Scientific Opportunities with an X-ray Free-Electron Laser Oscillator

An X-ray free-electron laser oscillator (XFELO) is a new type of hard X-ray source that would produce fully coherent pulses with meV bandwidth and stable intensity. The XFELO complements existing sources based on self-amplified spontaneous emission (SASE) from high-gain X-ray free-electron lasers (XFEL) that produce ultra-short pulses with broad-band chaotic spectra. This report is based on discussions of scientific opportunities enabled by an XFELO during a workshop held at SLAC on June 29 - July 1, 2016Comment: 21 pages, 12 figure

Impact of Hepatopulmonary Syndrome on Quality of Life and Survival in Liver Transplant Candidates

Hepatopulmonary syndrome (HPS) affects 10%–30% of patients with cirrhosis and portal hypertension, but the impact on functional status, quality of life, and survival is poorly defined. We assessed the impact of HPS in patients evaluated for liver transplantation

Quantitative Evidence for Revising the Definition of Primary Graft Dysfunction after Lung Transplant

RATIONALE: Primary graft dysfunction (PGD) is a form of acute lung injury that occurs after lung transplantation. The definition of PGD was standardized in 2005. Since that time, clinical practice has evolved, and this definition is increasingly used as a primary endpoint for clinical trials; therefore, validation is warranted. OBJECTIVES: We sought to determine whether refinements to the 2005 consensus definition could further improve construct validity. METHODS: Data from the Lung Transplant Outcomes Group multicenter cohort were used to compare variations on the PGD definition, including alternate oxygenation thresholds, inclusion of additional severity groups, and effects of procedure type and mechanical ventilation. Convergent and divergent validity were compared for mortality prediction and concurrent lung injury biomarker discrimination. MEASUREMENTS AND MAIN RESULTS: A total of 1,179 subjects from 10 centers were enrolled from 2007 to 2012. Median length of follow-up was 4 years (interquartile range = 2.4-5.9). No mortality differences were noted between no PGD (grade 0) and mild PGD (grade 1). Significantly better mortality discrimination was evident for all definitions using later time points (48, 72, or 48-72 hours; P < 0.001). Biomarker divergent discrimination was superior when collapsing grades 0 and 1. Additional severity grades, use of mechanical ventilation, and transplant procedure type had minimal or no effect on mortality or biomarker discrimination. CONCLUSIONS: The PGD consensus definition can be simplified by combining lower PGD grades. Construct validity of grading was present regardless of transplant procedure type or use of mechanical ventilation. Additional severity categories had minimal impact on mortality or biomarker discrimination

The relationship between plasma lipid peroxidation products and primary graft dysfunction after lung transplantation is modified by donor smoking and reperfusion hyperoxia

BACKGROUND: Donor smoking history and higher fraction of inspired oxygen (FIO2) at reperfusion are associated with primary graft dysfunction (PGD) after lung transplantation. We hypothesized that oxidative injury biomarkers would be elevated in PGD, with higher levels associated with donor exposure to cigarette smoke and recipient hyperoxia at reperfusion. METHODS: We performed a nested case-control study of 72 lung transplant recipients from the Lung Transplant Outcomes Group cohort. Using mass spectroscopy, F2-isoprostanes and isofurans were measured in plasma collected after transplantation. Cases were defined in 2 ways: grade 3 PGD present at day 2 or day 3 after reperfusion (severe PGD) or any grade 3 PGD (any PGD). RESULTS: There were 31 severe PGD cases with 41 controls and 35 any PGD cases with 37 controls. Plasma F2-isoprostane levels were higher in severe PGD cases compared with controls (28.6 pg/ml vs 19.8 pg/ml, p = 0.03). Plasma F2-isoprostane levels were higher in severe PGD cases compared with controls (29.6 pg/ml vs 19.0 pg/ml, p = 0.03) among patients reperfused with FIO2 >40%. Among recipients of lungs from donors with smoke exposure, plasma F2-isoprostane (38.2 pg/ml vs 22.5 pg/ml, p = 0.046) and isofuran (66.9 pg/ml vs 34.6 pg/ml, p = 0.046) levels were higher in severe PGD compared with control subjects. CONCLUSIONS: Plasma levels of lipid peroxidation products are higher in patients with severe PGD, in recipients of lungs from donors with smoke exposure, and in recipients exposed to higher Fio2 at reperfusion. Oxidative injury is an important mechanism of PGD and may be magnified by donor exposure to cigarette smoke and hyperoxia at reperfusion

