Fixed-target pump-probe SFX: eliminating the scourge of light contamination.

X-ray free-electron laser (XFEL) light sources have enabled the rapid growth of time-resolved structural experiments, which provide crucial information on the function of macromolecules and their mechanisms. Here, the aim was to commission the SwissMX fixed-target sample-delivery system at the SwissFEL Cristallina experimental station using the PSI-developed micro-structured polymer (MISP) chip for pump-probe time-resolved experiments. To characterize the system, crystals of the light-sensitive protein light-oxygen-voltage domain 1 (LOV1) from Chlamydomonas reinhardtii were used. Using different experimental settings, the accidental illumination, referred to as light contamination, of crystals mounted in wells adjacent to those illuminated by the pump laser was examined. It was crucial to control the light scattering from and through the solid supports otherwise significant contamination occurred. However, the results here show that the opaque MISP chips are suitable for defined pump-probe studies of a light-sensitive protein. The experiment also probed the sub-millisecond structural dynamics of LOV1 and indicated that at Δt = 10 µs a covalent thioether bond is established between reactive Cys57 and its flavin mononucleotide cofactor. This experiment validates the crystals to be suitable for in-depth follow-up studies of this still poorly understood signal-transduction mechanism. Importantly, the fixed-target delivery system also permitted a tenfold reduction in protein sample consumption compared with the more common high-viscosity extrusion-based delivery system. This development creates the prospect of an increase in XFEL project throughput for the field.

Micro-structured polymer fixed targets for serial crystallography at synchrotrons and XFELs.

Fixed targets are a popular form of sample-delivery system used in serial crystallography at synchrotron and X-ray free-electron laser sources. They offer a wide range of sample-preparation options and are generally easy to use. The supports are typically made from silicon, quartz or polymer. Of these, currently, only silicon offers the ability to perform an aperture-aligned data collection where crystals are loaded into cavities in precise locations and sequentially rastered through, in step with the X-ray pulses. The polymer-based fixed targets have lacked the precision fabrication to enable this data-collection strategy and have been limited to directed-raster scans with crystals randomly distributed across the polymer surface. Here, the fabrication and first results from a new polymer-based fixed target, the micro-structured polymer fixed targets (MISP chips), are presented. MISP chips, like those made from silicon, have a precise array of cavities and fiducial markers. They consist of a structured polymer membrane and a stabilization frame. Crystals can be loaded into the cavities and the excess crystallization solution removed through apertures at their base. The fiducial markers allow for a rapid calculation of the aperture locations. The chips have a low X-ray background and, since they are optically transparent, also allow for an a priori analysis of crystal locations. This location mapping could, ultimately, optimize hit rates towards 100%. A black version of the MISP chip was produced to reduce light contamination for optical-pump/X-ray probe experiments. A study of the loading properties of the chips reveals that these types of fixed targets are best optimized for crystals of the order of 25 µm, but quality data can be collected from crystals as small as 5 µm. With the development of these chips, it has been proved that polymer-based fixed targets can be made with the precision required for aperture-alignment-based data-collection strategies. Further work can now be directed towards more cost-effective mass fabrication to make their use more sustainable for serial crystallography facilities and users.

Ebola Response: A study of the Psychosocial Factors of Preparedness Among Commissioned Corps Officers of the United States Public Health Service.

INTRODUCTION: The purpose of the cross-sectional study was to explore the relationships between occupational and general-self efficacy, and perceived preparedness among Commissioned Corps officers in the United States Public Health Service (Commissioned Corps). Commissioned Corps officers fight to protect the United States from diseases and care for the survivors of natural disasters and terrorist attacks. Commissioned Corps officers play a vital role in the fight to protect the United States from diseases and care for the survivors of natural disasters and terrorist attacks. The Commissioned Corps provided healthcare services in Liberia during the 2014 Ebola crisis that underscored the challenges of emerging diseases in a globalized community. It is imperative that these health professionals maintain a high level of self-efficacy and feel confident in their overall preparedness training as they respond to public health emergencies. MATERIALS AND METHODS: This study used assessment instruments derived from Albert Bandura's concept of self-efficacy to analyze the occupational and general self-efficacy, and perceived preparedness levels of health services officers in the Commissioned Corps. 82 Commissioned Corps officers completed the assessment survey. To date, no study has examined the relationship between these constructs in this population. RESULTS: There was a statistically significant relationship between feeling confident in one's Commissioned Corps training and perceived preparedness (rs = 0.55, p < 0.001). CONCLUSION: This study reflects the training perceptions and self-beliefs of Commissioned Corps officers, fills an important gap in the empirical research in this population, and advances previous investigations, which suffered from an underrepresentation of female service members.

