Final amplifier of an ultra-intense all-OPCPA system with 13-J output signal energy and 41% pump-to-signal conversion efficiency.

Optical parametric chirped-pulse amplification (OPCPA) using high-energy Nd:glass lasers has the potential to produce ultra-intense pulses (>1023 W/cm2). We report on the performance of the final high-efficiency amplifier in an OPCPA system based on large-aperture (63 × 63-mm2) partially deuterated potassium dihydrogen phosphate (DKDP) crystals. The seed beam (180-nm bandwidth, 110 mJ) was provided by the preceding OPCPA stages. A maximum pump-to-signal conversion efficiency of 41% and signal energy up to 13 J were achieved with a 52-mm-long DKDP crystal due to the flattop super-Gaussian pump beam profile and flat-in-time pulse shape.

Opportunities to engage health system leaders in whole systems approaches to physical activity in England.

BACKGROUND: Physical activity plays an important role in maintaining good health and wellbeing, non-communicable disease prevention and can improve healthcare outcomes. Some progress is being made on incorporating physical activity into routine care, but less on engaging health system leaders in the 'whole systems' approaches which are increasingly recognised as important for addressing complex public health challenges such as physical inactivity. This commentary builds upon the findings of a recent study and aims to identify opportunities for engaging National Health Service (NHS) systems leaders in whole systems approaches to physical activity. OPPORTUNITIES FOR ACTION IN ENGLAND: Pockets of good practice exist from which lessons can be learned, but there are systemic issues that discourage and create barriers, and a need for meaningful engagement, leadership and action at national, regional and local levels. National and regional actors like Sport England, NHS England, health professional bodies, Active Partnerships, the Local Government Association and the Office for Health Improvement and Disparities can encourage and support government and the NHS to change policy drivers, culture and practices. Emerging opportunities include the 2021 White Paper Integration and Innovation, development of local integrated care systems, leadership from health charities and investment in non-clinical interventions ('social prescribing'). At local level, public health and physical activity specialists and other organisations have a key role as champions and facilitators of local whole systems approaches and engagement of local NHS leaderships. Finally, although whole systems action is about collaborative leadership, individual champions of physical activity can make a difference in influencing NHS leaders at every level towards whole systems working.

Pediatric lung function testing during a pandemic: An international perspective.

The COVID pandemic has passed its first peak for now in many countries while some are still on the rise, with some facing a second wave of cases. Precautions and infection control measures for both pediatric and adult pulmonary function testing (PFT) have been a topic of debate during the pandemic. Many centers had to close their PFT laboratories during the initial periods of the pandemic and are reopening as the numbers of new cases are decreasing. This review aims to summarize different practices of PFT laboratory management in different countries, including patient appointments, personal protective equipment, testing room requirements and telemedicine during and immediately following the COVID pandemic.

Optical characterization of the on-target OMEGA focal spot at high energy using the full-beam in-tank diagnostic.

The full-beam in-tank (FBIT) diagnostic has been deployed to directly measure the target-plane beam fluence profile, when operated at high energy, of the OMEGA Laser System at the University of Rochester's Laboratory for Laser Energetics. This paper presents the results of early measurements taken with this diagnostic and discusses an improvement that has overcome performance limitations discovered during the initial testing. The diagnostic gives new insight into the ability of the OMEGA Laser System to provide uniform fluence profiles that are consistent across all 60 beams in the laser. The ultimate goal of the FBIT diagnostic is to allow accurate assessment of the fluence uniformity on a spherical target in 60-beam implosion experiments.

Social & psychological factors associated with oral analgesic use in knee osteoarthritis management.

