With rapid advancements in imaging technology, cardiac computed tomography (CT) and magnetic resonance (MR) imaging are increasingly being used for anatomic evaluation, functional assessment, and ...pathologic diagnosis of the pulmonary valve and right ventricle. MR imaging is especially helpful in evaluating postoperative pulmonary valve function and grading of pulmonary regurgitation. On the other hand, CT has the advantage of high-resolution isovolumetric whole-chest coverage and is able to depict anatomic detail of the pulmonary valve, perivalvular structures, and pulmonary artery branches.
The caspase-recruitment domain-containing adaptor protein CARD9 regulates the innate signaling responses to fungal infection. Here we show that CARD9 is required for innate immune responses against ...intracellular pathogens. We generated Card9(-/-) mice and found that CARD9-deficient macrophages had defects in activation of the kinases p38 and Jnk but not of transcription factor NF-kappaB after bacterial and viral infection. CARD9-deficient mice failed to clear infection and showed altered cytokine production after challenge with Listeria monocytogenes. In wild-type cells, we found CARD9 inducibly associated with both the intracellular 'biosensor' Nod2 and the serine-threonine kinase RICK. Our data demonstrate that CARD9 has a critical function in Nod2-mediated activation of p38 and Jnk in innate immune responses to intracellular pathogens.
In 2012, two Kaiser Permanente Northern California (KPNC) hospitals began offering outpatient cervical ripening with oral misoprostol under a study protocol. We evaluated inpatient time from ...admission to delivery and adverse maternal and neonatal outcomes associated with outpatient use of misoprostol for cervical ripening among low-risk women with term pregnancies.
We conducted a retrospective cohort study comparing three groups: women who received misoprostol (1) outpatient, under a study protocol; (2) inpatient, at the study sites; and (3) inpatient, at all KPNC hospitals. Data were obtained from between 2012 and 2017. The primary outcome was time from inpatient admission to delivery. Secondarily, we evaluated maternal and neonatal outcomes, including the duration and maximum rate of oxytocin administered, rate of cesarean delivery, incidence of chorioamnionitis and blood transfusion, Apgar scores, and neonatal intensive care unit admissions. Demographic and clinical characteristics and outcomes of the outpatient group were compared with both inpatient misoprostol groups using the appropriate statistical test. Variables included in the regression analysis were either statistically significant in the bivariate analyses or have been reported in the literature to be potential confounders: maternal age at admission, race/ethnicity, body mass index, cervical dilation at initial misoprostol, and parity.
We analyzed data from 10,253 patients: (1) 345 outpatients, under a study protocol; (2) 1,374 inpatients, at the study sites; and (3) 9,908 inpatients, at all the Kaiser hospitals. Women in the outpatient group were more likely to be white than both inpatient groups (63.3 vs. 56.3% at study sites and 47.1% in all hospitals,
0.002 and <0.001, respectively); other demographics were clinically comparable. Most women undergoing labor induction were nulliparous; however, a greater proportion in the outpatient group were nulliparous compared with inpatient groups (70.8 vs. 61.8% and 64.3%,
= 0.002 and 0.01). On inpatient admission for delivery, women who received outpatient misoprostol were more likely to have a cervical dilation of ≥3 cm (39.8 vs. 12.5% at study sites and 9.7% at all KPNC hospitals,
< 0.001 for both). The outpatient group had a shorter mean time between admission and delivery (23.6 vs. 29.4 at study sites and 29.8 hours at all KPNC,
< 0.001 for both). The adjusted estimated mean difference between the outpatient and inpatient group at all the Kaiser hospitals in time from admission to delivery was -6.48 hours (
< 0.001), and the adjusted estimated mean difference in cervical dilation on admission was +1.02 cm (
< 0.001). There was no difference in cesarean delivery rates between groups. The rate of chorioamnionitis in the outpatient group was higher compared with inpatients at all hospitals (17.7 vs. 10.6%,
0
001), but similar when compared with the inpatients at the study sites (17.7 vs. 15.4%,
= 0.29).
Outpatient use of misoprostol for cervical ripening under the study protocol was associated with reduced inpatient time from admission to delivery compared with inpatient misoprostol. Although there was a higher rate of chorioamnionitis among outpatients under the study protocol compared with inpatients at all hospitals, there was no difference when compared with inpatients at the study sites. There was no difference in rates of cesarean delivery or maternal or neonatal complications with outpatient misoprostol.
