Cynomolgus macaques as a translational model of human immune responses to yellow fever 17D vaccination.

The non-human primate (NHP) model (specifically rhesus and cynomolgus macaques) has facilitated our understanding of the pathogenic mechanisms of yellow fever (YF) disease and allowed the evaluation of the safety and efficacy of YF-17D vaccines. However, the accuracy of this model in mimicking vaccine-induced immunity in humans remains to be fully determined. We used a systems biology approach to compare hematological, biochemical, transcriptomic, and innate and antibody-mediated immune responses in cynomolgus macaques and human participants following YF-17D vaccination. Immune response progression in cynomolgus macaques followed a similar course as in adult humans but with a slightly earlier onset. Yellow fever virus neutralizing antibody responses occurred earlier in cynomolgus macaques [by Day 7[(D7)], but titers > 10 were reached in both species by D14 post-vaccination and were not significantly different by D28 [plaque reduction neutralization assay (PRNT)50 titers 3.6 Log vs 3.5 Log in cynomolgus macaques and human participants, respectively; P = 0.821]. Changes in neutrophils, NK cells, monocytes, and T- and B-cell frequencies were higher in cynomolgus macaques and persisted for 4 weeks versus less than 2 weeks in humans. Low levels of systemic inflammatory cytokines (IL-1RA, IL-8, MIP-1α, IP-10, MCP-1, or VEGF) were detected in either or both species but with no or only slight changes versus baseline. Similar changes in gene expression profiles were elicited in both species. These included enriched and up-regulated type I IFN-associated viral sensing, antiviral innate response, and dendritic cell activation pathways D3-D7 post-vaccination in both species. Hematological and blood biochemical parameters remained relatively unchanged versus baseline in both species. Low-level YF-17D viremia (RNAemia) was transiently detected in some cynomolgus macaques [28% (5/18)] but generally absent in humans [except one participant (5%; 1/20)].IMPORTANCECynomolgus macaques were confirmed as a valid surrogate model for replicating YF-17D vaccine-induced responses in humans and suggest a key role for type I IFN.

Prebiotic fibre mixtures counteract the manifestation of gut microbial dysbiosis induced by the chemotherapeutic 5-Fluorouracil (5-FU) in a validated in vitro model of the colon.

BACKGROUND: 5-Fluorouracil (5-FU) is used as an antineoplastic agent in distinct cancer types. Increasing evidence suggests that the gut microbiota might modulate 5-FU efficacy and toxicity, potentially affecting the patient's prognosis. The current experimental study investigated 5-FU-induced microbiota alterations, as well as the potential of prebiotic fibre mixtures (M1-M4) to counteract these shifts. METHODS: A pooled microbial consortium was derived from ten healthy donors, inoculated in an in vitro model of the colon, and treated with 5-FU, with or without prebiotic fibre mixtures for 72 h. Four different prebiotic fibre mixtures were tested: M1 containing short-chain galacto-oligosaccharides (sc GOS), long-chain fructo-oligosaccharides (lcFOS), and low viscosity pectin (lvPect), M2 consisting of arabinoxylan, beta-glucan, pectin, and resistant starch, M3 which was a mixture of scGOS and lcFOS, and M4 containing arabinoxylan, beta-glucan, pectin, resistant starch, and inulin. RESULTS: We identified 5-FU-induced changes in gut microbiota composition, but not in microbial diversity. Administration of prebiotic fibre mixtures during 5-FU influenced gut microbiota composition and taxa abundance. Amongst others, prebiotic fibre mixtures successfully stimulated potentially beneficial bacteria (Bifidobacterium, Lactobacillus, Anaerostipes, Weissella, Olsenella, Senegalimassilia) and suppressed the growth of potentially pathogenic bacteria (Klebsiella, Enterobacter) in the presence of 5-FU. The short-chain fatty acid (SCFA) acetate increased slightly during 5-FU, but even more during 5-FU with prebiotic fibre mixtures, while propionate was lower due to 5-FU with or without prebiotic fibre mixtures, compared to control. The SCFA butyrate and valerate did not show differences among all conditions. The branched-chain fatty acids (BCFA) iso-butyrate and iso-valerate were higher in 5-FU, but lower in 5-FU + prebiotics, compared to control. CONCLUSIONS: These data suggest that prebiotic fibre mixtures represent a promising strategy to modulate 5-FU-induced microbial dysbiosis towards a more favourable microbiota, thereby possibly improving 5-FU efficacy and reducing toxicity, which should be evaluated further in clinical studies.