OBJECTIVE: Determine modifiable social and psychological health factors that are associated with use of oral opioid and non-opioid medications for OA. METHODS: Patients were categorized based on use of the following oral medications: opioids (with/without other oral analgesic treatments), non-opioid analgesics, and no oral analgesic treatment. We used multinomial logistic regression models to estimate adjusted relative risk ratios (RRRs) of using an opioid or a non-opioid analgesic (vs. no oral analgesic treatment), comparing patients by levels of social support (Medical Outcomes Study scale), health literacy ("How confident are you filling out medical forms by yourself?"), and depressive symptoms (Patient Health Questionnaire-8). Models were adjusted for demographic and clinical characteristics. RESULTS: In this sample (mean age 64.2 years, 23.6% women), 30.6% (n = 110) reported taking opioid analgesics for OA, 54.2% (n = 195) reported non-opioid use, and 15.3% (n = 55) reported no oral analgesic use. Opioid users had lower mean social support scores (10.0 vs 10.5 vs 11.9, P = 0.007) and were more likely to have moderate-severe depressive symptoms (42.7% vs 24.1% vs 14.5%, P < 0.001). Health literacy did not differ by treatment group type. Having moderate-severe depression was associated with higher risk of opioid analgesic use compared to no oral analgesic use (RRR 2.96, 95%CI 1.08-8.07) when adjusted for sociodemographic and clinical factors. Neither social support nor health literacy was associated with opioid or non-opioid oral analgesic use in fully adjusted models. CONCLUSIONS: Knee OA patients with more severe depression symptoms, compared to those without, were more likely to report using opioid analgesics for OA.

Urinary Markers of Fibrosis and Risk of Cardiovascular Events and Death in Kidney Transplant Recipients: The FAVORIT Trial.

Cardiovascular risk remains high in kidney transplant recipients (KTRs) despite improved kidney function after transplant. Urinary markers of kidney fibrosis and injury may help to reveal mechanisms of this risk. In a case-cohort study among stable KTRs who participated in the FAVORIT trial, we measured four urinary proteins known to correlate with kidney tubulointerstitial fibrosis on biopsy (urine alpha 1 microglobulin [α1m], monocyte chemoattractant protein-1 [MCP-1], procollagen type I [PINP] and type III [PIIINP] N-terminal amino peptide) and evaluated associations with cardiovascular disease (CVD) events (n = 300) and death (n = 371). In adjusted models, higher urine α1m (hazard ratio [HR] per doubling of biomarker 1.40 [95% confidence interval [CI] 1.21, 1.62]), MCP-1 (HR 1.18 [1.03, 1.36]), and PINP (HR 1.13 [95% CI 1.03, 1.23]) were associated with CVD events. These three markers were also associated with death (HR per doubling α1m 1.51 [95% CI 1.32, 1.72]; MCP-1 1.31 [95% CI 1.13, 1.51]; PINP 1.11 [95% CI 1.03, 1.20]). Higher concentrations of urine α1m, MCP-1, and PINP may identify KTRs at higher risk for CVD events and death. These markers may identify a systemic process of fibrosis involving both the kidney and cardiovascular system, and give new insights into mechanisms linking the kidney with CVD.

Filtration Markers, Cardiovascular Disease, Mortality, and Kidney Outcomes in Stable Kidney Transplant Recipients: The FAVORIT Trial.

Cystatin C and beta-2-microglobulin (B2M) are filtration markers associated with adverse outcomes in nontransplant populations, sometimes with stronger associations than for creatinine. We evaluated associations of estimated glomerular filtration rate from cystatin C (eGFRcys ), B2M (eGFRB2M ), and creatinine (eGFRcr ) with cardiovascular outcomes, mortality, and kidney failure in stable kidney transplant recipients using a case-cohort study nested within the Folic Acid for Vascular Outcome Reduction in Transplantation (FAVORIT) Trial. A random subcohort was selected (N = 508; mean age 51.6 years, median transplant vintage 4 years, 38% women, 23.6% nonwhite race) with enrichment for cardiovascular events (N = 306; 54 within the subcohort), mortality (N = 208; 68 within the subcohort), and kidney failure (N = 208; 52 within the subcohort). Mean eGFRcr , eGFRcys , and eGFRB2M were 46.0, 43.8, and 48.8 mL/min/1.73m2 , respectively. After multivariable adjustment, hazard ratios for eGFRcys and eGFRB2M <30 versus 60+ were 2.02 (95% confidence interval [CI] 1.09-3.76; p = 0.03) and 2.56 (1.35-4.88; p = 0.004) for cardiovascular events; 3.92 (2.11-7.31) and 4.09 (2.21-7.54; both p < 0.001) for mortality; and 9.49 (4.28-21.00) and 15.53 (6.99-34.51; both p < 0.001) for kidney failure. Associations persisted with additional adjustment for baseline eGFRcr . We conclude that cystatin C and B2M are strongly associated with cardiovascular events, mortality, and kidney failure in stable kidney transplant recipients.

