Subpercent-Scale Control of 3D Low Modes of Targets Imploded in Direct-Drive Configuration on OMEGA.

Multiple self-emission x-ray images are used to measure tomographically target modes 1, 2, and 3 up to the end of the target acceleration in direct-drive implosions on OMEGA. Results show that the modes consist of two components: the first varies linearly with the laser beam-energy balance and the second is static and results from physical effects including beam mistiming, mispointing, and uncertainty in beam energies. This is used to reduce the target low modes of low-adiabat implosions from 2.2% to 0.8% by adjusting the beam-energy balance to compensate these static modes.

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

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

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

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

Measurements of the Conduction-Zone Length and Mass Ablation Rate in Cryogenic Direct-Drive Implosions on OMEGA.

Measurements of the conduction-zone length (110±20 µm at t=2.8 ns), the averaged mass ablation rate of the deuterated plastic (7.95±0.3 µg/ns), shell trajectory, and laser absorption are made in direct-drive cryogenic implosions and are used to quantify the electron thermal transport through the conduction zone. Hydrodynamic simulations that use nonlocal thermal transport and cross-beam energy transfer models reproduce these experimental observables. Hydrodynamic simulations that use a time-dependent flux-limited model reproduce the measured shell trajectory and the laser absorption but underestimate the mass ablation rate by ∼10% and the length of the conduction zone by nearly a factor of 2.

Prevalence of transfusion-acquired hepatitis C in an Australian bleeding disorders population.

In Australia prior to 1992, many patients with bleeding disorders were exposed to hepatitis C through blood products. However, the incidence, complications and response to treatment of chronic hepatitis C (CHC) in this population are poorly characterized. The aim of this study was to examine the prevalence of CHC and response to treatment in an Australian bleeding disorders population. Demographic data, virological data and liver disease status from these 700 patients with inherited bleeding disorders were analysed. Of these 700 patients, 424 (61%) had been tested for CHC infection and 219 (52%) were hepatitis C antibody positive, with the prevalence approaching 100% in patients with severe bleeding disorders. Of 219 patients, 73 (33%) had received treatment for their infection with a response rate of 33/73 (45%) across all genotypes. Of 219 patients, 34 (16%) had spontaneous viral clearance. When measured with transient elastography, 44/98 (45%) patients with CHC had significant liver fibrosis and 15/98 (15%) had liver cirrhosis. Of 130 patients, 38 (29%) with CHC infection had no evidence of follow-up with an appropriate clinician in the past 2 years. This study demonstrates that testing for CHC in this population is incomplete and treatment rates are low. Given the substantial morbidity and mortality associated with CHC and new therapeutic options becoming available, it seems important to reengage patients to diagnose, offer treatment and monitor this infection.

Piloting the use of 2D barcode and patient safety-software in an Australian tertiary hospital setting.

OBJECTIVES: Errors in administration of blood products can lead to poor patient outcomes including fatal ABO incompatible transfusions. This pilot study sought to establish whether the use of two-dimensional (2D) barcode technology combined with patient identification software designed to assist in blood administration improves the bedside administration of transfusions in an Australian tertiary hospital. STUDY DESIGN AND METHODS: The study was conducted in a Haematology/Oncology Day Clinic of a major metropolitan hospital, to evaluate the use of 2D barcode technology and patient safety-software and hand-held PDAs to assist nursing staff in patient identification and blood administration. Comparative audits were conducted before and after the technology's implementation. RESULTS: The preimplementation transfusion practice audits demonstrated a poor understanding of the blood checking process, with focus on the product rather than patient identification. Following the implementation of 2D barcode technology and patient safety-software, there was significant improvement in administration practice. Positive, verbal patient identification improved from 57% (51/90) to 94% (75/80). Similarly, the cross-referencing of the patient's identification with the patient's wristband improved from 36% (32/90) to 94% (75/80), and the cross-referencing of patient ID on the compatibility tag to wristbands improved from 48% (43/90) to 99% (79/80). Importantly, the 2D barcode technology and patient safety-software saw 100% (80/80) of checks being conducted at the patient bedside, compared with 76% (68/90) in the preimplementation audits. CONCLUSION: This pilot study demonstrates that 2D barcode technology and patient safety-software significantly improves the bedside check of patient and blood product identification in an Australian setting.

Small molecule targeting the Rac1-NOX2 interaction prevents collagen-related peptide and thrombin-induced reactive oxygen species generation and platelet activation.

