Novel fabrication tools for dynamic compression targets with engineered voids using photolithography methods.

Mesoscale imperfections, such as pores and voids, can strongly modify the properties and the mechanical response of materials under extreme conditions. Tracking the material response and microstructure evolution during void collapse is crucial for understanding its performance. In particular, imperfections in the ablator materials, such as voids, can limit the efficiency of the fusion reaction and ultimately hinder ignition. To characterize how voids influence the response of materials during dynamic loading and seed hydrodynamic instabilities, we have developed a tailored fabrication procedure for designer targets with voids at specific locations. Our procedure uses SU-8 as a proxy for the ablator materials and hollow silica microspheres as a proxy for voids and pores. By using photolithography to design the targets' geometry, we demonstrate precise and highly reproducible placement of a single void within the sample, which is key for a detailed understanding of its behavior under shock compression. This fabrication technique will benefit high-repetition rate experiments at x-ray and laser facilities. Insight from shock compression experiments will provide benchmarks for the next generation of microphysics modeling.

Multi-frame, ultrafast, x-ray microscope for imaging shockwave dynamics.

Inertial confinement fusion (ICF) holds increasing promise as a potential source of abundant, clean energy, but has been impeded by defects such as micro-voids in the ablator layer of the fuel capsules. It is critical to understand how these micro-voids interact with the laser-driven shock waves that compress the fuel pellet. At the Matter in Extreme Conditions (MEC) instrument at the Linac Coherent Light Source (LCLS), we utilized an x-ray pulse train with ns separation, an x-ray microscope, and an ultrafast x-ray imaging (UXI) detector to image shock wave interactions with micro-voids. To minimize the high- and low-frequency variations of the captured images, we incorporated principal component analysis (PCA) and image alignment for flat-field correction. After applying these techniques we generated phase and attenuation maps from a 2D hydrodynamic radiation code (xRAGE), which were used to simulate XPCI images that we qualitatively compare with experimental images, providing a one-to-one comparison for benchmarking material performance. Moreover, we implement a transport-of-intensity (TIE) based method to obtain the average projected mass density (areal density) of our experimental images, yielding insight into how defect-bearing ablator materials alter microstructural feature evolution, material compression, and shock wave propagation on ICF-relevant time scales.

A Pilot Study to Assess Opportunistic Use of CT-Scan for Osteoporosis Screening in Chronic Pancreatitis.

Objectives: CT scans are commonly performed in patients with chronic pancreatitis (CP). Osteopathy and fractures are recognized in CP but no osteoporosis screening guidelines are recommended. "Opportunistic" CT scan-derived bone density thresholds are assessed for identifying osteoporosis in CP. Methods: Retrospective pilot cohort study. CP subjects who had CT scans and dual-energy x-ray absorptiometry (DXA) within 1 year were included. CT-derived bone density was measured at the L1 level. Pearson's correlation was performed between age and CT-derived bone density in Hounsfield unit (HU). Univariate analysis using HU to identify osteoporosis was performed at various thresholds of bone density. The discriminatory ability of the model was evaluated with the area under the receiver operating characteristic (ROC) curve (AUC). Several HU thresholds were tested. Results: Twenty-seven CP subjects were included, of whom 11 had normal bone density, 12 osteopenia, and four osteoporosis on DXA. The mean age was 59.9 years (SD 13.0). There was a negative correlation of age with HU (r = -0.519, p = 0.006). CT-derived bone density predicted DXA-based osteoporosis in the univariable analysis (Odds Ratio (OR) = 0.97 95% Confidence Interval (CI) 0.94-1.00, p = 0.03). HU thresholds were tested. A threshold of 106 HU maximized the accuracy (AUC of 0.870). Conclusions: CT scan may be repurposed for "opportunistic" screening to rule out osteoporosis in CP. A larger study is warranted to confirm these results.

Identification of Malnutrition Risk Using Malnutrition Screening Tool in an Ambulatory Pancreas Clinic.