Inducing humoral and cellular responses to multiple sporozoite and liver-stage malaria antigens using exogenous plasmid DNA.

A vaccine candidate that elicits humoral and cellular responses to multiple sporozoite and liver-stage antigens may be able to confer protection against Plasmodium falciparum malaria; however, a technology for formulating and delivering such a vaccine has remained elusive. Here, we report the preclinical assessment of an optimized DNA vaccine approach that targets four P. falciparum antigens: circumsporozoite protein (CSP), liver stage antigen 1 (LSA1), thrombospondin-related anonymous protein (TRAP), and cell-traversal protein for ookinetes and sporozoites (CelTOS). Synthetic DNA sequences were designed for each antigen with modifications to improve expression and were delivered using in vivo electroporation (EP). Immunogenicity was evaluated in mice and nonhuman primates (NHPs) and assessed by enzyme-linked immunosorbent assay (ELISA), gamma interferon (IFN-γ) enzyme-linked immunosorbent spot (ELISpot) assay, and flow cytometry. In mice, DNA with EP delivery induced antigen-specific IFN-γ production, as measured by ELISpot assay and IgG seroconversion against all antigens. Sustained production of IFN-γ, interleukin-2, and tumor necrosis factor alpha was elicited in both the CD4(+) and CD8(+) T cell compartments. Furthermore, hepatic CD8(+) lymphocytes produced LSA1-specific IFN-γ. The immune responses conferred to mice by this approach translated to the NHP model, which showed cellular responses by ELISpot assay and intracellular cytokine staining. Notably, antigen-specific CD8(+) granzyme B(+) T cells were observed in NHPs. Collectively, the data demonstrate that delivery of gene sequences by DNA/EP encoding malaria parasite antigens is immunogenic in animal models and can harness both the humoral and cellular arms of the immune system.

Kidney function and risk of cardiovascular disease and mortality in kidney transplant recipients: the FAVORIT trial.

In kidney transplant recipients, cardiovascular disease (CVD) is the leading cause of death. The relationship of kidney function with CVD outcomes in transplant recipients remains uncertain. We performed a post hoc analysis of the Folic Acid for Vascular Outcome Reduction in Transplantation (FAVORIT) Trial to assess risk factors for CVD and mortality in kidney transplant recipients. Following adjustment for demographic, clinical and transplant characteristics, and traditional CVD risk factors, proportional hazards models were used to explore the association of estimated GFR with incident CVD and all-cause mortality. In 4016 participants, mean age was 52 years and 20% had prior CVD. Mean eGFR was 49 ± 18 mL/min/1.73 m(2) . In 3676 participants with complete data, there were 527 CVD events over a median of 3.8 years. Following adjustment, each 5 mL/min/1.73 m(2) higher eGFR at levels below 45 mL/min/1.73 m(2) was associated with a 15% lower risk of both CVD [HR = 0.85 (0.80, 0.90)] and death [HR = 0.85 (0.79, 0.90)], while there was no association between eGFR and outcomes at levels above 45 mL/min/1.73 m(2) . In conclusion, in stable kidney transplant recipients, lower eGFR is independently associated with adverse events, suggesting that reduced kidney function itself rather than preexisting comorbidity may lead to CVD.

The phase-2 particle x-ray temporal diagnostic for simultaneous measurement of multiple x-ray and nuclear emission histories from OMEGA implosions (invited).