Sterile Protection against Plasmodium knowlesi in Rhesus Monkeys from a Malaria Vaccine: Comparison of Heterologous Prime Boost Strategies

Using newer vaccine platforms which have been effective against malaria in rodent models, we tested five immunization regimens against Plasmodium knowlesi in rhesus monkeys. All vaccines included the same four P. knowlesi antigens: the pre-erythrocytic antigens CSP, SSP2, and erythrocytic antigens AMA1, MSP1. We used four vaccine platforms for prime or boost vaccinations: plasmids (DNA), alphavirus replicons (VRP), attenuated adenovirus serotype 5 (Ad), or attenuated poxvirus (Pox). These four platforms combined to produce five different prime/boost vaccine regimens: Pox alone, VRP/Pox, VRP/Ad, Ad/Pox, and DNA/Pox. Five rhesus monkeys were immunized with each regimen, and five Control monkeys received a mock vaccination. The time to complete vaccinations was 420 days. All monkeys were challenged twice with 100 P. knowlesi sporozoites given IV. The first challenge was given 12 days after the last vaccination, and the monkeys receiving the DNA/Pox vaccine were the best protected, with 3/5 monkeys sterilely protected and 1/5 monkeys that self-cured its parasitemia. There was no protection in monkeys that received Pox malaria vaccine alone without previous priming. The second sporozoite challenge was given 4 months after the first. All 4 monkeys that were protected in the first challenge developed malaria in the second challenge. DNA, VRP and Ad5 vaccines all primed monkeys for strong immune responses after the Pox boost. We discuss the high level but short duration of protection in this experiment and the possible benefits of the long interval between prime and boost

COVID-19 symptoms at hospital admission vary with age and sex: results from the ISARIC prospective multinational observational study

Background: The ISARIC prospective multinational observational study is the largest cohort of hospitalized patients with COVID-19. We present relationships of age, sex, and nationality to presenting symptoms. Methods: International, prospective observational study of 60 109 hospitalized symptomatic patients with laboratory-confirmed COVID-19 recruited from 43 countries between 30 January and 3 August 2020. Logistic regression was performed to evaluate relationships of age and sex to published COVID-19 case definitions and the most commonly reported symptoms. Results: ‘Typical’ symptoms of fever (69%), cough (68%) and shortness of breath (66%) were the most commonly reported. 92% of patients experienced at least one of these. Prevalence of typical symptoms was greatest in 30- to 60-year-olds (respectively 80, 79, 69%; at least one 95%). They were reported less frequently in children (≤ 18 years: 69, 48, 23; 85%), older adults (≥ 70 years: 61, 62, 65; 90%), and women (66, 66, 64; 90%; vs. men 71, 70, 67; 93%, each P &lt; 0.001). The most common atypical presentations under 60 years of age were nausea and vomiting and abdominal pain, and over 60 years was confusion. Regression models showed significant differences in symptoms with sex, age and country. Interpretation: This international collaboration has allowed us to report reliable symptom data from the largest cohort of patients admitted to hospital with COVID-19. Adults over 60 and children admitted to hospital with COVID-19 are less likely to present with typical symptoms. Nausea and vomiting are common atypical presentations under 30 years. Confusion is a frequent atypical presentation of COVID-19 in adults over 60 years. Women are less likely to experience typical symptoms than men

Acute Demyelinating Polyneuropathy after Lung Transplantation: Guillain-Barré Syndrome or Tacrolimus Toxicity?

