Lung epithelial and endothelial damage, loss of tissue repair, inhibition of fibrinolysis, and cellular senescence in fatal COVID-19.

Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is characterized by respiratory distress, multiorgan dysfunction, and, in some cases, death. The pathological mechanisms underlying COVID-19 respiratory distress and the interplay with aggravating risk factors have not been fully defined. Lung autopsy samples from 18 patients with fatal COVID-19, with symptom onset-to-death times ranging from 3 to 47 days, and antemortem plasma samples from 6 of these cases were evaluated using deep sequencing of SARS-CoV-2 RNA, multiplex plasma protein measurements, and pulmonary gene expression and imaging analyses. Prominent histopathological features in this case series included progressive diffuse alveolar damage with excessive thrombosis and late-onset pulmonary tissue and vascular remodeling. Acute damage at the alveolar-capillary barrier was characterized by the loss of surfactant protein expression with injury to alveolar epithelial cells, endothelial cells, respiratory epithelial basal cells, and defective tissue repair processes. Other key findings included impaired clot fibrinolysis with increased concentrations of plasma and lung plasminogen activator inhibitor-1 and modulation of cellular senescence markers, including p21 and sirtuin-1, in both lung epithelial and endothelial cells. Together, these findings further define the molecular pathological features underlying the pulmonary response to SARS-CoV-2 infection and provide important insights into signaling pathways that may be amenable to therapeutic intervention.

MRI-Derived Sarcopenia Associated with Increased Mortality Following Yttrium-90 Radioembolization of Hepatocellular Carcinoma.

PURPOSE: To evaluate the influence of sarcopenia on survival in patients with hepatocellular carcinoma (HCC) treated with 90Y radioembolization. MATERIALS AND METHODS: This single-center retrospective cohort study analyzed 82 consecutive patients (65 men and 17 women, mean age 65 years, range 31-83 years) with HCC treated with 90Y radioembolization between December 2013 and December 2017. Sarcopenia was assessed on pre-procedure MRI performed within 100 days prior to 90Y radioembolization by segmenting the paraspinal musculature at the level of the superior mesenteric artery origin and subtracting fat-intensity pixels to yield fat-free muscle area (FFMA). Sarcopenia was defined as FFMA ≤31.97 cm2 for men and ≤28.95 cm2 for women. Survival at 90 days, 180 days, 1 year, and 3 years following initial treatment was assessed using medical and public obituary records. RESULTS: Sarcopenia was identified in 30% (25/82) of patients. Death was reported for 49% (32/65) of males and 71% (8/17) of females (mean follow-up 19.6 months, range 21 days-58 months). Patients with sarcopenia were found to have increased mortality at 180 days (31.8% vs. 8.9%) and 1 year (68.2% vs. 21.2%). Sarcopenia was an independent predictor of mortality adjusted for BCLC stage and sub-analysis demonstrated that sarcopenia independently predicted increased mortality for patients with BCLC stage B disease. CONCLUSION: Sarcopenia was associated with increased 180-day and 1-year mortality in HCC patients undergoing 90Y radioembolization. Sarcopenia was an independent predictor of survival adjusted for BCLC stage with significant deviation in the survival curves of BCLC stage B patients with and without sarcopenia.

Comparing cortico-motor hotspot identification methods in the lower extremities post-stroke: MEP amplitude vs. latency.

Transcranial magnetic stimulation (TMS) is a technique used to probe and measure cortico-motor responses of the nervous system. However, lower extremity (LE) specific methodology has been slow to develop. In this retrospective analysis, we investigated what motor evoked potential metric, amplitude (MEPamp) or latency (MEPlat), best distinguished the motor-cortical target, i.e. hotspot, of the tibialis anterior and soleus post-stroke. Twenty-three participants with stroke were included in this investigation. Neuronavigation was used to map hotspots, derived via MEPamp and MEPlat, over a 3cm × 5cm grid. Distances between points with the greatest response within a session and between days were compared. Both criterion, amplitude and latency, provided poor identification of locations between trials within a session, and between multiple visits. Identified hotspots were similar only 15 % and 8% of the time between two assessments within the same session, for amplitude and latency respectively. However, MEPamp was more consistent in identifying hotspots, evidenced by locations being less spatially distant from each other (Amplitude: 1.4 cm (SD 0.10) Latency: 1.7 (SD 1.04), P = 0.008) within a session and between days (Amplitude: 1.3 cm (SD 0.95), Latency 1.9 cm (SD 1.14), P = 0.004). While more work is needed to develop LE specific methodology for TMS, especially as it applies to investigating gait impairments, MEPamp appears to be a more consistent criterion for hotspot identification when compared to MEPlat. It is recommended that future works continue to use MEPamp when identifying tibialis anterior and soleus hotspots using neuronavigation.