Essentials Reactive oxygen species (ROS) generation by NOX2 plays a critical role in platelet activation. Rac1 regulation of NOX2 is important for ROS generation. Small molecule inhibitor of the Rac1-p67phox interaction prevents platelet activation. Pharmacologic targeting of Rac1-NOX2 axis can be a viable approach for antithrombotic therapy. SUMMARY: Background Platelets from patients with X-linked chronic granulomatous disease or mice deficient in nicotinamide adenine dinucleotide (phosphate) (NAD(P)H) oxidase isoform NOX2 exhibit diminished reactive oxygen species (ROS) generation and platelet activation. Binding of Rac1 GTPase to p67phox plays a critical role in NOX2 activation by facilitating the assembly of the NOX2 enzyme complex. Objective We tested the hypothesis that Phox-I, a rationally designed small molecule inhibitor of Rac-p67phox interaction, may serve as an antithrombosis agent by suppressing ROS production and platelet activation. Results Collagen-related peptide (CRP) induced ROS generation in a time-dependent manner. Platelets from Rac1-/- mice or human platelets treated with NSC23766, a specific Rac inhibitor, produced significantly less ROS in response to CRP. Treatment of platelets with Phox-I inhibited diverse CRP-induced responses, including: (i) ROS generation; (ii) release of P-selectin; (iii) secretion of ATP; (iv) platelet aggregation; and (v) phosphorylation of Akt. Similarly, incubation of platelets with Phox-I inhibited thrombin-induced: (i) secretion of ATP; (ii) platelet aggregation; (iii) rise in cytosolic calcium; and (iv) phosphorylation of Akt. In mouse models, intraperitoneal administration of Phox-I inhibited: (i) collagen-induced platelet aggregation without affecting the tail bleeding time and (ii) in vivo platelet adhesion/accumulation at the laser injury sites on the saphenous vein without affecting the time for complete cessation of blood loss. Conclusions Small molecule targeting of the Rac1-p67phox interaction may present an antithrombosis regimen by preventing GPVI- and non-GPVI-mediated NOX2 activation, ROS generation and platelet function without affecting the bleeding time.

Measurement of the shell decompression in direct-drive inertial-confinement-fusion implosions.

A series of direct-drive implosions performed on OMEGA were used to isolate the effect of an adiabat on the in-flight shell thickness. The maximum in-flight shell thickness was measured to decrease from 75±2 to 60±2µm when the adiabat of the shell was reduced from 6 to 4.5, but when decreasing the adiabat further (1.8), the shell thickness increased to 75±2µm due to the growth of the Rayleigh-Taylor instability. Hydrodynamic simulations suggest that a laser imprint is the dominant seed for these nonuniformities.

ABO incompatible renal transplantation following lung transplantation.

We present management strategies utilised for the first case of an urgent live-donor ABO incompatible B blood group renal transplant, in a patient with a prior A blood group lung transplant for cystic fibrosis. Three years on, renal function is excellent and stable, whilst lung function has improved.

X-ray self-emission imaging used to diagnose 3-D nonuniformities in direct-drive ICF implosions.

As hydrodynamics codes develop to increase understanding of three-dimensional (3-D) effects in inertial confinement fusion implosions, diagnostics must adapt to evaluate their predictive accuracy. A 3-D radiation postprocessor was developed to investigate the use of soft x-ray self-emission images of an imploding target to measure the size of nonuniformities on the target surface. Synthetic self-emission images calculated from 3-D simulations showed a narrow ring of emission outside the ablation surface of the target. Nonuniformities growing in directions perpendicular to the diagnostic axis were measured through angular variations in the radius of the steepest intensity gradient on the inside of the ring and through changes in the peak x-ray intensity in the ring as a function of angle. The technique was applied to an implosion to measure large 3-D nonuniformities resulting from two dropped laser beam quads at the National Ignition Facility.

Mechanical circulatory support is associated with loss of platelet receptors glycoprotein Ibα and glycoprotein VI.