Twenty-first century emergency response efforts of the Commissioned Corps of the US Public Health Service.

The impact of the Commissioned Corps of the US Public Health Service (Commissioned Corps) on the health and safety of the nation spans more than two centuries. The public health efforts of the highly qualified health professionals of this often-underreported uniformed service include fighting threats like the great flu pandemic of 1918, the anthrax attacks, Ebola, and natural disasters such as Hurricanes Maria, Irma, and Katrina. As we near the first quarter of the twenty-first century, it is important to take a snapshot of the critical contributions and response efforts the Commissioned Corps has made in the first 18 years of the twenty-first century. Today, the Commissioned Corps faces new challenges in the form of emerging diseases and a rapidly growing opioid epidemic, but under the guidance of the US Surgeon General, it remains vigilant and fully capable of minimizing any public health threat it encounters.

A novel molten-salt electrochemical cell for investigating the reduction of uranium dioxide to uranium metal by lithium using in situ synchrotron radiation.

A novel electrochemical cell has been designed and built to allow for in situ energy-dispersive X-ray diffraction measurements to be made during reduction of UO2 to U metal in LiCl-KCl at 500°C. The electrochemical cell contains a recessed well at the bottom of the cell into which the working electrode sits, reducing the beam path for the X-rays through the molten-salt and maximizing the signal-to-noise ratio from the sample. Lithium metal was electrodeposited onto the UO2 working electrode by exposing the working electrode to more negative potentials than the Li deposition potential of the LiCl-KCl eutectic electrolyte. The Li metal acts as a reducing agent for the chemical reduction of UO2 to U, which appears to proceed to completion. All phases were fitted using Le Bail refinement. The cell is expected to be widely applicable to many studies involving molten-salt systems.

In-operando high-speed tomography of lithium-ion batteries during thermal runaway.

Prevention and mitigation of thermal runaway presents one of the greatest challenges for the safe operation of lithium-ion batteries. Here, we demonstrate for the first time the application of high-speed synchrotron X-ray computed tomography and radiography, in conjunction with thermal imaging, to track the evolution of internal structural damage and thermal behaviour during initiation and propagation of thermal runaway in lithium-ion batteries. This diagnostic approach is applied to commercial lithium-ion batteries (LG 18650 NMC cells), yielding insights into key degradation modes including gas-induced delamination, electrode layer collapse and propagation of structural degradation. It is envisaged that the use of these techniques will lead to major improvements in the design of Li-ion batteries and their safety features.

A novel high-temperature furnace for combined in situ synchrotron X-ray diffraction and infrared thermal imaging to investigate the effects of thermal gradients upon the structure of ceramic materials.

A new technique combining in situ X-ray diffraction using synchrotron radiation and infrared thermal imaging is reported. The technique enables the application, generation and measurement of significant thermal gradients, and furthermore allows the direct spatial correlation of thermal and crystallographic measurements. The design and implementation of a novel furnace enabling the simultaneous thermal and X-ray measurements is described. The technique is expected to have wide applicability in material science and engineering; here it has been applied to the study of solid oxide fuel cells at high temperature.

Comparison of drugs for pulmonary hypertension reversibility testing: A meta-analysis.

Multiple drugs are used for reversibility testing of pulmonary hypertension (PH) in advanced heart failure (HF), especially in the process of heart transplant evaluation. Effects of these drugs were never systematically compared. The aim of this meta-analysis was to compare hemodynamic effects of different drugs. We identified 20 prospective studies reporting hemodynamic variables before and after acute pharmacologic testing for PH reversibility in patients with advanced HF. The data from individual studies were grouped by an outcome measure and analyzed. A mixed model meta-analysis was performed using SAS to give weighted mean effect of pre- and post-test change and inverse variance. The mean effects were weighted by the published sample size. Prostacyclin, inhaled or intravenous, and prostaglandin E1 (PGE1) had the most potent effect on pulmonary vascular resistance (PVR). Sodium nitroprusside and nitroglycerin decreased pulmonary capillary wedge pressure (PCWP), and mean pulmonary arterial pressure (MPAP) better than other drugs. Sildenafil provided overall good hemodynamic outcomes but was not the strongest drug with regard to any particular outcome. PCWP, MPAP, and systolic pulmonary arterial pressure respond better to nitroglycerin and sodium nitroprusside than to other drugs in the setting of reversibility testing. Prostacyclin and PGE1 are superior to other drugs in their acute effects on PVR.

Improving prostate cancer detection in veterans through the development of a clinical decision rule for prostate biopsy.