Serum concentrations of DDE, PCBs, and other persistent organic pollutants and mammographic breast density in Triana, Alabama, a highly exposed population.

INTRODUCTION: Although some persistent organic pollutants (POPs) are considered human carcinogens, results from studies evaluating exposures and breast cancer risk have been inconsistent, potentially related to varying ages at exposure. Additionally, few studies evaluated the association between POPs exposure and mammographic breast density (MBD), an intermediate biomarker of breast cancer risk. We carried out a cross-sectional study to investigate associations between serum POPs concentrations and MBD measured in 1998 in female residents of Triana, Alabama, in a predominately African American population with high POPs exposures, particularly to p,p'-DDT (1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane). METHODS: We measured lipid-adjusted serum concentrations (ng/g lipid) of p,p'-DDT and its main metabolite p,p'-DDE (1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene), polychlorinated biphenyls (PCBs), ß-hexachlorocyclohexane (ß-HCCH), heptachlor epoxide, oxychlordane, trans-nonachlor, mirex, and aldrin for each woman in our study (n = 210). We also measured two MBD metrics, percent MBD (%MBD) and area of MBD (aMBD). Using adjusted Spearman correlation coefficients (rs) we evaluated correlations between %MBD and aMBD with individual POPs in the overall population and by age group (19-40, 41-54, and 55-91 years) and also estimated adjusted mean measures of MBD with 95% confidence intervals across tertiles of analytes using generalized linear models (GLM). We calculated p-values for multiplicative interaction by age group using GLM. Additional analyses excluded women with current hormone replacement therapy (HRT) use and evaluated early-life exposure (prior to age 18) during the heaviest contamination period in Triana (1947-90). RESULTS: Among all women, we found no correlation between p,p'-DDE and %MBD, but after age stratification and exclusion of HRT users, there was a suggestion of a difference by age group, with younger women having a weak positive correlation (rs = 0.12, p = 0.37) and older women having a weak negative correlation (rs = -0.12, p = 0.43); pinteraction = 0.06. In contrast, PCBs were weakly positively correlated with %MBD among all women, with the correlation magnitudes increasing after excluding current HRT users (rs-total PCBs = 0.17, p = 0.03). After age stratification and exclusion of HRT users, correlations for PCBs were higher among younger and middle-age women, with only a handful of these correlations being statistically significant. For ß-HCCH, the strongest finding was a negative correlation among older women (rs = -0.26, p = 0.07). Correlations were positive predominantly in the younger age group for heptachlor epoxide (rs = 0.27, p = 0.04), oxychlordane (rs = 0.35, p = 0.006), and trans-nonachlor (rs = 0.37, p = 0.003), and largely null for the middle and older age groups; pinteraction range: 0.03-0.05. Similar patterns were found in GLM analyses using tertiles of exposure and aMBD as the metric for MBD. Women exposed during the heaviest chemical contamination period in Triana prior to age 18 had positive correlations between %MBD and PCBs, heptachlor epoxide, mirex, oxychlordane, and trans-nonachlor. CONCLUSIONS: In this population, despite high exposures to p,p'-DDT and thus high serum concentrations of its main metabolite, p,p'-DDE, we did not find strong evidence of a positive association with MBD. In fact, there was some evidence of a negative association among older women for p,p'-DDE; a similar pattern was found for ß-HCCH. However, younger women with higher serum levels of PCBs, heptachlor epoxide, oxychlordane, and trans-nonachlor, who were likely exposed in early life, had higher MBD. These findings should be replicated in larger studies.

