter create feed shortages for livestock. Ornithopus spp. (serradella) are broadly adapted annual pasture legumes that produce high-quality forage in soil types considered marginal for other temperate legume species. However, serradella establishment is perceived to be difficult in cool-season environments. We used survival analysis to compare germination rate and seedling emergence for two serradella species (yellow serradella and French serradella) against three reference species (Medicago sativa, M. polymorpha and Trifolium subterraneum ) in four temperature treatments (10/5, 15/10, 20/15 and 25/20°C; max/min). We also compared shoot relative growth rate and photosynthetic rate at 15/10°C (cool) and 23/18°C (warm). Cool temperatures (10/5, 15/10°C) did not slow germination rates for serradella relative to the reference species, but warm temperatures (20/15, 25/20°C) delayed emergence and reduced post-emergent shoot growth rates. Once established, Ornithopus spp. had similar mean photosynthetic rates and stomatal conductance at cool temperatures to the reference species. We conclude that, contrary to common perception, cool temperatures did not adversely influence germination, emergence, or early growth of Ornithopus spp. relative to the reference species.

Timeline to dysphagia resolution after endoscopic intervention of an interarytenoid defect based on Video Fluoroscopic Swallow Study dysphagia severity.

INTRODUCTION: We previously reported that endoscopic repair of a Type 1 Laryngeal Cleft (LC1) or Deep Interarytenoid Groove (DIG) improves swallowing function postoperatively. However, caregivers often ask about the timeline to resolution of the need for thickening. This study re-examines this cohort to answer this important caregiver-centered question. METHODS: We reassessed a 3-year retrospective, single-center dataset of children with dysphagia found to have a LC-1 or DIG on endoscopic exam. The primary outcome was rate of complete resolution of dysphagia at 2, 6, and 12 months after endoscopic intervention. A sub-group analysis was made based on severity of dysphagia prior to intervention and by type of endoscopic repair. RESULTS: Thirty-nine patients with mean age 1.35 years that had a LC-1 or DIG met criteria for inclusion. Rate of complete dysphagia resolution increased over time. Those with mild dysphagia (flow-reducing nipple and/or IDDSI consistency 1 or 2) had brisker resolution than those with moderate dysphagia (IDDSI consistency 3 or 4) at 2 months (67% vs 5%, p < 0.01) and at 6 months (80% vs 18%, p < 0.01) after endoscopic repair. There was no difference in dysphagia resolution between patients grouped by type of endoscopic repair. CONCLUSION: Addressing an interarytenoid defect in patients will not result in immediate, complete dysphagia resolution in most patients. However, patients that only require a flow-reducing nipple and/or thickening to an IDDSI consistency 1 or 2 have brisker resolution of the need for thickening than those that require an IDSSI consistency 3 or 4 prior to intervention. These results inform pre-operative discussions of the timeline to resolution based upon severity of dysphagia and help manage caregiver expectations.

Drug combinations identified by high-throughput screening promote cell cycle transition and upregulate Smad pathways in myeloma.

Drug resistance and disease progression are common in multiple myeloma (MM) patients, underscoring the need for new therapeutic combinations. A high-throughput drug screen in 47 MM cell lines and in silico Huber robust regression analysis of drug responses revealed 43 potentially synergistic combinations. We hypothesized that effective combinations would reduce MYC expression and enhance p16 activity. Six combinations cooperatively reduced MYC protein, frequently over-expressed in MM and also cooperatively increased p16 expression, frequently downregulated in MM. Synergistic reductions in viability were observed with top combinations in proteasome inhibitor-resistant and sensitive MM cell lines, while sparing fibroblasts. Three combinations significantly prolonged survival in a transplantable Ras-driven allograft model of advanced MM closely recapitulating high-risk/refractory myeloma in humans and reduced viability of ex vivo treated patient cells. Common genetic pathways similarly downregulated by these combinations promoted cell cycle transition, whereas pathways most upregulated were involved in TGFß/SMAD signaling. These preclinical data identify potentially useful drug combinations for evaluation in drug-resistant MM and reveal potential mechanisms of combined drug sensitivity.

A flexible proton beam imaging energy spectrometer (PROBIES) for high repetition rate or single-shot high energy density (HED) experiments (invited).