Essentials Relationship of acquired von Willebrand disease (VWD) and platelet dysfunction is explored. Patients with ventricular assist devices and on extracorporeal membrane oxygenation are investigated. Acquired VWD and platelet receptor shedding is demonstrated in the majority of patients. Loss of platelet adhesion receptors glycoprotein (GP) Ibα and GPVI may increase bleeding risk. SUMMARY: Background Ventricular assist devices (VADs) and extracorporeal membrane oxygenation (ECMO) are associated with bleeding that is not fully explained by anticoagulant or antiplatelet use. Exposure of platelets to elevated shear in vitro leads to increased shedding. Objectives To investigate whether loss of platelet receptors occurs in vivo, and the relationship with acquired von Willebrand syndrome (AVWS). Methods Platelet counts, coagulation tests and von Willebrand factor (VWF) analyses were performed on samples from 21 continuous flow VAD (CF-VAD), 20 ECMO, 12 heart failure and seven aortic stenosis patients. Levels of platelet receptors were measured by flow cytometry or ELISA. Results The loss of high molecular weight VWF multimers was observed in 18 of 19 CF-VAD and 14 of 20 ECMO patients, consistent with AVWS. Platelet receptor shedding was demonstrated by elevated soluble glycoprotein (GP) VI levels in plasma and significantly reduced surface GPIbα and GPVI levels in CF-VAD and ECMO patients as compared with healthy donors. Platelet receptor levels were also significantly reduced in heart failure patients. Conclusions These data link AVWS and increased platelet receptor shedding in patients with CF-VADs or ECMO for the first time. Loss of the platelet surface receptors GPIbα and GPVI in heart failure, CF-VAD and ECMO patients may contribute to ablated platelet adhesion/activation, and limit thrombus formation under high/pathologic shear conditions.

Proteoglycans are present in the transverse tubule system of skeletal muscle.

The transverse tubule system (T-tubule, T-system) of skeletal muscle is a membranous network that penetrates the interior of myofibers. The T-system is continuous with the sarcolemma and therefore provides a path for membrane excitation to reach internal myofibrils. In this study we demonstrate that T-tubules in elasmobranch fish, frog, and rat skeletal muscle contain a matrix of chondroitin sulfate proteoglycans. We used anti-T1, a mouse monoclonal antibody that recognizes a rare chondroitin sulfate epitope, for immunolocalization and biochemical studies. First, we find that T1 immunoreactivity colocalizes with a T-tubule marker, the dihydropyridine receptor alpha 2 subunit, in both frog and fish muscle. Secondly, the distribution of T1 immunoreactivity exactly matches the different distribution of T-tubules in rat and frog muscle. In rat muscle, two bands of T1 immunoreactivity are detected per sarcomere, a distribution that corresponds to the T-tubules located at the two A-I junctions of each sarcomere. In frog muscle, we detect one band of T1 immunoreactivity per sarcomere that corresponds to the one T-tubule per sarcomere located at the Z line. Lastly, we have isolated and biochemically characterized T1 antigenicity from fish skeletal muscle. Like extracellular matrix proteoglycans of cartilage, T1 antigenicity requires denaturing conditions to be solubilized. In fish muscle, two chondroitin sulfate proteoglycans bear T1: a heavily glycosylated proteoglycan with a molecular mass of about 1000 kDa, and a smaller proteoglycan that has a mobility on SDS-PAGE like a protein of molecular mass 280 kDa. We propose that proteoglycans function as structural components in the T-system. The proteoglycans may form a matrix, like the one formed by the cartilage proteoglycans they resemble, that can withstand the cytosolic osmotic pressures present in muscle cells and therefore may prevent the T-tubule from collapsing. We present a quantitative argument in support of this hypothesis.

Nitric oxide synthase activity in placentae from women with pre-eclampsia.

The syncytiotrophoblast (ST) cell layer of the human villous placenta expresses nitric oxide (NO) synthase. Because NO is a potent relaxant of vascular smooth muscle and inhibitor of platelet activity, we postulated that exaggerated intervillous aggregation of platelets and reduced fetoplacental blood flow in pre-eclampsia result from reduced expression of NO synthase (and production of NO) by the ST. Conversion of [3H]arginine to [3H]citrulline and Lineweaver-Burk transformation were used to derive the Vmax and K(M) of NO synthase. Contrary to our expectations, the Vmax was not significantly different between villous placenta obtained from nulliparous normal and pre-eclamptic women (n = 11 each). The Vmax and K(M) were 22.3 +/- 2.3 pmol/mg per min and 1.3 +/- 0.1 microns, and 22.0 +/- 2.7 pmol/mg per min and 1.4 +/- 0.1 microns, for villous placenta from the nulliparous normal and pre-eclamptic women, respectively. The Vmax and K(M) of placental NO synthase were also comparable among multiparous normal and pre-eclamptic women, as well as women with gestational hypertension. When compared with the enzyme activity of the villous, that of the basal plate was reduced by approximately one-half in all placentae. The calcium-independent activity was consistently 40-fold less than the calcium-dependent activity, and it was similar between villous and basal plate, and between placentae from normal and hypertensive women. We suggest that expression of NO synthase is not different in placentae obtained from normal and pre-eclamptic women.