OBJECTIVES: The aim of this project was to assess malnutrition risk in a well-defined cohort of pancreatic diseases. METHODS: We performed a retrospective, cross-sectional study of 401 subjects with available malnutrition screening tool scores who received care at a single outpatient pancreas clinic during a 6-month study period. Univariate analyses were performed to compare demographic, anthropometric, symptoms/diseases, and risk for malnutrition characteristics across 3 strata of diseases: acute pancreatitis (n = 141), chronic pancreatitis (n = 193), and other pancreatic diagnoses (n = 67). RESULTS: A total of 18% of subjects were identified as at risk for malnutrition, including 25% who reported involuntary weight loss and/or decreased appetite. Subjects categorized as at risk for malnutrition were more likely to have gastrointestinal symptoms. Although the nutrition consultation rates were higher in subjects at risk for malnutrition (P = 0.03), 66% did not receive a clearly indicated dietary evaluation or management recommendations. One fifth of all patients in an ambulatory pancreas clinic are identified as at risk for malnutrition using a simple, validated tool. CONCLUSIONS: The majority of patients at increased risk for nutritional complications did not receive nutritional recommendations.

Rationale for and Development of the Pancreatic Quantitative Sensory Testing Consortium to Study Pain in Chronic Pancreatitis.

OBJECTIVES: Abdominal pain is the primary symptom of chronic pancreatitis (CP), but pain is difficult to assess, and objective methods for pain assessment are lacking. The characterization of the sensory component of pain as a surrogate for nociception can be achieved by sensory testing using standardized stimuli. Herein, we describe the rationale for and development of an international consortium to better understand and characterize CP pain. METHODS: A collaboration was initially formed between the University of Aalborg, Johns Hopkins University, and the University of Pittsburgh. This group refined the protocol for pancreatic quantitative sensory testing (P-QST) and then expanded the collaboration with plans for incorporating P-QST into prospective studies. RESULTS: The collaboration has successfully developed a P-QST nomogram. Chronic pancreatitis patients identified with P-QST as having widespread hyperalgesia had higher pain intensity scores, higher prevalence of constant pain, and decreased quality of life. Psychiatric comorbidities were independent of pain phenotypes. Multiple studies are underway to validate these findings and evaluate their utility in clinical trials. CONCLUSIONS: Development of the P-QST Consortium will facilitate collaborative efforts to use P-QST as a means for evaluation and characterization of pain in CP patients, and optimize methods to guide individualized pain management approaches.

The ePix10k 2-megapixel hard X-ray detector at LCLS.

The ePix10ka2M (ePix10k) is a new large area detector specifically developed for X-ray free-electron laser (XFEL) applications. The hybrid pixel detector was developed at SLAC to provide a hard X-ray area detector with a high dynamic range, running at the 120 Hz repetition rate of the Linac Coherent Light Source (LCLS). The ePix10k consists of 16 modules, each with 352 × 384 pixels of 100 µm × 100 µm distributed on four ASICs, resulting in a 2.16 megapixel detector, with a 16.5 cm × 16.5 cm active area and ∼80% coverage. The high dynamic range is achieved with three distinct gain settings (low, medium, high) as well as two auto-ranging modes (high-to-low and medium-to-low). Here the three fixed gain modes are evaluated. The resulting dynamic range (from single photon counting to 10000 photons pixel-1 pulse-1 at 8 keV) makes it suitable for a large number of different XFEL experiments. The ePix10k replaces the large CSPAD in operation since 2011. The dimensions of the two detectors are similar, making the upgrade from CSPAD to ePix10k straightforward for most setups, with the ePix10k improving on experimental performance. The SLAC-developed ePix cameras all utilize a similar platform, are tailored to target different experimental conditions and are designed to provide an upgrade path for future high-repetition-rate XFELs. Here the first measurements on this new ePix10k detector are presented and the performance under typical XFEL conditions evaluated during an LCLS X-ray diffuse scattering experiment measuring the 9.5 keV X-ray photons scattered from a thin liquid jet.