Guillain-Barré syndrome (GBS) has been described after solid organ and bone marrow transplantation mostly due to viral infections and possibly calcineurin inhibitors. Incidence after bone marrow transplant is 0.3–0.7%, though incidence in other transplants is not well known. We present the first description of tacrolimus associated GBS in lung transplant recipients in the English language literature. The pathophysiology of tacrolimus-induced polyneuropathy is not known, but some have hypothesized that tacrolimus induces an inflammatory phenomenon by differential effects on T cell subsets. Diagnosis of association may be challenging and requires high index of suspicion. The optimal treatment of GBS-associated with tacrolimus after lung transplantation is unknown, although drug discontinuation may result in improvement in some patients, while some reports suggest that the use of IVIG and/or plasmapheresis may be helpful and safe in organ transplant recipients with severe symptoms

Pulmonary artery enlargement is associated with pulmonary hypertension and decreased survival in severe cystic fibrosis: A cohort study.

BackgroundPulmonary artery (PA) enlargement, defined as pulmonary artery to ascending aorta diameter ratio (PA:A)>1 on computed tomography (CT), is a marker of pulmonary vascular disease in chronic lung diseases. PA enlargement is prevalent in cystic fibrosis (CF), but its relationship to hemodynamics and prognostic utility in severe CF are unknown. We hypothesized that the PA:A would have utility in identifying pulmonary hypertension (PH) in severe CF and that PA enlargement would be associated with reduced transplant-free survival.MethodsWe conducted a retrospective study of adults with CF undergoing lung transplant evaluation at a single center between 2000 and 2015. CT, right heart catheterization (RHC), and clinical data were collected. The PA:A was measured from a single CT slice. We measured associations between PA:A and invasive hemodynamic parameters including PH defined as a mPAP ≥25mmHg using adjusted linear and logistic regression models. Kaplan-Meier and adjusted Cox regression models were used to measure associations between PA:A>1, RHC-defined PH, and transplant-free survival in severe CF.ResultsWe analyzed 78 adults with CF that had CT scans available for review, including 44 that also had RHC. RHC-defined PH defined as a mPAP ≥25mmHg was present in 36% of patients with CF undergoing transplant evaluation. The PA:A correlated with mPAP (r = 0.73; 95% CI 3.87-7.80; p1 was an independent predictor of PH (aOR 4.50; 95% CI 1.05-19.2; p = 0.042). PA:A>1 was independently associated with increased hazards for death or transplant (aHR 2.69; 95% CI 1.41-5.14; P = 0.003). The presence of mPAP ≥25mmHg was independently associated with decreased survival in this cohort.ConclusionsPA enlargement is associated with pulmonary hemodynamics and PH in severe CF. PA enlargement is an independent prognostic indicator of PH and decreased survival in this population

Standard versus High-Dose CVVHDF for ICU-Related Acute Renal Failure

The effect of dosage of continuous venovenous hemodiafiltration (CVVHDF) on survival in patients with acute renal failure (ARF) is unknown. In this study, 200 critically ill patients with ARF were randomly assigned to receive CVVHDF with prefilter replacement fluid at an effluent rate of either 35 ml/kg per h (high dosage) or 20 ml/kg per h (standard dosage). The primary study outcome, survival to the earlier of either intensive care unit discharge or 30 d, was 49% in the high-dosage arm and 56% in the standard-dosage arm (odds ratio 0.75; 95% confidence interval 0.43 to 1.32; P = 0.32). Among hospital survivors, 69% of those in the high-dosage arm recovered renal function compared with 80% of those in the standard-dosage arm (P = 0.29); therefore, a difference in patient survival or renal recovery was not detected between patients receiving high-dosage or standard-dosage CVVHDF