The PROBIES diagnostic is a new, highly flexible, imaging and energy spectrometer designed for laser-accelerated protons. The diagnostic can detect low-mode spatial variations in the proton beam profile while resolving multiple energies on a single detector or more. When a radiochromic film stack is employed for "single-shot mode," the energy resolution of the stack can be greatly increased while reducing the need for large numbers of films; for example, a recently deployed version allowed for 180 unique energy measurements spanning ∼3 to 75 MeV with <0.4 MeV resolution using just 20 films vs 180 for a comparable traditional film and filter stack. When utilized with a scintillator, the diagnostic can be run in high-rep-rate (>Hz rate) mode to recover nine proton energy bins. We also demonstrate a deep learning-based method to analyze data from synthetic PROBIES images with greater than 95% accuracy on sub-millisecond timescales and retrained with experimental data to analyze real-world images on sub-millisecond time-scales with comparable accuracy.

Trans-Atlantic aeromedical repatriation of multiple COVID-19 patients: a hybrid military-civilian model.

Here, we report the first known transcontinental aeromedical evacuation of a large number (55) of patients with known and suspected positive COVID-19. These patients were evacuated from Havana, Cuba, to the UK through MOD Boscombe Down as part of Operation BROADSHARE, the British military's overseas response to COVID-19. We describe the safe transfer of patients with COVID-19 using a combined military-civilian model. In our view, we have demonstrated that patients with COVID-19 can be aeromedically transferred while ensuring the safety of patients and crew using a hybrid military-civilian model; this report contains lessons for future aeromedical evacuation of patients with COVID-19.

Ultra-compact x-ray spectrometer for high-repetition-rate laser-plasma experiments.

We present in this work the development of an ultra-compact, multi-channel x-ray spectrometer (UCXS). This diagnostic has been specially built and adapted to perform at high-repetition-rate (>1 Hz) for high-intensity, short-pulse laser plasma experiments. X-ray filters of varying materials and thicknesses are chosen to provide spectral resolution up to ΔE ≈ 1 keV over the x-ray energy range of 1-30 keV. These filters are distributed over a total of 25 channels, where each x-ray filter is coupled to a single scintillator. The UCXS is designed to detect and resolve a large variety of laser-driven x-ray sources such as low energy bremsstrahlung emission, fluorescence, and betatron radiation (up to 30 keV). Preliminary results from commissioning experiments at the ABL laser facility at Colorado State University are provided.

Single-shot measurements of pulse-front tilt in intense ps laser pulses and its effect on accelerated electron and ion beam characteristics (invited).

We report recent single-shot spatiotemporal measurements of laser pulses, including pulse-front tilt (PFT) and spatial chirp, taken at the Compact Multipulse Terawatt laser at the Jupiter Laser Facility in Livermore, CA. STRIPED FISH, a device that measures the complete 3D electric field of fs to ps laser pulses on a single shot, was adapted to near infrared for these measurements. We present the design of the instrument used for these experiments, the on-shot measurements of systematic high-order PFT, and shot-to-shot variations in the measurements of spatiotemporal couplings. Finally, we simulate the effect of PFT in target normal sheath acceleration experiments. These simulations showed that pulse front tilt can steer hot electrons, shape the distribution of the accelerating sheath field, and increase the variability of cutoff energy in the resulting proton spectra. While these effects may be detrimental to experimental accuracy if the pulse front tilt is left unmeasured, hot electron steering shows promise for precision manipulation of the particle source for a range of applications, including irradiation of secondary targets for opacity measurements, radiography, or neutron generation.

Dual-energy fast neutron imaging using tunable short-pulse laser-driven sources.

A novel dual-energy fast neutron imaging technique is presented using short-pulse laser-driven neutron sources to leverage their inherent adaptive spectral control to enable 3D volume segmentation and reconstruction. Laser-accelerated ion beams incident onto secondary targets create directional, broadband, MeV-class neutrons. Synthetic radiographs are produced of multi-material objects using ion and neutron spectra derived from analytic and numerical models. It is demonstrated that neutron images generated from small changes to the neutron spectra, controlled by altering the initial laser conditions, are sufficient to isolate materials with differing attenuation coefficients. This is first demonstrated using a simplistic combinatorial isolation method and then by employing more advanced reconstruction algorithms to reduce artifacts and generate a segmentation volume of the constituent materials.

Host CLIC4 expression in the tumor microenvironment is essential for breast cancer metastatic competence.