BACKGROUND: We sought to improve prostate cancer (PC) detection through developing a prostate biopsy clinical decision rule (PBCDR), based on an elevated PSA and laboratory biomarkers. This decision rule could be used after initial PC screening, providing the patient and clinician information to consider prior to biopsy. METHODS: This case-control study evaluated men from the Tampa, Florida, James A. Haley (JH) Veteran's Administration (VA) (N = 1,378), from January 1, 1998, through April 15, 2005. To assess the PBCDR we did all of the following: 1) Identified biomarkers that are related to PC and have the capability of improving the efficiency of PC screening; 2) Developed statistical models to determine which can best predict the probability of PC; 3) Compared each potential model to PSA alone using Receiver Operator Characteristic (ROC) curves, to evaluate for improved overall effectiveness in PC detection and reduction in (negative) biopsies; and 4) Evaluated dose-response relationships between specified lab biomarkers (surrogates for extra-prostatic disease development) and PC progression. RESULTS: The following biomarkers were related to PC: hemoglobin (HGB) (OR = 1.42 95% CI 1.27, 1.59); red blood cell (RBC) count (OR = 2.52 95% CI 1.67, 3.78); PSA (OR = 1.04 95% CI 1.03, 1.05); and, creatinine (OR = 1.55 95% CI 1.12, 2.15). Comparing all PC stages versus non-cancerous conditions, the ROC curve area under the curve (AUC) enlarged (increasing the probability of correctly classifying PC): PSA (alone) 0.59 (95% CI 0.55, 0.61); PBCDR model 0.68 (95% CI 0.65, 0.71), and the positive predictive value (PPV) increased: PSA 44.7%; PBCDR model 61.8%. Comparing PC (stages II, III, IV) vs. other, the ROC AUC increased: PSA (alone) 0.63 (95% CI 0.58, 0.66); PBCDR model 0.72 (95% CI 0.68, 0.75), and the PPV increased: 20.6% (PSA); PBCDR model 55.3%. CONCLUSIONS: These results suggest evaluating certain common biomarkers in conjunction with PSA may improve PC prediction prior to biopsy. Moreover, these biomarkers may be more helpful in detecting clinically relevant PC. Follow-up studies should begin with replicating the study on different U.S. VA patients involving multiple practices.

Does warfarin therapy influence the risk of bladder cancer?

There has been growing interest in studying the biological effects of certain drugs and their potential to reduce the risk of various cancers. One study reported a decrease in the incidence of urogenital cancers in a trial with patients who received warfarin for treatment of venous thromboembolism, but a limitation to this study of urogenital cancers was the very small number of bladder cancer cases that developed following warfarin therapy. The objective of the present study is to measure the association between warfarin use and bladder cancer. A total of 330 cases with bladder cancer were identified at the James A. Haley Veterans' Administration (VA) Hospital in Tampa, Florida, using a combination of computerized pathology records and inpatient and outpatient diagnoses. Controls were randomly selected from the VA computerized administrative database and 1293 controls were included for analysis. Unconditional logistic regression analysis was performed to assess the risk of bladder cancer after adjusting for age, gender, and cigarette smoking. Among warfarin users, although there was a 27% elevation in risk, it did not differ significantly from nonusers (OR = 1.27, 95% CI = 0.85, 1.89). No duration-response relationship was observed between anticoagulant use and risk of bladder cancer. The results suggest that warfarin does not protect against bladder cancer, at least in male smokers, the highest risk population for bladder cancer.

Analgesic therapy and the prevention of bladder cancer.

The aim of this study was to measure the association between analgesic use and risk of bladder cancer among patients seen at the James A. Haley Veterans' Administration (VA) Hospital in Tampa, FL. A total of 330 cases were obtained using a combination of computerized pathology records, and inpatient and outpatient diagnoses. Controls were randomly selected from the VA computerized administrative database, and 1293 controls were included for analysis. Unconditional logistic regression analysis was performed to assess the risk of bladder cancer after adjusting for age, gender, and cigarette smoking. Among analgesic users, we were able to identify a nearly 20% reduction in risk potentially consistent with a protective role (OR = 0.81, 95% CI = 0.63, 1.05). Nonsmokers had a 43% decrease in risk (OR = 0.57, 95% CI = 0.33, 0.98). While smoking is a strong and recognized cause of bladder cancer, 50% of bladder cancer cases are not attributable to tobacco consumption. Given that nonsmokers prescribed nonsteroidal anti-inflammatory drugs (NSAIDs) were observed to have a 43% reduction in risk, it is important to study whether nonsmokers may benefit from therapy with NSAIDs.