Immediate Postoperative Insulin Requirements May Predict Metabolic Outcome after Total Pancreatectomy and Islet Autotransplantation.

Chronic pancreatitis (CP) is a progressive disease that leads to eventual loss of endocrine and exocrine function. Total pancreatectomy and islet autotransplantation (TPIAT) is a treatment option for patients with CP; however, predicting postoperative metabolic outcomes remains elusive. In this single-center retrospective study, we report pre-TPIAT characteristics, beta cell function indices, islet yield, and post-TPIAT glucose management data to further understand their relationship. Islet yield, glucose level, and insulin requirement for 72 hours postoperatively were collected for a total of 13 TPIAT recipients between 9-2013 and 9-2018. In addition, their glucose control and basal insulin requirements at 3, 6, and 12 months post-TPIAT were analyzed. All 13 subjects had normal baseline fasting glucose levels. Median islet yield was 4882 IEq/kg (interquartile range 3412 to 8987). Median postoperative total insulin requirement on day 3 was 0.43 units/kg. Pre-TPIAT baseline glucose, insulin, or c-peptide level did not have a significant correlation with the islet yield. Similarly, there was no correlation between islet yield and insulin requirement at 72-hour postoperatively. However, there was an inverse correlation between the absolute islet yield (IEq) and insulin requirement at 6 months and 12 months following post-TPIAT. Further analysis of the relationship between 72-hour post-op insulin requirement and insulin requirement at discharge, 3, 6, and 12 months showed a positive correlation. Despite the finding of inverse correlation of islet yield with long-term basal insulin requirement, this study was not able to detect a correlation between the preoperative parameters to postoperative short-term or long-term outcome as noted in other studies. The 72-hour postoperative insulin requirement is a helpful postoperative predictor of patients needing long-term insulin management following TPIAT. This observation may identify a high-risk group of patients in need of more intensive diabetes education and insulin treatment prior to hospital discharge.

Assessment of the College of Intensive Care Medicine's capacity to train: a survey of trainees and directors.

BACKGROUND: In Australia and New Zealand, the numbers of intensive care medicine trainees have increased significantly over the past 15 years. This has implications for supervision, clinical and procedural experience, and availability of rotations. The College of Intensive Care Medicine of Australia and New Zealand (CICM) decided to estimate the current training resources using several domains. METHODS: An online survey was sent to all CICM trainees (n = 528) and all directors of intensive care units (ICUs) (n = 106), using the SurveyMonkey tool. RESULTS: The overall response rate for the survey was 44% (trainees, 38%; directors, 72%). Most trainees had a 1:1 day-night roster system. Experience among trainees with common ICU procedures appeared limited. Fifty-six per cent of trainees reported spending more than 20% of their time attending medical emergency team calls. Difficulty accessing anaesthesia, medicine, paediatric and rural terms were reported by 35%, 26% 46% and 40% of trainees, respectively. Thirty-seven percent of trainees reported having to wait at least 1 year and 10% waited up to 2 years over and above their required training time to secure an anaesthesia term. Owing to gaps in experience in certain modules, one-third of final-year trainees felt underprepared to take on a role as a specialist, an observation shared by 15% of directors. CONCLUSION: This report has provided an assessment of the available resources within Australia and New Zealand for training doctors in intensive care medicine, and has identified significant limitations and concerns among trainees and ICU directors regarding the capacity to train. The findings call for a review of the training program, including a determination of optimal numbers of training positions.

Electrospray sample injection for single-particle imaging with x-ray lasers.

The possibility of imaging single proteins constitutes an exciting challenge for x-ray lasers. Despite encouraging results on large particles, imaging small particles has proven to be difficult for two reasons: not quite high enough pulse intensity from currently available x-ray lasers and, as we demonstrate here, contamination of the aerosolized molecules by nonvolatile contaminants in the solution. The amount of contamination on the sample depends on the initial droplet size during aerosolization. Here, we show that, with our electrospray injector, we can decrease the size of aerosol droplets and demonstrate virtually contaminant-free sample delivery of organelles, small virions, and proteins. The results presented here, together with the increased performance of next-generation x-ray lasers, constitute an important stepping stone toward the ultimate goal of protein structure determination from imaging at room temperature and high temporal resolution.