Relational and lexical similarity in analogical reasoning and recognition memory: Behavioral evidence and computational evaluation.

We examined the role of different types of similarity in both analogical reasoning and recognition memory. On recognition tasks, people more often falsely report having seen a recombined word pair (e.g., flower: garden) if it instantiates the same semantic relation (e.g., is a part of) as a studied word pair (e.g., house: town). This phenomenon, termed relational luring, has been interpreted as evidence that explicit relation representations-known to play a central role in analogical reasoning-also impact episodic memory. We replicate and extend previous studies, showing that relation-based false alarms in recognition memory occur after participants encode word pairs either by making relatedness judgments about individual words presented sequentially, or by evaluating analogies between pairs of word pairs. To test alternative explanations of relational luring, we implemented an established model of recognition memory, the Generalized Context Model (GCM). Within this basic framework, we compared representations of word pairs based on similarities derived either from explicit relations or from lexical semantics (i.e., individual word meanings). In two experiments on recognition memory, best-fitting values of GCM parameters enabled both similarity models (even the model based solely on lexical semantics) to predict relational luring with comparable accuracy. However, the model based on explicit relations proved more robust to parameter variations than that based on lexical similarity. We found this same pattern of modeling results when applying GCM to an independent set of data reported by Popov, Hristova, and Anders (2017). In accord with previous work, we also found that explicit relation representations are necessary for modeling analogical reasoning. Our findings support the possibility that explicit relations, which are central to analogical reasoning, also play an important role in episodic memory.

School Climate, Cortical Structure, and Socioemotional Functioning: Associations across Family Income Levels.

School climates are important for children's socioemotional development and may also serve as protective factors in the context of adversity. Nevertheless, little is known about the potential neural mechanisms of such associations, as there has been limited research concerning the relation between school climate and brain structure, particularly for brain regions relevant for mental health and socioemotional functioning. Moreover, it remains unclear whether the role of school climate differs depending on children's socioeconomic status. We addressed these questions in baseline data for 9- to 10-year-olds from the Adolescent Brain and Cognitive Development study (analytic sample for socioemotional outcomes, n = 8887), conducted at 21 sites across the United States. Cortical thickness, cortical surface area, and subcortical volume were derived from T1-weighted brain magnetic resonance imaging. School climate was measured by youth report, and socioemotional functioning was measured by both youth and parent report. A positive school climate and higher family income were associated with lower internalizing and externalizing symptoms, with no evidence of moderation. There were no associations between school climate and cortical thickness or subcortical volume, although family income was positively associated with hippocampal volume. For cortical surface area, however, there was both a positive association with family income and moderation: There was an interaction between school climate and income for total cortical surface area and locally in the lateral orbitofrontal cortex. In all cases, there was an unexpected negative association between school climate and cortical surface area in the lower-income group. Consequently, although the school climate appears to be related to better socioemotional function for all youth, findings suggest that the association between a positive school environment and brain structure only emerges in the context of socioeconomic stress and adversity. Longitudinal data are needed to understand the role of these neural differences in socioemotional functioning over time.

The 'Viennese epidemic' of acute HCV in the era of direct-acting antivirals.