Liver-specific overexpression of LPCAT3 reduces postprandial hyperglycemia and improves lipoprotein metabolic profile in mice.

Previous studies have shown that group 1B phospholipase A2-mediated absorption of lysophospholipids inhibits hepatic fatty acid ß-oxidation and contributes directly to postprandial hyperglycemia and hyperlipidemia, leading to increased risk of cardiometabolic disease. The current study tested the possibility that increased expression of lysophosphatidylcholine acyltransferase-3 (LPCAT3), an enzyme that converts lysophosphatidylcholine to phosphatidylcholine in the liver, may alleviate the adverse effects of lysophospholipids absorbed after a lipid-glucose mixed meal. The injection of an adenovirus vector harboring the human LPCAT3 gene into C57BL/6 mice increased hepatic LPCAT3 expression fivefold compared with mice injected with a control LacZ adenovirus. Postprandial glucose tolerance tests after feeding these animals with a bolus lipid-glucose mixed meal revealed that LPCAT3 overexpression improved postprandial hyperglycemia and glucose tolerance compared with control mice with LacZ adenovirus injection. Mice with LPCAT3 overexpression also showed reduced very low density lipoprotein production and displayed elevated levels of the metabolic- and cardiovascular-protective large apoE-rich high density lipoproteins in plasma. The mechanism underlying the metabolic benefits of LPCAT3 overexpression was shown to be due to the alleviation of lysophospholipid inhibition of fatty acid ß-oxidation in hepatocytes. Taken together, these results suggest that specific LPCAT3 induction in the liver may be a viable strategy for cardiometabolic disease intervention.

Outcomes following laparoscopic transhiatal esophagectomy for esophageal cancer.

BACKGROUND: Most published minimally invasive esophagectomy techniques involve a multiple field approach, including laparoscopic and thoracoscopic esophageal mobilization. Laparoscopic transhiatal esophagectomy (LTE) should potentially reduce the complications associated with thoracotomy. This study aims to compare outcomes of LTE with open transhiatal esophagectomy (OTE) and en-bloc esophagectomy (EBE). METHODS: Retrospective chart review was performed on all patients who had an LTE for cancer between July 2008 and July 2012 at our institution. Data was compared with an historic cohort of patients who underwent OTE and EBE at the same institution from July 2002 to July 2008. RESULTS: There were 33 patients with LTE, compared with 60 patients with OTE and 139 with EBE. The presence of minor operative complications was similar (p = 0.36), but major complications were significantly less common in the LTE group (12, 23 and 33 %, respectively; p = 0.04). The median number of blood transfusions during hospitalization was significantly lower in the LTE group (0, 2.5 and 3, respectively; p = 0.005). Median tumor size was significantly smaller (1.5, 2.2, and 3 cm, respectively; p = 0.03), but the LTE group had a significantly higher percentage of patients with neoadjuvant treatment (39, 14 and 29 %, respectively; p = 0.008). Median lymph node yield for LTE was lower (24, 36 and 48, respectively; p < 0.0001), but the percentage of patients with positive nodes was similar (33, 33 and 39 %, respectively; p = 0.69). Mortality was equivalent among the groups (0, 2 and 4 %, respectively; p = 0.38). The median LOS for the LTE group was significantly lower (10, 13 and 15 days, respectively; p < 0.0001). Overall survival was not different between the three groups (p = 0.65), with median survival at 24 months of 70, 65 and 65 %, respectively. CONCLUSION: LTE can be performed safely with less major complications and shorter hospital stay than open esophagectomy. The reduced lymph-node harvest did not impact overall survival.

Pancreatic acinar cell-specific overexpression of group 1B phospholipase A2 exacerbates diet-induced obesity and insulin resistance in mice.