The Macromolecular Femtosecond Crystallography Instrument at the Linac Coherent Light Source.

The Macromolecular Femtosecond Crystallography (MFX) instrument at the Linac Coherent Light Source (LCLS) is the seventh and newest instrument at the world's first hard X-ray free-electron laser. It was designed with a primary focus on structural biology, employing the ultrafast pulses of X-rays from LCLS at atmospheric conditions to overcome radiation damage limitations in biological measurements. It is also capable of performing various time-resolved measurements. The MFX design consists of a versatile base system capable of supporting multiple methods, techniques and experimental endstations. The primary techniques supported are forward scattering and crystallography, with capabilities for various spectroscopic methods and time-resolved measurements. The location of the MFX instrument allows for utilization of multiplexing methods, increasing user access to LCLS by running multiple experiments simultaneously.

In consensus we trust? Persuasive effects of scientific consensus communication.

Scholars have recently suggested that communicating levels of scientific consensus (e.g. the percentage of scientists who agree about human-caused climate change) can shift public opinion toward the dominant scientific opinion. Initial research suggested that consensus communication effectively reduces public skepticism. However, other research failed to find a persuasive effect for those with conflicting prior beliefs. This study enters this contested space by experimentally testing how different levels of consensus shape perceptions of scientific certainty. We further examine how perceptions of certainty influence personal agreement and policy support. Findings indicate that communicating higher levels of consensus increases perceptions of scientific certainty, which is associated with greater personal agreement and policy support for non-political issues. We find some suggestive evidence that this mediated effect is moderated by participants' overall trust in science, such that those with low trust in science fail to perceive higher agreement as indicative of greater scientific certainty.

Coherent X-rays reveal the influence of cage effects on ultrafast water dynamics.

The dynamics of liquid water feature a variety of time scales, ranging from extremely fast ballistic-like thermal motion, to slower molecular diffusion and hydrogen-bond rearrangements. Here, we utilize coherent X-ray pulses to investigate the sub-100 fs equilibrium dynamics of water from ambient conditions down to supercooled temperatures. This novel approach utilizes the inherent capability of X-ray speckle visibility spectroscopy to measure equilibrium intermolecular dynamics with lengthscale selectivity, by measuring oxygen motion in momentum space. The observed decay of the speckle contrast at the first diffraction peak, which reflects tetrahedral coordination, is attributed to motion on a molecular scale within the first 120 fs. Through comparison with molecular dynamics simulations, we conclude that the slowing down upon cooling from 328 K down to 253 K is not due to simple thermal ballistic-like motion, but that cage effects play an important role even on timescales over 25 fs due to hydrogen-bonding.

Perioperative cytokine levels portend early death after pancreatectomy for ductal adenocarcinoma.

BACKGROUND: Soluble signaling molecules may play an important role in malignant pathogenesis. We hypothesize that perioperative cytokine levels are associated with outcomes in patients with pancreatic adenocarcinoma (PDAC) undergoing surgical resection. METHODS: One hundered and eighteen patients with benign or malignant pancreatic disease were enrolled in a prospective study through a protocol for banking biologic samples. Peripheral blood was drawn at time of operation, and a multiplex cytokine assay was performed. Statistical analysis was via χ2 and Kaplan Meier methods. RESULTS: Of 118 patients enrolled, 85 (72%) had a diagnosis of PDAC, and 60 (70%) ultimately underwent partial pancreatectomy. Cytokine levels were not associated with postoperative complications in this initial cohort. A plasma level of monocyte chemoattractant protein-1 (MCP-1) pg/mL ≤118 was associated with better overall survival (OS) (median survival 21 months vs 12.8 months, P = 0.023), as was non-detectable interleukin-8 (IL-8) (19 months) versus detectable IL-8 (12.8 months, P = 0.05). Patients with both MCP-1 >118 pg/mL and detectable IL-8 had a median survival of 10.6 months (P = 0.028). CONCLUSIONS: MCP-1 and IL-8 cytokine levels are associated with decreased survival following pancreatectomy for PDAC, and may be useful biomarkers. Measurement of these cytokine levels at different time points in future investigations will be important to validate these findings.