The recently reported epidemic of acute hepatitis C virus (HCV) infections -observed predominantly among men who have sex with men (MSM)-may now decline due to wide availability of direct-acting antivirals (DAAs). This study aimed to investigate the current trends of acute hepatitis C in Vienna. Patients presenting with acute hepatitis C between 01/2007 and12/2020 at the Vienna General Hospital were retrospectively enrolled and followed after virologic clearance/eradication. The introduction of unrestricted DAA access after 09/17 defined the 'DAA era', as compared to the 'pre-DAA era' prior to 09/17. We identified 134 acute hepatitis C cases in 119 patients with a mean age of 39 ± 9 years at inclusion. The majority of patients were male (92%), HIV-positive (88%) and MSM (85%). In the DAA era, a history of prior chronic HCV infection at inclusion was found in 24% (11/46) compared to 7% (5/73) in the pre-DAA era (p = .012). The annual rate of acute hepatitis C cases increased in the DAA era (17.11 per year) compared to the pre-DAA era (7.76 per year). The DAA era included an AHC-genotype-2 cluster and more HIV-negative acute hepatitis C cases (0% (0/73) vs. 30% (14/46), p < .001). Patients were followed after spontaneous clearance or sustained virologic treatment response (SVR) for a total of 251.88 patient-years (median 1.39 years per patient). In the DAA era, we recorded 15 acute hepatitis C-reinfections - corresponding to an incidence rate of 5.96 (95% CI: 3.57-9.66) reinfections per 100-patient-years. We continue to observe a high incidence of acute hepatitis C in Vienna in the DAA era-primarily among HIV-positive MSM, but increasingly also in HIV-negative MSM.

Noninvasive Risk Stratification After HCV Eradication in Patients With Advanced Chronic Liver Disease.

BACKGROUND AND AIMS: Risk stratification after cure from hepatitis C virus (HCV) infection remains a clinical challenge. We investigated the predictive value of noninvasive surrogates of portal hypertension (liver stiffness measurement [LSM] by vibration-controlled transient elastography and von Willebrand factor/platelet count ratio [VITRO]) for development of hepatic decompensation and hepatocellular carcinoma in patients with pretreatment advanced chronic liver disease (ACLD) who achieved HCV cure. APPROACH AND RESULTS: A total of 276 patients with pretreatment ACLD and information on pretreatment and posttreatment follow-up (FU)-LSM and FU-VITRO were followed for a median of 36.6 months after the end of interferon-free therapy. FU-LSM (area under the receiver operating characteristic curve [AUROC]: 0.875 [95% confidence interval [CI]: 0.796-0.954]) and FU-VITRO (AUROC: 0.925 [95% CI: 0.874-0.977]) showed an excellent predictive performance for hepatic decompensation. Both parameters provided incremental information and were significantly associated with hepatic decompensation in adjusted models. A previously proposed combined approach (FU-LSM < 12.4 kPa and/or FU-VITRO < 0.95) to rule out clinically significant portal hypertension (CSPH, hepatic venous pressure gradient ≥10 mm Hg) at FU assigned most (57.3%) of the patients to the low-risk group; none of these patients developed hepatic decompensation. In contrast, in patients in whom FU-CSPH was ruled in (FU-LSM > 25.3 kPa and/or FU-VITRO > 3.3; 25.0% of patients), the risk of hepatic decompensation at 3 years following treatment was high (17.4%). Patients within the diagnostic gray-zone for FU-CSPH (17.8% of patients) had a very low risk of hepatic decompensation during FU (2.6%). The prognostic value of this algorithm was validated in an internal (n = 86) and external (n = 162) cohort. CONCLUSION: FU-LSM/FU-VITRO are strongly and independently predictive of posttreatment hepatic decompensation in HCV-induced ACLD. An algorithm combining these noninvasive markers not only rules in or rules out FU-CSPH, but also identifies populations at negligible versus high risk for hepatic decompensation. FU-LSM/FU-VITRO are readily accessible and enable risk stratification after sustained virological response, and thus facilitate personalized management.

Ultra-compact diode-pumped single-frequency Ti:sapphire laser.