Genome-wide association studies have identified significant association between polymorphisms of the Group 1B phospholipase A(2) (PLA2G1B) gene and central obesity in humans. Previous studies have shown that Pla2g1b inactivation decreases post-prandial lysophospholipid absorption, and as a consequence increases hepatic fatty acid oxidation and protects against diet-induced obesity and glucose intolerance in mice. The present study showed that transgenic mice with pancreatic acinar cell-specific overexpression of the human PLA2G1B gene gained significantly more weight and displayed elevated insulin resistance characteristics, such as impaired glucose tolerance, compared with wild-type (WT) mice, when challenged with a high-fat/carbohydrate diet. Pre- and post-prandial plasma ß-hydroxybutyrate levels were also lower, indicative of decreased hepatic fatty acid oxidation, in the hypercaloric diet-fed PLA2G1B transgenic mice. These, along with earlier observations of Pla2g1b-null mice, document that Pla2g1b expression level is an important determinant of susceptibility to diet-induced obesity and diabetes, suggesting that the relationship between PLA2G1B polymorphisms and obesity may be due to differences in PLA2G1B expression levels between these individuals. The ability of pancreas-specific overexpression of PLA2G1B to promote obesity and glucose intolerance suggests that target phospholipase activity in the digestive tract with non-absorbable inhibitors should be considered as a therapeutic option for metabolic disease therapy.

An efficient method-of-lines simulation procedure for organic semiconductor devices.

We describe an adaptive grid method-of-lines (MOL) solution procedure for modelling charge transport and recombination in organic semiconductor devices. The procedure we describe offers an efficient, robust and versatile means of simulating semiconductor devices that allows for much simpler coding of the underlying equations than alternative simulation procedures. The MOL technique is especially well-suited to modelling the extremely stiff (and hence difficult to solve) equations that arise during the simulation of organic-and some inorganic-semiconductor devices. It also has wider applications in other areas, including reaction kinetics, combustion and aero- and fluid dynamics, where its ease of implementation also makes it an attractive choice. The MOL procedure we use converts the underlying semiconductor equations into a series of coupled ordinary differential equations (ODEs) that can be integrated forward in time using an appropriate ODE solver. The time integration is periodically interrupted, the numerical solution is interpolated onto a new grid that is better matched to the solution profile, and the time integration is then resumed on the new grid. The efficacy of the simulation procedure is assessed by considering a single layer device structure, for which exact analytical solutions are available for the electric potential, the charge distributions and the current-voltage characteristics. Two separate state-of-the-art ODE solvers are tested: the single-step Runge-Kutta solver Radau5 and the multi-step solver ODE15s, which is included as part of the Matlab ODE suite. In both cases, the numerical solutions show excellent agreement with the exact analytical solutions, yielding results that are accurate to one part in 1 x 10(4). The single-step Radau5 solver, however, is found to provide faster convergence since its efficiency is not compromised by the periodic interruption of the time integration when the grid is updated.

Ozone and hydrogen peroxyacetic acid treatment to reduce or remove EBDCs and ETU residues in a solution.

Laboratory studies were conducted in a model system to determine the effects of ozone (1 and 3 ppm) and hydrogen peroxyacetic acid (HPA) (5 and 50 ppm) at pH 4.6, 7.0, and 10.7 and at 10 and 21 degrees C on the degradation of mancozeb in solution over a 30 min period. All samples were analyzed for residues by GLC and HPLC. Ozonation and HPA treatment were effective in degrading mancozeb in solution. Rate of mancozeb degradation was dependent on pH, with the fastest rate at pH 7.0. Ethylenethiourea (ETU) residue concentrations in the mancozeb solutions were monitored over 60 min. Under controlled conditions, the ETU residue concentrations increased during the 15 min reaction time and then decreased for all three pH values. At 3 ppm of ozone treatment, no ETU residues were detected at all three pH ranges after 15 min of reaction time. Degradation of ETU by HPA was greatest at pH 4.6, and no ETU residues remained after 5 min at either 5 or 50 ppm. The results showed that ozone and HPA gave excellent degradation of pesticide residues depending on pH and temperature. These experiments indicated the potential for the removal of pesticide residues on fruit and in processed products.

Pre-treatment affinity for LJP 394 influences pharmacodynamic response in lupus patients.