Electron-temperature (Te) measurements in implosions provide valuable diagnostic information, as Te is negligibly affected by residual flows and other non-thermal effects unlike ion-temperature inferred from a fusion product spectrum. In OMEGA cryogenic implosions, measurement of Te(t) can be used to investigate effects related to time-resolved hot-spot energy balance. The newly implemented phase-2 Particle X-ray Temporal Diagnostic (PXTD) utilizes four fast-rise (∼15 ps) scintillator-channels with distinct x-ray filtering. Titanium and stepped aluminum filtering were chosen to maximize detector sensitivity in the 10-20 keV range, as it has been shown that these x rays have similar density and temperature weighting to the emitted deuterium-tritium fusion neutrons (DTn) from OMEGA Cryo-DT implosions. High quality data have been collected from warm implosions at OMEGA. These data have been used to infer spatially integrated Te(t) with <10% uncertainty at peak emission. Nuclear and x-ray emission histories are measured with 10 ps relative timing uncertainty for x rays and DTn and 12 ps for x rays and deuterium-He3 protons (D3Hep). A future upgrade to the system will enable spatially integrated Te(t) with 40 ps time-resolution from cryogenic DT implosions.

Prototype development and preclinical immunogenicity analysis of a novel minimally invasive electroporation device.

The magnitude of the immune response to a DNA vaccine depends on three criteria--the optimized vector design, the use of a suitable adjuvant and the successful delivery and subsequent expression of the plasmid in the target tissue. In vivo electroporation (EP) has proved to be particularly effective in efficiently delivering DNA immunogens to the muscle and the skin, and indeed several devices have entered into human clinical trials. Here, we report on a novel concept of DNA delivery to the dermal tissue using a minimally invasive EP device, which is powered using low-voltage parameters. We show that this prototype device containing a novel 4 × 4-electrode array results in robust and reproducible transfection of dermal tissue and subsequent antigen expression at the injection site. Using DNA encoding for NP and M2e influenza antigens, we further show induction of potent cellular responses in a mouse model as measured by antigen-specific T-cell ELISpot assays. Importantly, 100% of the immunized animals were protected when challenged with VN/1203/04 (H5N1) strain of influenza. We have also extended our findings to a guinea-pig model and demonstrated induction of HI titers greater than 1:40 against a pandemic novel H1N1 virus showing proof of concept efficacy for DNA delivery with the prototype device in a broad spectrum of species and using multiple antigens. Finally, we were able to generate protective HI titers in macaques against the same novel H1N1 strain. Our results suggest that the minimally invasive dermal device may offer a safe, tolerable and efficient method to administer DNA vaccinations in a prophylactic setting, and thus potentially represents an important new option for improved DNA vaccine delivery in vivo.

Molecular adjuvant HMGB1 enhances anti-influenza immunity during DNA vaccination.

DNA-based vaccines, while highly immunogenic in mice, generate significantly weaker responses in primates. Therefore, current efforts are aimed at increasing their immunogenicity, which include optimizing the plasmid/gene, the vaccine formulation and method of delivery. For example, co-immunization with molecular adjuvants encoding an immunomodulatory protein has been shown to improve the antigen (Ag)-specific immune response. Thus, the incorporation of enhancing elements, such as these, may be particularly important in the influenza model in which high titered antibody (Ab) responses are critical for protection. In this regard, we compared the ability of plasmid-encoded high-mobility group box 1 protein (HMGB1), a novel cytokine in which we have previously mutated in order to increase DNA vaccine immunogenicity, with boost Ag-specific immune responses during DNA vaccination with influenza A/PR/8/34 nucleoprotein or the hemagglutinin of A novel H1N1/09. We show that the HMGB1 adjuvant is capable of enhancing adaptive effector and memory immune responses. Although Ag-specific antibodies were detected in all vaccinated animals, a greater neutralizing Ab response was associated with the HMGB1 adjuvant. Furthermore, these responses improved CD8 T+-cell effector and memory responses and provided protection against a lethal mucosal influenza A/PR/8/34 challenge. Thus, co-immunization with HMGB1 has strong in vivo adjuvant activity during the development of immunity against plasmid-encoded Ag.

HIV-1 Vpr suppresses immune activation and apoptosis through regulation of nuclear factor kappa B.

The HIV-1 accessory gene product Vpr can influence viral pathogenesis by affecting viral replication as well as host cell transcription and proliferation. We have investigated the effects of Vpr on host cell activation and confirm that it influences cellular proliferation. However, we have also found that Vpr modulates T-cell receptor (TCR)-triggered apoptosis in a manner similar to that of glucocorticoids. In the absence of TCR-mediated activation, Vpr induces apoptosis whereas in its presence, Vpr interrupts the expected induction of apoptosis. This regulation of apoptosis is linked to Vpr suppression of NF-kappa B activity via the induction of I kappa B, an inhibitor of NF-kappa B. Further, Vpr suppresses expression of IL-2, IL-10, IL-12, TNF alpha and IL-4, all of which are NF-kappa B-dependent. The effects of Vpr could be reversed by RU486. Our finding that Vpr can regulate NF-kappa B supports the hypothesis that some aspects of viral pathogenesis are the consequence of cell dysregulation by Vpr.