In this Letter, we report on the development of an ultra-compact single-frequency Ti:sapphire laser under direct diode pumping. Single-longitudinal-mode operation is realized from a miniature plane-parallel resonator using a volume Bragg grating as an output coupler. InGaN laser diodes operating at around 470 nm and 490 nm with a combined power of 6.7 W are used as an optical pump. A maximum output power of 700 mW is generated during single-frequency operation at 813.4 nm. A laser linewidth of 2.4 MHz is measured during free-running operation, which is reduced to about 180 kHz when the laser is locked to an external reference cavity.

Age-adjusted mortality and predictive value of liver chemistries in a Viennese cohort of COVID-19 patients.

BACKGROUND AND AIMS: The coronavirus disease of 2019 (COVID-19) causes considerable mortality worldwide. We aimed to investigate the frequency and predictive role of abnormal liver chemistries in different age groups. METHODS: Patients with positive severe acute respiratory distress syndrome-coronavirus-2 (SARS-CoV-2) polymerase chain reaction (PCR) test between 03/2020-07/2021 at the Vienna General Hospital were included. Patients were stratified for age: 18-39 vs. 40-69 vs. ≥70 years (y). Aspartate aminotransferase (AST), alanine-aminotransferase (ALT), alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT) and total bilirubin (BIL) were recorded. RESULTS: 900 patients (18-39 years: 32.2%, 40-69 years: 39.7%, ≥70 years: 28.1%) were included. Number of comorbidities, median D-dimer and C-reactive protein increased with age. During COVID-19, AST/ALT and ALP/GGT levels significantly increased. Elevated hepatocellular transaminases (AST/ALT) and cholestasis parameters (ALP/GGT/BIL) were observed in 40.3% (n  = 262/650) and 45.0% (n  = 287/638) of patients respectively. Liver-related mortality was highest among patients with pre-existing decompensated liver disease (28.6%, p < .001). 1.7% of patients without pre-existing liver disease died of liver-related causes, that is consequences of hepatic dysfunction or acute liver failure. Importantly, COVID-19-associated liver injury (16.0%, p < .001), abnormal liver chemistries and liver-related mortality (6.5%, p < .001) were most frequent among 40-69 years old patients. Elevated AST and BIL after the first positive SARS-CoV-2 PCR independently predicted mortality in the overall cohort and in 40-69 years old patients. CONCLUSIONS: Almost half of the COVID-19 patients exhibit abnormal hepatocellular and cholestasis-related liver chemistries with 40-69 years old patients being at particularly high risk for COVID-19-related liver injury and liver-related mortality. Elevated AST and BIL after SARS-CoV-2 infection are independent predictors of mortality, especially in patients aged 40-69 years.

Individual Differences in the Neural Localization of Relational Networks of Semantic Concepts.

Semantic concepts relate to each other to varying degrees to form a network of zero-order relations, and these zero-order relations serve as input into networks of general relation types as well as higher order relations. Previous work has studied the neural mapping of semantic concepts across domains, although much work remains to be done to understand how the localization and structure of those architectures differ depending on various individual differences in attentional bias toward different content presentation formats. Using an item-wise model of semantic distance of zero-order relations (Word2vec) between stimuli (presented both in word and picture forms), we used representational similarity analysis to identify individual differences in the neural localization of semantic concepts and how those localization differences can be predicted by individual variance in the degree to which individuals attend to word information instead of pictures. Importantly, there were no reliable representations of this zero-order semantic relational network when looking at the full group, and it was only through considering individual differences that a stable localization difference became evident. These results indicate that individual differences in the degree to which a person habitually attends to word information instead of picture information substantially affects the neural localization of zero-order semantic representations.

Safety of direct oral anticoagulants in patients with advanced liver disease.