Effects of tissue preincubation and hypoxia on CA3 hippocampal neurons in the in vitro slice preparation.

Using the in vitro hippocampal slice preparation, we studied the electrophysiological properties of pyramidal cells in tissue that was 'preincubated' (2-6 h in a large, static volume of oxygenated bathing medium) before being placed in an interface chamber for study. Striking differences were found in 'preincubated' vs 'non-preincubated' CA3 cells. The preincubated cells had more negative resting potentials, higher input resistance, lower threshold for stimulus-evoked burst discharge and larger hyperpolarizing afterpotentials. Cells in the preincubated CA3 region were also more likely to show spontaneous synchronized burst discharge, but were relatively resistant to hypoxia-induced spreading depression. CA1 cells were less dramatically affected by preincubation, showing little difference from their non-preincubated counterparts. Possible mechanisms involved in the CA3 preincubation effect, including glial buffering alterations and changes in Na+, K+-ATPase activity, are discussed.

The interdisciplinary generalist curriculum project: a national medical school demonstration project.

The United States is facing the challenge of producing more generalists for the physician workforce. The Primary Care Organizations' Consortium (PCOC) has responded by focusing on how medical education can be modified to enhance and support medical students' interest in and commitment to generalism early in their training. Evolving from PCOC's developmental work, the five-year Interdisciplinary Generalist Curriculum (IGC) Project was developed to encourage the nation's schools of medicine and colleges of osteopathic medicine to implement interdisciplinary generalist curricula in the preclinical years. Funded by the Division of Medicine in the Bureau of Health Professions of the Health Resources and Services Administration (HRSA), the IGC Project has successfully developed and implemented a nationally competitive medical school demonstration project. Thirty-three schools submitted proposals for an IGC Project award; nine were selected for site visits, from which five were chosen to receive three-year awards. Rigorous attention to creating and maintaining an interdisciplinary focus has characterized the first phase of the IGC Project. Shared leadership among the Executive Committee's project director and two project codirectors and parity in representation among the three disciplines of family medicine, internal medicine, and pediatrics on the Advisory Committee have formed a critical foundation for interdisciplinary functioning within the project. Growing national interest in generalist training and other funding initiatives have contributed to acceptance of the IGC Project. The high level of interest in the IGC Project and the successful interdisciplinary collaboration during the first phase would indicate that the interdisciplinary process can be replicated to move the nation's medical education institutions toward the production of needed generalist physicians.

Emerging lessons of the Interdisciplinary Generalist Curriculum (IGC) Project.

The Interdisciplinary Generalist Curriculum Project (IGC) was funded in 1993 by the Health Resources and Services Administration with the goal of developing innovative preclinical generalist curricula in ten of the nation's medical and osteopathic schools. The IGC successfully completed two competitive cycles in which ten schools were awarded three-year contracts. Although the long-term goal of the project is to increase the proportion of medical students choosing generalist careers, much has been learned thus far about the processes of curricular change and interdisciplinary cooperation. Drawing on information from school reports, site visits, external evaluations, academic presentations, and annual project meetings, this report presents the emerging lessons learned in the key areas of interdisciplinary collaboration, recruitment and retention of community preceptors, faculty development, and integration of generalist-related components into the four-year medical school curriculum. These lessons should prove useful for other schools embarking upon significant curricular innovations.

Long-term evaluation of a substance abuse fellowship program in family medicine.

BACKGROUND: Faculty development fellowship programs provide avenues for physicians to develop careers in academic medicine. However, the long-term impact of these programs has not been evaluated. This paper examines the impact of an 18-month substance abuse faculty development fellowship administered by the Society of Teachers of Family Medicine (STFM) 7 years after the fellowship's completion. METHODS: Fellows were interviewed by telephone. Their CVs were examined to assess how their present substance abuse teaching, clinical, research, administrative, scholarly, and networking activities compared with those prior to the fellowship. RESULTS: Initially, fellows contributed modules to an STFM publication and increased substance abuse teaching in their home institutions. Seven years later, fellows reported increased activity in substance abuse teaching, clinical, administrative, and research activities over those prior to the fellowship and attributed these increases to the fellowship. Fellows' CVs reflected increased publications, presentations, and networking activities with each other, including the creation of the STFM Group on Substance Abuse. CONCLUSIONS: In a 7-year follow-up, STFM's substance abuse fellowship program met its original goals, strengthened the academic and professional achievements of the fellows, and fostered the development of several fellows as leaders within the substance abuse field.