Five prospective clinical studies in lupus patients have shown that LJP 394 can reduce circulating anti-dsDNA antibody levels without causing generalized immunosuppression. The compound is currently being evaluated in a phase III clinical trial for the prevention of renal flares in patients with high-affinity antibodies to LJP 394 and a history of lupus nephritis. The current study analyzed the affinity of patient IgG for LJP 394 prior to and following 4 months of treatment with LJP 394 to determine if pretreatment affinity influenced pharmacodynamic response. Patient serum samples from a multicenter, double-blind, placebo-controlled trial were evaluated prior to and following 4 months of weekly, biweekly or monthly treatment with placebo (n = 9) or weekly treatment with 10 mg LJP 394 (n = 6) or 50 mg LJP 394 (n = 4). After treatment there was a dose-dependent reduction in affinity in the 10 mg/week and 50 mg/week groups (P < 0.05 and P < 0.01, respectively), whereas the placebo group was unchanged. This study demonstrates that weekly treatment with LJP 394 produces a dose-dependent reduction in titer-weighted average affinity. These results suggest it may be possible to use an affinity assay to define prospectively patients that are most likely to exhibit the desired pharmacodynamic response to LJP 394.

Postharvest treatments for the reduction of mancozeb in fresh apples.

The objective of this study was to determine the effectiveness of chlorine, chlorine dioxide, ozone, and hydrogen peroxyacetic acid (HPA) treatments on the degradation of mancozeb and ethylenethiourea (ETU) in apples. This study was based on model experiments at neutral pH and temperature. Fresh apples were treated with two different levels of mancozeb (1 and 10 microg/mL). Several of the treatments were effective in reducing or removing mancozeb and ETU residues on spiked apples. Mancozeb residues decreased 56-99% with chlorine and 36-87% with chlorine dioxide treatments. ETU was completely degraded by 500 ppm of calcium hypochlorite and 10 ppm of chlorine dioxide at a 1 ppm spike level. However, at a 10 ppm spike level, the effectiveness of ETU degradation was lower than observed at 1 ppm level. Mancozeb residues decreased 56-97% with ozone treatment. At 1 and 3 ppm of ozone, no ETU residue was detected at 1 ppm of spiked mancozeb after both 3 and 30 min. HPA was also effective in degrading the mancozeb residues, with 44-99% reduction depending on treatment time and HPA concentrations. ETU was completely degraded at 500 ppm of HPA after 30 min of reaction time. These treatments indicated good potential for the removal of pesticide residues on fruit and in processed products.

Pharmacokinetics and pharmacodynamics of ranitidine in critically ill children.

OBJECTIVE: To determine the pharmacokinetics and pharmacodynamics of ranitidine in critically ill children and to design a dosage regimen that achieves a gastric pH > or =4. DESIGN: Prospective, open-label, pharmacokinetic-pharmacodynamic study. SETTING: Pediatric intensive care unit in a tertiary care children's hospital. PATIENTS: Mechanically ventilated, critically ill children > or =10 kg who required intravenous ranitidine for stress ulcer prophylaxis. INTERVENTIONS: Ranitidine pharmacokinetics were determined after a single intravenous dose. Gastric pH was monitored hourly via nasogastric pH probe. After the last blood sample, patients received an intravenous bolus of ranitidine (0.5 mg/kg) followed by a continuous infusion (0.1 mg x kg(-1) x hr(-1)). The infusion was increased incrementally (0.05 mg x kg(-1) x hr(-1)) until reaching gastric pH > or =4 for > or =75% of a 24-hr period, after which steady-state plasma concentrations were measured. Plasma concentrations were analyzed by high-pressure liquid chromatography. MEASUREMENTS AND MAIN RESULTS: Twenty-three children (ranging in age from 1.4 to 17.1 yrs) were studied. Pharmacokinetic variables included a clearance of 511.7 +/- 219.7 mL x kg(-1) x hr(-1), volume of distribution of 1.53 +/- 0.99 L/kg, and half-life of 3.01 +/- 1.35 hrs. After the single intravenous dose (1.52 +/- 0.47 mg/kg), gastric pH increased from 1.6 +/- 1.0 to 5.1 +/- 1.1 (p <.001), which was associated with a plasma concentration of 373 +/- 257 ng/mL. Based on the pharmacokinetic variables, the dose of intravenous ranitidine required to target 373 ng/mL as the average steady-state concentration is 1.5 mg/kg administered every 8 hrs. During the continuous infusion, the mean steady-state ranitidine concentration associated with gastric pH > or =4 was 287 +/- 133 ng/mL. This concentration may be achieved with an intravenous loading dose of 0.45 mg/kg followed by a continuous infusion of 0.15 mg x kg(-1) x hr(-1). CONCLUSIONS: The pharmacokinetics of ranitidine in critically ill children are variable. The description of ranitidine's pharmacokinetics and pharmacodynamics in this study may used to design an initial ranitidine dosage regimen that targets a gastric pH > or =4. Thereafter, gastric pH should be monitored and the dose of ranitidine adjusted accordingly.