BACKGROUND & AIMS: While direct oral anticoagulants (DOACs) are increasingly used in patients with liver disease, safety data especially in advanced chronic liver disease (ACLD) are limited. METHODS: Liver disease patients receiving DOAC treatment (ACLD: n = 104; vascular liver disease: n = 29) or vitamin K antagonists (VKA)/low-molecular-weight heparin (LMWH; ACLD: n = 45; vascular: n = 13) between January 2010 and September 2020 were retrospectively included. Invasive procedures and bleeding events were recorded. Calibrated anti-Xa peak levels and thrombomodulin-modified thrombin generation assays (TM-TGAs) were measured in a subgroup of 35/28 DOAC patients. RESULTS: Among patients receiving DOAC, 55 (41.3%) had advanced liver dysfunction (Child-Pugh-stage [CPS] B/C) and 66 (49.6%) had experienced decompensation. Overall, 205 procedures were performed in 60 patients and procedure-related bleedings occurred in 7 (11.7%) patients. Additionally, 38 (28.6%) patients experienced spontaneous (15 minor, 23 major) bleedings during a median follow-up of 10.5 (IQR: 4.0-27.8) months. Spontaneous bleedings in ACLD patients were more common in CPS-B/C (at 12 months: 36.9% vs CPS-A: 15.9%, subdistribution hazard ratio [SHR]: 3.23 [95% CI: 1.59-6.58], P < .001), as were major bleedings (at 12 months: 22.0% vs 5.0%, SHR: 5.82 [95% CI: 2.00-16.90], P < .001). Importantly, CPS (adjusted SHR: 4.12 [91% CI: 1.82-9.37], P < .001), but not the presence of hepatocellular carcinoma or varices, was independently associated with major bleeding during DOAC treatment. Additionally, ACLD patients experiencing bleeding had worse overall survival (at 12 months: 88.9% vs 95.0% without bleeding; P < .001). Edoxaban anti-Xa peak levels were higher in patients with CPS-B/C (345 [95% CI: 169-395] vs CPS-A: 137 [95% CI: 96-248] ng/mL, P = .048) and were associated with lower TM-TGA. Importantly, spontaneous bleeding rates were comparable to VKA/LMWH patients. CONCLUSIONS: Anticoagulants including DOACs should be used with caution in patients with advanced liver disease due to a significant rate of spontaneous bleeding events.

Epidemiological trends of HBV and HDV coinfection among Viennese HIV+ patients.

BACKGROUND AND AIMS: Despite vaccination recommendations, hepatitis B (HBV) and D (HDV) coinfections are common in HIV+individuals. METHODS: HBV immunization status (anti-HBs) as well as HBV (HBsAg/HBV-DNA) and HDV (anti-HDV) coinfection rates were assessed in 1870 HIV+individuals at HIV diagnosis (baseline, BL) and last follow-up (FU). RESULTS: Sixty-eight (3.6%) HIV patients were never tested for HBV. At BL, 89/1802 (4.9%) HIV patients were HBV coinfected. Four hundred and fifteen (23.0%) showed virological HBV clearance [HBsAg(-)/anti-HBc(+)/anti-HBs(+)] and 210 (11.7%) presented with anti-HBc(+) only. Seven hundred and ten (39.4%) were HBV naïve [HBsAg(-)/anti-HBs(-)/anti-HBc(-)/HBV-DNA(-)], but only 378 (21.0%) received vaccinations with detectable anti-HBs(+) titres. Among the 89 HBV/HIV-coinfected patients, only 52 (58.4%) were tested for HDV: 11/49 (22.4%) had anti-HDV(+) and 3/12 (25.0%) showed HDV-RNA viraemia. During a median FU of 6.5 (IQR 7.2) years, 44 (4.6%) of the 953 retested BL HBV-negative patients acquired new HBV infection (including 15/304, 4.9% of vaccinated patients). Of the 89 patients, 22 (24.7%) patients cleared their HBsAg, resulting in 60/1625 (3.7%) HIV/HBV individuals at FU: 34 (56.7%) showed HBV-DNA suppression and 15 (25.0%) were HBV viraemic, while 12/89 (13.5%) remained without a FU test. Vaccinations induced anti-HBs(+) in 137 of the retested 649 (21.1%) BL HBV-naïve patients. CONCLUSION: HBV testing is well established among Viennese HIV+patients with HBV coinfection rates around 4%-5%. HBV vaccinations are insufficiently implemented since anti-HBs titres were detected in only 21.1% of HBV-naive HIV(+) patients and new HBV infections occurred in previously vaccinated patients. HDV testing is not systematically performed despite up to 25% of HIV/HBV patients may show HDV coinfection.