· Outpatient misoprostol patients had 6.46 fewer hours from admission to delivery compared with inpatients at all hospitals.. · There was no difference in the rate of cesareans between the outpatient versus inpatient misoprostol groups.. · Other maternal and neonatal complications were low and comparable among outpatients and inpatients who received misoprostol; this study was not large enough to assess rare safety outcomes..
The pattern recognition receptors TLR2 and Dectin-1 play key roles in coordinating the responses of macrophages and dendritic cells (DC) to fungi. Induction of proinflammatory cytokines is instructed ...by signals from both TLR2 and Dectin-1. A recent report identified a role for CARD9 in innate anti-fungal responses, demonstrating CARD9-Bcl10-mediated activation of NF-kappaB and proinflammatory cytokine induction in murine bone marrow-derived DC stimulated via Dectin-1. We now report that Dectin-1-CARD9 signals fail to activate NF-kappaB and drive TNF-alpha induction in murine bone marrow-derived macrophages. However, priming of bone marrow-derived macrophages with GM-CSF or IFN-gamma permits Dectin-1-CARD9-mediated TNF-alpha induction. Analysis of other macrophage/DC populations revealed further variation in the ability of Dectin-1-CARD9 signaling to drive TNF-alpha production. Resident peritoneal cells and alveolar macrophages produce TNF-alpha upon Dectin-1 ligation, while thioglycollate-elicited peritoneal macrophages and Flt3L-derived DC do not. We present data demonstrating that CARD9 is recruited to phagosomes via its CARD domain where it enhances TLR-induced cytokine production even in cells in which Dectin-1 is insufficient to drive cytokine production. In such cells, Dectin-1, CARD9, and Bcl10 levels are not limiting, and data indicate that these cells express additional factors that restrict Dectin-1-CARD9 signaling for TNF-alpha induction.
It is important to know the contribution of specific allergens to a complex allergenic extract and to have a dependable method to assess the effector activity of an extract specifically depleted of ...that allergen. We have previously shown that removal of the major peanut allergen, Ara h 2, from a crude peanut extract (CPE) minimally altered the effector activity of the extract. Here we describe in detail the methodology used to generate specific rabbit anti-peptide antibodies to remove a related peanut allergen, Ara h 6, from CPE and describe an improvement in the RBL SX-38 cell assay used to assess the effector activity of treated extracts. Our results show that although Ara h 2 and Ara h 6 can be selectively removed from a CPE, removal of each alone from a CPE had no significant effect on the effector activity. However, removal of Ara h 2 and Ara h 6 together significantly reduced the effector activity of CPE.
► Immunodepletion of Ara h 2 and Ara h 6 from a crude peanut extract (CPE). ► Improvement in the RBL SX-38 cell assay used to assess peanut allergens. ► Removal of Ara h 2 and Ara h 6 together reduced the effector activity of a CPE.
Crystal chemical algorithms were used to estimate the chemical composition of selected mineral phases observed with the CheMin X-ray diffractometer onboard the NASA Curiosity rover in Gale crater, ...Mars. The sampled materials include two wind-blown soils, Rocknest and Gobabeb, six mudstones in the Yellowknife Bay formation (John Klein and Cumberland) and the Murray formation (Confidence Hills, Mojave2, and Telegraph Peak), as well as five sandstones, Windjana and the samples of the unaltered Stimson formation (Big Sky and Okoruso) and the altered Stimson formation (Greenhorn and Lubango). The major mineral phases observed with the CheMin instrument in the Gale crater include plagioclase, sanidine, P21/c and C2/c clinopyroxene, orthopyroxene, olivine, spinel, and alunite-jarosite group minerals. The plagioclase analyzed with CheMin has an overall estimated average of An40(11) with a range of An30(8) to An63(6). The soil samples, Rocknest and Gobabeb, have an average of An56(8) while the Murray, Yellowknife Bay, unaltered Stimson, and altered Stimson formations have averages of An38(2), An37(5), An45(7), and An35(6), respectively. Alkali feldspar, specifically sanidine, average composition is Or74(17) with fully disordered Al/Si. Sanidine is most abundant in the Wind-jana sample (∼26 wt% of the crystalline material) and is fully disordered with a composition of Or87(5). The P21/c clinopyroxene pigeonite observed in Gale crater has a broad compositional range {Mg0.95(12)-1.54(17)Fe0.18(17)-1.03(9)Ca0.00-0.28(6)Σ2Si2O6} with an overall average of Mg1.18(19)Fe0.72(7)Ca0.10(9)Si2O6. The soils have the lowest Mg and highest Fe compositions Mg0.95(5)Fe1.02(7)Ca0.03(4)Si2O6 of all of the Gale samples. Of the remaining samples, those of the Stimson formation exhibit the highest Mg and