Protection of chimpanzees from high-dose heterologous HIV-1 challenge by DNA vaccination.

Novel approaches for the generation of more effective vaccines for HIV-1 are of significant importance. In this report we analyze the immunogenicity and efficacy of an HIV-1 DNA vaccine encoding env, rev and gag/pol in a chimpanzee model system. The immunized animals developed specific cellular and humoral immune responses. Animals were challenged with a heterologous chimpanzee titered stock of HIV-1 SF2 virus and followed for 48 weeks after challenge. Polymerase chain reaction coupled with reverse transcription (RT-PCR) results indicated infection in the control animal, whereas those animals vaccinated with the DNA constructs were protected from the establishment of infection. These studies serve as an important benchmark for the use of DNA vaccine technology for the production of protective immune responses.

A multi-channel x-ray temporal diagnostic for measurement of time-resolved electron temperature in cryogenic deuterium-tritium implosions at OMEGA.

Electron-temperature (Te) measurements in implosions provide valuable diagnostic information, as Te is unaffected by residual flows and other non-thermal effects unlike ion temperature inferred from a fusion product spectrum. In OMEGA cryogenic implosions, measurement of Te(t) can be used to investigate effects related to time-resolved hot-spot energy balance. The proposed diagnostic utilizes five fast-rise (∼15 ps) scintillator channels with distinct x-ray filtering. Titanium and stepped aluminum filtering were chosen to maximize detector sensitivity in the 10 keV-20 keV range, as it has been shown that these x rays have similar density and temperature weighting to the emitted deuterium-tritium fusion neutrons. Initial data collected using a prototype nosecone on the existing neutron temporal diagnostic demonstrate the validity of this diagnostic technique. The proposed system will be capable of measuring spatially integrated Te(t) with 20 ps time resolution and <10% uncertainty at peak emission in cryogenic DT implosions.

Plasmids encoding the mucosal chemokines CCL27 and CCL28 are effective adjuvants in eliciting antigen-specific immunity in vivo.

A hurdle facing DNA vaccine development is the ability to generate strong immune responses systemically and at local immune sites. We report a novel systemically administered DNA vaccination strategy using intramuscular codelivery of CCL27 or CCL28, which elicited elevated peripheral IFN-gamma and antigen-specific IgG while driving antigen-specific T-cell secretion of cytokine and antibody production in the gut-associated lymphoid tissue and lung. This strategy resulted in induction of long-lived antibody responses that neutralized influenza A/PR8/34 and protected mice from morbidity and mortality associated with a lethal intranasal viral challenge. This is the first example of the use of CCL27 and CCL28 chemokines as adjuvants to influence a DNA vaccine strategy, suggesting further examination of this approach for manipulation of vaccine-induced immunity impacting both quality and phenotype of responses.

In situ detection and analysis of laser-induced damage on a 1.5-m multilayer-dielectric grating compressor for high-energy, petawatt-class laser systems.

A grating-inspection system and a damage-analysis method have been developed to measure in situ laser-induced damage on a 1.5-m tiled-grating assembly of the OMEGA EP pulse compressor during a 15-ps, 2.2-kJ energy ramp. The beam fluence at which significant damage growth occurred was determined. This is the first report on beam fluence versus laser-induced-damage growth of meter-sized multilayer-dielectric-diffraction gratings. This result was correlated to the damage-probability measurement conducted on a small grating sample and is consistent with the fluence, corresponding to 100% damage probability.

Effects of cigarette smoke on salivary protein tyrosine nitration.