Characterising non-linear associations between airborne pollen counts and respiratory symptoms from the AirRater smartphone app in Tasmania, Australia: A case time series approach.

Pollen is a well-established trigger of asthma and allergic rhinitis, yet concentration-response relationships, lagged effects, and interactions with other environmental factors remain poorly understood. Smartphone technology offers an opportunity to address these challenges using large, multi-year datasets that capture individual symptoms and exposures in real time. We aimed to characterise associations between six pollen types and respiratory symptoms logged by users of the AirRater smartphone app in Tasmania, Australia. We analyzed 44,820 symptom reports logged by 2272 AirRater app users in Tasmania over four years (2015-2019). With these data we evaluated associations between daily respiratory symptoms and atmospheric pollen concentrations. We implemented Poisson regression models, using the case time series approach designed for app-sourced data. We assessed potentially non-linear and lagged associations with (a) total pollen and (b) six individual pollen taxa. We adjusted for seasonality and meteorology and tested for interactions with particulate air pollution (PM2.5). We found evidence of non-linear associations between total pollen and respiratory symptoms for up to three days following exposure. For total pollen, the same-day relative risk (RR) increased to 1.31 (95% CI: 1.26-1.37) at a concentration of 50 grains/m3 before plateauing. Associations with individual pollen taxa were also non-linear with some diversity in shapes. For all pollen taxa the same-day RR was highest. The interaction between total pollen and PM2.5 was positive, with risks associated with pollen significantly higher in the presence of high concentrations of PM2.5. Our results support a non-linear response between airborne pollen and respiratory symptoms. The association was strongest on the day of exposure and synergistic with particulate air pollution. The associations found with Dodonaea and Myrtaceae highlight the need to further investigate the role of Australian native pollen types in allergic respiratory disease.

Evaluation of a commercial loop-mediated isothermal amplification assay, 3MTM Molecular Detection Assay 2 - Campylobacter, for the detection of Campylobacter from poultry matrices.

1. The objective of this study was to evaluate performance of a commercial loop-mediated isothermal amplification (LAMP) method as an alternative method for the detection of Campylobacter spp. in primary production samples, poultry rinses and raw poultry products, as compared to the US Department of Agriculture Food Inspection Service Microbiology Laboratory Guide Book PCR reference method, MLG 41A.2. The Campylobacter spp. LAMP was used in conjunction with a ready-to-use enrichment broth that does not require microaerophilic incubation. After enrichment, boot swabs from poultry farms, carcase rinses and raw poultry products were tested by the LAMP method and the MLG 41A PCR method.3. The ready-to-use enrichment broth enabled the growth of Campylobacter spp. within 22 to 28 hours under aerobic incubation conditions. The LAMP method enabled Campylobacter detection in the enriched samples of various poultry matrices and had equivalent sensitivity and specificity to the MLG 41A PCR method.4. No significant difference (95% confidence interval) was found between the alternative and the MLG 41A PCR method, as determined by probability of detection analysis, except for neutralising buffered peptone water post-chill rinsates. For the post-chill neutralising buffered peptone water rinsates, the LAMP method had significantly higher confirmed portions.

Developing a neurally informed ontology of creativity measurement.