lowest Fe average = Mg1.45(7)Fe0.35(13)Ca0.19(6)Si2O6. Augite, C2/c clinopyroxene, is detected in just three samples, the soil samples average = Mg0.92(5)Ca0.72(2)Fe0.36(5)Si2O6 and Windjana (Mg1.03(7)Ca0.75(4)Fe0.21(9)Si2O6). Orthopyroxene was not detected in the soil samples and has an overall average composition of Mg0.79(6)Fe1.20(6)Ca0.01(2)Si2O6 and a range of Mg0.69(7)-0.86(20)Fe1.14(20)-1.31(7)Ca0.00-0.04(4)Σ2Si2O6, with Big Sky exhibiting the lowest Mg content Mg0.69(7)Fe1.31(7)Si2O6 and Okoruso exhibiting the highest Mg0.86(20)Fe1.14(20)Si2O6. Appreciable olivine was observed in only three of the Gale crater samples, the soils and Windjana. Assuming no Mn or Ca, the olivine has an average composition of Mg1.19(12)Fe0.81(12)SiO4 with a range of 1.08(3) to 1.45(7) Mg apfu. The soil samples average = Mg1.11(4)Fe0.89SiO4 are significantly less magnesian than Windjana Mg1.35(7)Fe0.65(7)SiO4. We assume magnetite (Fe3O4) is cation-deficient (Fe3-x∎xO4) in Gale crater samples average = Fe2.83(5)∎0.14O4; range 2.75(5) to 2.90(5) Fe apfu, but we also report other plausible cation substitutions such as Al, Mg, and Cr that would yield equivalent unit-cell parameters. Assuming cation-deficient magnetite, the Murray formation average = Fe2.77(2)∎0.23O4 is noticeably more cation-deficient than the other Gale samples analyzed by CheMin. Note that despite the presence of Ti-rich magnetite in martian meteorites, the unit-cell parameters of Gale magnetite do not permit significant Ti substitution. Abundant jarosite is found in only one sample, Mojave2; its estimated composition is (K0.51(12)Na0.49)(Fe2.68(7)Al0.32)(SO4)2(OH)6. In addition to providing composition and abundances of the crystalline phases, we calculate the lower limit of the abundance of X-ray amorphous material and the composition thereof for each of the samples analyzed with CheMin. Each of the CheMin samples had a significant proportion of amorphous SiO2, except Windjana that has 3.6 wt% SiO2. Excluding Windjana, the amorphous materials have an SiO2 range of 24.1 to 75.9 wt% and an average of 47.6 wt%. Windjana has the highest FeOT (total Fe content calculated as FeO) at 43.1 wt%, but most of the CheMin samples also contain appreciable Fe, with an average of 16.8 wt%. With the exception of the altered Stimson formation samples, Greenhorn and Lubango, the majority of the observed SO3 is concentrated in the amorphous component (average = 11.6 wt%). Furthermore, we provide average amorphous-component compositions for the soils and the Mount Sharp group formations, as well as the limiting element for each CheMin sample.
Though misoprostol is commonly used for inpatient cervical ripening, its use in outpatient settings has been limited by safety concerns. This study was conducted to assess the association between ...early fetal heart tracing (FHT) and maternal tocodynamometry patterns and the incidence of adverse fetal and pregnancy outcomes after the administration of oral misoprostol for cervical ripening.
We conducted a retrospective cohort study of 9908 low-risk patients at ≥37 weeks gestation who received oral misoprostol for cervical ripening prior to rupture of membranes between 01/01/2012 and 12/31/2017 at Kaiser Permanente Northern California hospitals as inpatients. We excluded patients who received a different agent for cervical ripening or had any need for additional inpatient monitoring, including hypertensive disorders of pregnancy, diabetes, or intrauterine growth restriction. Abnormal FHT, abnormal uterine activity, and adverse pregnancy or fetal-related events documented in the electronic health record in the four hours after administration of the first and second doses of misoprostol were assessed using descriptive statistics.
We found that 0.9% of patients experienced tachysystole after the first dose of misoprostol (0.6% without decelerations; 0.3% with decelerations). The incidence of variable decelerations only and other FHT abnormalities (i.e. bradycardia, late or prolonged decelerations, or absent or minimal variability) in the first hour after misoprostol administration were 7.1% and 6.7% respectively, and diminished over time. The need for tocolytic use was 0.2% in the first hour and declined over time to 0.03% in the fourth hour after the first dose. Urgent cesarean delivery occurred in 0.1% of patients after receiving the first dose of misoprostol. Patients who did not experience variable, prolonged, or late decelerations in the first hour after the initial misoprostol dose were less likely to have such FHT abnormalities in the subsequent three hours compared to patients who had other FHT abnormalities (11.8% among patients with no FHT abnormalities vs. 43.7% among patients with other FHT abnormalities; p <.001). The overall trends in outcomes over time were similar after the second dose of misoprostol.