Coherent soft X-ray diffraction imaging of coliphage PR772 at the Linac coherent light source.

Single-particle diffraction from X-ray Free Electron Lasers offers the potential for molecular structure determination without the need for crystallization. In an effort to further develop the technique, we present a dataset of coherent soft X-ray diffraction images of Coliphage PR772 virus, collected at the Atomic Molecular Optics (AMO) beamline with pnCCD detectors in the LAMP instrument at the Linac Coherent Light Source. The diameter of PR772 ranges from 65-70 nm, which is considerably smaller than the previously reported ~600 nm diameter Mimivirus. This reflects continued progress in XFEL-based single-particle imaging towards the single molecular imaging regime. The data set contains significantly more single particle hits than collected in previous experiments, enabling the development of improved statistical analysis, reconstruction algorithms, and quantitative metrics to determine resolution and self-consistency.

Patient experience with intravenous biologic therapies for ankylosing spondylitis, Crohn's disease, psoriatic arthritis, psoriasis, rheumatoid arthritis, and ulcerative colitis.

OBJECTIVE: The objective of this study was to describe patient experience with intravenous (IV) biologics for ankylosing spondylitis, Crohn's disease, psoriatic arthritis, psoriasis, rheumatoid arthritis, or ulcerative colitis. METHODS: Semi-structured telephone interviews were conducted in 405 patients with these autoimmune diseases who were receiving an IV biologic to treat their disease. RESULTS: On a 7-point scale (1= not at all satisfied; 7= very satisfied), mean satisfaction with IV medication was rated 6.1; 77% of patients rated satisfaction as 6 or 7. The most frequently perceived benefits of IV therapy were related to supervision provided by health care professionals. Most patients (82%, n=332) preferred their IV medication to subcutaneous injection. The three most common reasons for preferring IV were not wanting to self-inject (43%), less frequent dosing (34%), and preference for administration by a health care professional (24%). African-American/black patients had a stronger preference for IV administration than Caucasian/white patients (97% vs 80%, P<0.05) and a greater dislike of needles/self-injection (71% vs 40%, P<0.05). Hospital outpatient departments were not rated as well as physician in-office infusion. Only half (49%) of the patients reported that both they and their physician equally influenced the choice to switch from subcutaneous to IV therapy, and only 30% were given a choice of infusion center. CONCLUSION: Users of IV biologics are highly satisfied with their medications and perceive the opportunity for health care provider interaction at their infusion facilities as an advantage of their regimen. These findings support continued need for IV therapeutic options and shared decision-making between patients and physicians while selecting biologic treatments.

Application of an ePix100 detector for coherent scattering using a hard X-ray free-electron laser.

A prototype ePix100 detector was used in small-angle scattering geometry to capture speckle patterns from a static sample using the Linac Coherent Light Source (LCLS) hard X-ray free-electron laser at 8.34 keV. The average number of detected photons per pixel per pulse was varied over three orders of magnitude from about 23 down to 0.01 to test the detector performance. At high average photon count rates, the speckle contrast was evaluated by analyzing the probability distribution of the pixel counts at a constant scattering vector for single frames. For very low average photon counts of less than 0.2 per pixel, the `droplet algorithm' was first applied to the patterns for correcting the effect of charge sharing, and then the pixel count statistics of multiple frames were analyzed collectively to extract the speckle contrast. Results obtained using both methods agree within the uncertainty intervals, providing strong experimental evidence for the validity of the statistical analysis. More importantly it confirms the suitability of the ePix100 detector for X-ray coherent scattering experiments, especially at very low count rates with performances surpassing those of previously available LCLS detectors.

Femtosecond X-ray magnetic circular dichroism absorption spectroscopy at an X-ray free electron laser.