A central challenge for creativity research-as for all areas of experimental psychology and cognitive neuroscience-is to establish a mapping between constructs and measures (i.e., identifying a set of tasks that best captures a set of creative abilities). A related challenge is to achieve greater consistency in the measures used by different researchers; inconsistent measurement hinders progress toward shared understanding of cognitive and neural components of creativity. New resources for aggregating neuroimaging data, and the emergence of methods for identifying structure in multivariate data, present the potential for new approaches to address these challenges. Identifying meta-analytic structure (i.e., similarity) in neural activity associated with creativity tasks might help identify subsets of these tasks that best reflect the similarity structure of creativity-relevant constructs. Here, we demonstrated initial proof-of-concept for such an approach. To build a model of similarity between creativity-relevant constructs, we first surveyed creativity researchers. Next, we used NeuroSynth meta-analytic software to generate maps of neural activity robustly associated with tasks intended to measure the same set of creativity-relevant constructs. A representational similarity analysis-based approach identified particular constructs-and particular tasks intended to measure those constructs-that positively or negatively impacted the model fit. This approach points the way to identifying optimal sets of tasks to capture elements of creativity (i.e., dimensions of similarity space among creativity constructs), and has long-term potential to meaningfully advance the ontological development of creativity research with the rapid growth of creativity neuroscience. Because it relies on neuroimaging meta-analysis, this approach has more immediate potential to inform longer-established fields for which more extensive sets of neuroimaging data are already available.

Math anxiety and executive function: Neural influences of task switching on arithmetic processing.

Math anxiety (MA) is associated with negative thoughts and emotions when encountering mathematics, often resulting in under-performance on math tasks. One hypothesized mechanism by which MA affects performance is through anxiety-related increases in working memory (WM) load, diverting resources away from mathematical computations. We examined whether this effect is specific to WM or whether the impact of MA extends to an overall depletion of executive function (EF) resources. In this fMRI experiment, we manipulated two separate factors known to impact EF demands-task-switching (TS) and increased WM load-in order to evaluate how MA relates to behavioral performance and neural activity related to mathematical calculations. Relative to a difficult non-math task (analogies), we observed MA-related deficits in math performance and reduced neural activity in a network of regions in the brain associated with arithmetic processing. In response to TS demands, higher levels of math anxiety were associated with a pattern of avoidance and disengagement. When switching from the control task, high math anxiety (HMA) was associated with disengagement from math trials, speeding through these trials, and exhibiting reduced neural activity in regions associated with arithmetic processing. The effects of math anxiety and WM were most pronounced at the lowest levels of WM load. Overall, the results of this study indicate that the effects of MA are broader than previously demonstrated and provide further insight into how EF deficits in MA might impact recruitment of neural resources that are important for successful math computations.

Widely-tunable mid-infrared ring cavity pump-enhanced OPO and application in photo-thermal interferometric trace ethane detection.

The development of a broadly and accurately tunable single-frequency mid-infrared laser source and its application to a sensitive laser absorption detection method are described. Photo-thermal interferometric spectroscopy is employed as a phase-sensitive method to detect the minute refractive index change caused by the heating of a gas under laser radiation. A separate probe beam allows for the spectrally-interesting mid-infrared region to be examined whilst utilizing low cost, high detectivity photodetectors in the visible/near-infrared region. We also describe the implementation of a Sagnac interferometer to minimize the effects of environmental perturbation and provide inherent passive stability. A continuous-wave ring-cavity pump-enhanced OPO has been developed to provide excitation light from 3-4 µm at 140 mW with the ability to mode-hop tune continuously over 90 cm-1 in 0.07 cm-1 steps. Complementary use of both detection apparatus and excitation source has allowed for presence of ethane to be detected down to 200 parts per billion.

Non-invasive detection of portal hypertension by enhanced liver fibrosis score in patients with different aetiologies of advanced chronic liver disease.