The risk of short-term adverse outcomes associated with misoprostol is low among relatively low-risk patients. FHT abnormalities occurred in up to 32% of patients in the first four hours of monitoring post-misoprostol. Patients with no FHT abnormalities in the first hour after receiving misoprostol had a low risk of developing adverse outcomes and FHT abnormalities on continued monitoring, while patients with any type of deceleration in the first hour were at higher risk of adverse outcomes and FHT abnormalities. Our data may inform the development of protocols for cervical ripening that allow reduced monitoring for a subset of low-risk patients, however, more research is needed to validate findings and develop clinical protocols.
The scaffold protein CARD9 plays an essential role in anti-fungus immunity and is implicated in mediating Dectin-1/Syk-induced NF-κB activation in response to Candida albicans infection. However, the ...molecular mechanism by which CARD9 mediates C. albicans-induced NF-κB activation is not fully characterized. Here we demonstrate that CARD9 is involved in mediating NF-κB activation induced by the hyphal form of C. albicans hyphae (Hyphae) but not by its heat-inactivated unicellular form. Our data show that inhibiting Dectin-2 expression selectively blocked Hyphae-induced NF-κB, whereas inhibiting Dectin-1 mainly suppressed zymosan-induced NF-κB, indicating that Hyphae-induced NF-κB activation is mainly through Dectin-2 and not Dectin-1. Consistently, we find that the hyphae stimulation induces CARD9 association with Bcl10, an adaptor protein that functions downstream of CARD9 and is also involved in C. albicans-induced NF-κB activation. This association is dependent on Dectin-2 but not Dectin-1 following the hyphae stimulation. Finally, we find that although both CARD9 and Syk are required for Hyphae-induced NF-κB activation, they regulate different signaling events in which CARD9 mediates IκBα kinase ubiquitination, whereas Syk regulates IκBα kinase phosphorylation. Together, our data demonstrated that CARD9 is selectively involved in Dectin-2-induced NF-κB activation in response to C. albicans hyphae challenging.
Introduction:
Very little artificial intelligence (AI) work has been performed to investigate acetaminophen-associated hepatotoxicity. The objective of this study was to develop an AI algorithm for ...analyzing weighted features for toxic hepatitis after acetaminophen poisoning.
Methods:
The medical records of 187 patients with acetaminophen poisoning treated at Chang Gung Memorial Hospital were reviewed. Patients were sorted into two groups according to their status of toxic hepatitis. A total of 40 clinical and laboratory features recorded on the first day of admission were selected for algorithm development. The random forest classifier (RFC) and logistic regression (LR) were used for artificial intelligence algorithm development.
Results:
The RFC-based AI model achieved the following results: accuracy = 92.5 ± 2.6%; sensitivity = 100%; specificity = 60%; precision = 92.3 ± 3.4%; and F1 = 96.0 ± 1.8%. The area under the receiver operating characteristic curve (AUROC) was approximately 0.98. The LR-based AI model achieved the following results: accuracy = 92.00 ± 2.9%; sensitivity = 100%; specificity = 20%; precision = 92.8 ± 3.4%; recall = 98.8 ± 3.4%; and F1 = 95.6 ± 1.5%. The AUROC was approximately 0.68. The weighted features were calculated, and the 10 most important weighted features for toxic hepatitis were aspartate aminotransferase (ALT), prothrombin time, alanine aminotransferase (AST), time to hospital, platelet count, lymphocyte count, albumin, total bilirubin, body temperature and acetaminophen level.
Conclusion:
The top five weighted features for acetaminophen-associated toxic hepatitis were ALT, prothrombin time, AST, time to hospital and platelet count.
Abstract
We administered severe acute respiratory syndrome coronavirus-2 viral-specific T cells (VSTs) under emergency investigational new drug applications to 6 immunocompromised patients with ...persistent coronavirus disease 2019 (COVID-19) and characterized clinical and virologic responses. Three patients had partial responses after failing other therapies but then died. Two patients completely recovered, but the role of VSTs in recovery was unclear due to concomitant use of other antivirals. One patient had not responded to 2 courses of remdesivir and experienced sustained recovery after VST administration. The use of VSTs in immunocompromised patients with persistent COVID-19 requires further study.
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