The TGF-ß-regulated Chloride Intracellular Channel 4 (CLIC4) is an essential participant in the formation of breast cancer stroma. Here, we used data available from the TCGA and METABRIC datasets to show that CLIC4 expression was higher in breast cancers from younger women and those with early-stage metastatic disease. Elevated CLIC4 predicted poor outcome in breast cancer patients and was linked to the TGF-ß pathway. However, these associations did not reveal the underlying biological contribution of CLIC4 to breast cancer progression. Constitutive ablation of host Clic4 in two murine metastatic breast cancer models nearly eliminated lung metastases without reducing primary tumor weight, while tumor cells ablated of Clic4 retained metastatic capability in wildtype hosts. Thus, CLIC4 was required for host metastatic competence. Pre- and post-metastatic proteomic analysis identified circulating pro-metastatic soluble factors that differed in tumor-bearing CLIC4-deficient and wildtype hosts. Vascular abnormalities and necrosis increased in primary tumors from CLIC4-deficient hosts. Transcriptional profiles of both primary tumors and pre-metastatic lungs of tumor-bearing CLIC4-deficient hosts were consistent with a microenvironment where inflammatory pathways were elevated. Altogether, CLIC4 expression in human breast cancers may serve as a prognostic biomarker; therapeutic targeting of CLIC4 could reduce primary tumor viability and host metastatic competence.

CCL5 production in lung cancer cells leads to an altered immune microenvironment and promotes tumor development.

Current immunotherapies for lung cancer are only effective in a subset of patients. Identifying tumor-derived factors that facilitate immunosuppression offers the opportunity to develop novel strategies to supplement and improve current therapeutics. We sought to determine whether expression of driver oncogenes in lung cancer cells affects cytokine secretion, alters the local immune environment, and influences lung tumor progression. We demonstrate that oncogenic EGFR and KRAS mutations, which are early events in lung tumourigenesis, can drive cytokine and chemokine production by cancer cells. One of the most prominent changes was in CCL5, which was rapidly induced by KRASG12V or EGFRL858R expression, through MAPK activation. Immunocompetent mice implanted with syngeneic KRAS-mutant lung cancer cells deficient in CCL5 have decreased regulatory T cells (Tregs), evidence of T cell exhaustion, and reduced lung tumor burden, indicating tumor-cell CCL5 production contributes to an immune suppressive environment in the lungs. Furthermore, high CCL5 expression correlates with poor prognosis, immunosuppressive regulatory T cells, and alteration to CD8 effector function in lung adenocarcinoma patients. Our data support targeting CCL5 or CCL5 receptors on immune suppressive cells to prevent formation of an immune suppressive tumor microenvironment that promotes lung cancer progression and immunotherapy insensitivity.

Demonstration of plasma mirror capability for the OMEGA Extended Performance laser system.

A plasma mirror platform was developed for the OMEGA-EP facility to redirect beams, thus enabling more flexible experimental configurations as well as a platform that can be used in the future to improve laser contrast. The plasma mirror reflected a short pulse focusing beam at 22.5° angle of incidence onto a 12.5 µm thick Cu foil, generating Bremsstrahlung and kα x rays, and accelerating ions and relativistic electrons. By measuring these secondary sources, the plasma mirror key performance metrics of integrated reflectivity and optical quality are inferred. It is shown that for a 5 ± 2 ps, 310 J laser pulse, the plasma mirror integrated reflectivity was 62 ± 13% at an operating fluence of 1670 J cm-2, and that the resultant short pulse driven particle acceleration and x-ray generation indicate that the on target intensity was 3.1 × 1018 W cm-2, which is indicative of a good post-plasma mirror interaction beam optical quality. By deriving the plasma mirror performance metrics from the secondary source scalings, it was simultaneously demonstrated that the plasma mirror is ready for adoption in short pulse particle acceleration and high energy photon generation experiments using the OMEGA-EP system.

Universal use of surgical masks is tolerated and prevents respiratory viral infection in stem cell transplant recipients.

Prevention of respiratory viral infection in stem cell transplant patients is important due to its high risk of adverse outcome. This single-centre, mixed methods study, conducted before the severe acute respiratory syndrome coronavirus-2 pandemic, explored the barriers and facilitators to a policy of universal mask use by visitors and healthcare workers, and examined the impact of the first year of introduction of the policy on respiratory viral infection rates compared with preceding years, adjusted for overall incidence. Education around universal mask use was highlighted as being particularly important in policy implementation. A significant decrease in respiratory viral infection was observed following introduction.