Driven electron transfer in an environment with slow and fast degrees of freedom.

Driven electron transfer in a polar medium with slow and fast degrees of freedom is studied in the framework of a spin-boson Hamiltonian. Evolution dynamics is rigorously found when omega(s)(c)/(Gamma(a))sqrt[E(rs)/kT]<<1, where omega(s)(c) is the Debye cutoff frequency in the spectral function for the slow modes, E(rs) is the reorganization energy of slow degrees of freedom, and Gamma(-1)(a) is the reaction time dependent on the laser intensity parameter a=muE(0)/Planck's over 2piomega. Here omega and E0 are the frequency and the amplitude of a cw electric field, and mu is the electron dipole moment difference between the initial and final states. The master equation is derived for an arbitrary driving force affecting both the transition matrix element and the potential energy. For a cw electric field, the time dependent probability of staying at the product state, P1(t), is shown to be strongly dependent on the field intensity parameter a: P1(a,t) approximately (Gamma(m(1),m(2))t)(-E(rf)/E(rs)) or P1(a,t) approximately (Gamma(m(0))t)(-E(rf)/E(rs)), double or single resonances, respectively. Here E(rf) is the reorganization energy of fast degrees of freedom, Gamma(m(1),m(2)) approximately J(2)(m(1))(a)+J(2)(m(2))(a), and Gamma(m(0)) approximately J(2)(m(0))(a), where J(a) is a Bessel function. By changing the parameter a, one is able to manipulate the rate and direction of the reaction. When J(2)(m(0))(a) is close to zero the reaction is slow. Hence, slow modes turn out to be fast. This changes the character of the evolution dynamics from non- to mono- exponential decay, respectively. For the double resonance, the equilibrium constant is studied with the field intensity. It is shown that the reaction is almost insensitive to temperature. However, it strongly depends on the reaction heat, which provides a condition for the resonance.

Treatment of systemic lupus erythematosus with LJP 394.

OBJECTIVE: LJP 394 is a novel therapy under development for the treatment of systemic lupus erythematosus (SLE). We investigated the optimal LJP 394 dosing regimen required to maximally reduce serum dsDNA antibodies. We also evaluated the safety and tolerability of repeated doses of LJP 394 as well as the effects of therapy on SLE related disease activity and health related quality of life. METHODS: This was a multicenter, partially randomized, placebo controlled, double blind, dose-ranging trial. Study drug or placebo was administered at weekly, biweekly, or monthly intervals for a total of 17, 9, or 5 doses, respectively. Fifty-eight patients were randomly assigned to receive 1, 10, or 50 mg LJP 394 or placebo. After a 2 month pretreatment period, dosing visits continued for 16 weeks, after which there was a 2 month posttreatment period. RESULTS: The greatest reductions in mean dsDNA antibody titers were observed in the group of patients who received 50 mg LJP 394 weekly (38.1% and 37.1 % at Weeks 16 and 24, respectively). A reduction (29.3%) in dsDNA antibody titers was also observed at Week 24 in the group of patients who received 10 mg LJP 394 weekly. The frequencies of adverse events were comparable in the placebo and active treatment groups. CONCLUSION: This clinical trial, in which a large number of patients with SLE were treated with LJP 394, expanded the safety profile of LJP 394 and demonstrated its capacity to reduce dsDNA antibodies.