X-ray magnetic circular dichroism spectroscopy using an X-ray free electron laser is demonstrated with spectra over the Fe L(3,2)-edges. The high brightness of the X-ray free electron laser combined with high accuracy detection of incident and transmitted X-rays enables ultrafast X-ray magnetic circular dichroism studies of unprecedented sensitivity. This new capability is applied to a study of all-optical magnetic switching dynamics of Fe and Gd magnetic sublattices in a GdFeCo thin film above its magnetization compensation temperature.

X-ray detectors at the Linac Coherent Light Source.

Free-electron lasers (FELs) present new challenges for camera development compared with conventional light sources. At SLAC a variety of technologies are being used to match the demands of the Linac Coherent Light Source (LCLS) and to support a wide range of scientific applications. In this paper an overview of X-ray detector design requirements at FELs is presented and the various cameras in use at SLAC are described for the benefit of users planning experiments or analysts looking at data. Features and operation of the CSPAD camera, which is currently deployed at LCLS, are discussed, and the ePix family, a new generation of cameras under development at SLAC, is introduced.

Rituximab for IgG4-related disease: a prospective, open-label trial.

OBJECTIVES: To evaluate the efficacy of rituximab (RTX) in IgG4-related disease (IgG4-RD) in an open-label pilot trial. METHODS: We treated 30 IgG4-RD patients with two doses of RTX (1000 mg each). The participants were either treated with RTX alone (n = 26; 87%) or required to discontinue baseline glucocorticoids (GC) within 2 months (n = 4; 13%). Disease activity was measured by the IgG4-RD Responder Index (IgG4-RD RI) and physician's global assessment (PGA). Disease response was defined as the improvement of the IgG4-RD RI by two points. The primary outcome, measured at 6 months, was defined as: (1) decline of the IgG4-RD RI ≥2 points compared with baseline; (2) no disease flares before month 6; and (3) no GC use between months 2 and 6. Complete remission was defined as an IgG4-RD RI score of 0 with no GC use. RESULTS: Disease responses occurred in 97% of participants. The baseline IgG4-RD RI and PGA values, 11±7 and 63±22 mm, respectively, declined to 1±2 and 11±16 mm at 6 months (both p<0.00001). The primary outcome was achieved by 23 participants (77%). Fourteen (47%) were in complete remission at 6 months, and 12 (40%) remained in complete remission at 12  months. Among the 19 with elevated baseline serum IgG4, IgG4 concentrations declined from a mean of 911 mg/dL (range 138-4780 mg/dL) to 422 mg/dL (range 56-2410 mg/dL) at month 6 (p<0.05). However, only 8 (42%) of the 19 achieved normal values. CONCLUSIONS: RTX appears to be an effective treatment for IgG4-RD, even without concomitant GC therapy. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov identifier: NCT01584388.

Pancreatic juice prostaglandin e2 concentrations are elevated in chronic pancreatitis and improve detection of early disease.

OBJECTIVES: Chronic pancreatitis (CP) may be difficult to diagnose in early stages. We aimed to measure pancreatic juice (PJ) prostaglandin E2 (PGE2) concentrations to determine whether they are elevated in CP and improve diagnosis of early disease. METHODS: We measured PJ PGE2 in 10 patients with established CP, 25 patients who met criteria for "minimal change" chronic pancreatitis (MCCP), and 10 normal control participants. RESULTS: Median PJ PGE2 was elevated in CP (307 pg/ml, IQR (249-362)) and MCCP (568 pg/ml, (418-854)) compared with normal controls (104 pg/ml, (68-206)) (P≤ 0.001). Area under receiving operator curve (AUROC) for diagnosis of CP and MCCP was 0.9 and 0.62, respectively, for PJ bicarbonate concentration alone; AUROC was 1.0 and 0.94 for the combination of PJ bicarbonate and PGE2 concentrations. CONCLUSIONS: PJ PGE2 appears to be a biomarker for CP and is elevated in both established and "minimal change" chronic pancreatitis.