INTRODUCTION: Nitration of tyrosine and tyrosine-containing proteins and their roles in pathophysiology have just recently been reviewed. Despite low yields of tyrosine modifications, nitration of tyrosine residues may inactivate important proteins. Nitrotyrosine can be formed by various nitrating agents, including peroxynitrite. Thus, the occurrence of nitrotyrosine-containing proteins in vivo should be regarded as a general indication of tissue damage induced by reactive nitrogen species such as peroxynitrite. This strongly suggests that peroxynitrite could be formed in vivo under certain pathophysiological conditions. OBJECTIVE: Our aim in this study was to elucidate the effect of cigarette smoke (CS) on nitrotyrosine formation in saliva proteins. METHODS: We exposed saliva to CS, in vitro, and used Western Blotting (WB) and monoclonal anti-nitrotyrosine antibody to assess the level of saliva protein nitration. RESULTS: As saliva contains extensive amounts of nitrites, it was no surprise that at basal levels, saliva proteins, albumin, and α-amylase all were already nitrated. The WB also revealed that with continuous exposure to CS the tyrosine nitration of both albumin and α-amylase is declining significantly after 3 h. A quite similar effect was seen after exposure to aldehydes, but to a less extent as compared to CS. Exposure of nitrotyrosine-modified bovine serum albumin (BSA-N) to aldehydes, produced a similar effect, meaning a decrease in tyrosine nitration. CONCLUSIONS: These findings might be explained by the possible ability of CS aldehydes to reduce protein-bound nitro group to an amine. Another proposed mechanism is that CS unsaturated aldehydes react with proteins mainly through Michael addition reaction; leading to the generation of stable aldehyde-protein adducts (APA). Thus, it may react with nitro groups of saliva proteins, like albumin or α-amylase, to generate APA, which ultimately, may not be recognized by our antibody. Another possible mechanism, is interaction between the aldehyde group with the hydroxyl group of the 3-nitrotyrosine, forming a hemiacetal, which is not recognized by the antibody. This mechanism might explain the difference in the denitration effects caused by the saturated aldehyde acetaldehyde, which exists in large amounts in CS, and unsaturated aldehydes. Therefore, it is possible that the main player in the CS smoke denitration effect on salivary proteins is the aldehyde group and not the double bond of unsaturated aldehydes.

CCR10 expression is required for the adjuvant activity of the mucosal chemokine CCL28 when delivered in the context of an HIV-1 Env DNA vaccine.

An effective prophylactic vaccine targeting HIV must induce a robust humoral response and must direct the bulk of this response to the mucosa-the primary site of HIV transmission. The chemokine, CCL28, is secreted by epithelial cells at mucosal surfaces and recruits' cells expressing its receptor CCR10. CCR10 is predominantly expressed by IgA + ASCs. We hypothesized that co-immunization with plasmid DNA encoding consensus envelope antigens with plasmid-encoded CCL28 would enhance anti-HIV IgA responses at mucosal surfaces. Indeed, animals receiving pCCL28 and pEnvA/C had significantly increased HIV-specific IgA in fecal extract. Surprisingly, CCL28 co-immunization induced a significant increase in anti-HIV IgG in the serum in mice compared to those receiving pEnvA/C alone. These robust antibody responses were not associated with changes in the frequency of germinal center B cells but depended upon the expression of CCR10, as these responses we abolished in CCR10-deficient animals. Finally, immunization with CCL28 led to increased frequencies in HIV-specific CCR10 + and CCR10 + IgA + B cells in the small intestine and Peyer's patches of vaccinated animals as compared to those receiving pEnvA/C alone. These data indicate that CCL28 administration can enhance antigen-specific humoral responses systemically and at mucosal surfaces.

Submolecular features of epitaxially grown PTCDA on Cu(111) analyzed by force field spectroscopy.

Submolecular features of epitaxially grown 3,4,9,10-perylenetetra-carboxylic-dianhydride (PTCDA) on Cu(111) are resolved in non-contact atomic force microscopy topography scans in ultrahigh vacuum. While molecules in the first layer above the Cu substrate are depicted as featureless ovals, the second layer molecules show an intramolecular structure with a height corrugation of up to 40 pm. Force field spectroscopy experiments with submolecular resolution show that the tip-molecule forces differ significantly on the first and second layer molecules. Possible contributions to these force differences from mechanical deformations of the molecules as well as the internal charge density distribution are discussed.