BACKGROUND AND AIMS: The enhanced liver fibrosis (ELF) score comprises serum markers of fibrogenesis and matrix remodelling and was developed to detect liver fibrosis, however, it may also be useful for the non-invasive detection of portal hypertension (PHT). METHODS: ELF score and its single components (TIMP1/PIIINP/HA) were analysed in 201 patients with advanced chronic liver disease (ACLD; ie hepatic venous pressure gradient (HVPG) ≥6 mm Hg). Patients with pre-/post-hepatic PHT, hepatocellular carcinoma beyond Milan criteria, and history of TIPS implantation or liver transplantation were excluded. RESULTS: ELF and its single components correlated with HVPG in the overall cohort: ELF: r = .443, TIMP1: r = .368, PIIINP:r = .332, and HA:r = .419 (all P < .001). The strength of the correlation between ELF and HVPG decreased in higher HVPG strata: 6-9 mm Hg:r = .569(P = .004), 10-19 mm Hg:r = .304 (P = .001) and ≥20 mm Hg:r = -.023(P = .853). Area under the receiver operating characteristics (AUROC) of ELF score to detect clinically significant PHT (CSPH; HVPG ≥ 10 mm Hg) was 0.833. Importantly, HA alone yielded an AUROC of 0.828. Detection of CSPH in strictly compensated ACLD (cACLD) patients was less accurate: AUROC: 0.759 (P < .001). CSPH was ruled-in by ELF ≥ 11.1 with a PPV of 98% (sensitivity: 61%/specificity: 92%/NPV:24%), but CSPH could not be ruled-out. ELF score had a low AUROC of 0.677 (0.60-0.75; P < .001) for the diagnosis of high-risk PHT (HRPH; HVPG ≥ 20mm Hg) and, thus, HRPH could not be ruled-in by ELF. However, ELF < 10.1 ruled-out HRPH with a NPV of 95% (sensitivity: 97%/specificity: 26%/PPV: 39%). CONCLUSION: The ELF score correlates with HVPG at values <20 mm Hg. An ELF ≥ 11.1 identifies patients with a high probability of CSPH, while an ELF < 10.1 may be used to rule-out HRPH.

Safety and Immunogenicity of a Heterologous Prime-Boost Ebola Virus Vaccine Regimen in Healthy Adults in the United Kingdom and Senegal.

BACKGROUND: The 2014 West African outbreak of Ebola virus disease highlighted the urgent need to develop an effective Ebola vaccine. METHODS: We undertook 2 phase 1 studies assessing safety and immunogenicity of the viral vector modified vaccinia Ankara virus vectored Ebola Zaire vaccine (MVA-EBO-Z), manufactured rapidly on a new duck cell line either alone or in a heterologous prime-boost regimen with recombinant chimpanzee adenovirus type 3 vectored Ebola Zaire vaccine (ChAd3-EBO-Z) followed by MVA-EBO-Z. Adult volunteers in the United Kingdom (n = 38) and Senegal (n = 40) were vaccinated and an accelerated 1-week prime-boost regimen was assessed in Senegal. Safety was assessed by active and passive collection of local and systemic adverse events. RESULTS: The standard and accelerated heterologous prime-boost regimens were well-tolerated and elicited potent cellular and humoral immunogenicity in the United Kingdom and Senegal, but vaccine-induced antibody responses were significantly lower in Senegal. Cellular immune responses measured by flow cytometry were significantly greater in African vaccinees receiving ChAd3 and MVA vaccines in the same rather than the contralateral limb. CONCLUSIONS: MVA biomanufactured on an immortalized duck cell line shows potential for very large-scale manufacturing with lower cost of goods. This first trial of MVA-EBO-Z in humans encourages further testing in phase 2 studies, with the 1-week prime-boost interval regimen appearing to be particularly suitable for outbreak control. CLINICAL TRIALS REGISTRATION: NCT02451891; NCT02485912.

Putting the pieces together: Generating a novel representational space through deductive reasoning.

How does the brain represent a newly-learned mental model? Representational similarity analysis (RSA) has revealed the neural basis of common representational spaces learned early in development, such as categories of natural kinds. This study uses RSA to examine the neural implementation of a newly-learned mental model-i.e., a representational space created through deductive reasoning-and study the structure of previously found parietal activity in reasoning tasks. Specifically, all the information in this mental model could only be obtained through abstract transitive reasoning, as there were no predictive differences between observable features in the stimuli, and stimuli were counterbalanced across participants. Participants were shown unfamiliar face portraits paired with names and asked to learn about the height of each person pictured in the portraits through comparison to other individuals in the set. Participants learned the relative heights only of adjacent pairs in the set and then used transitive reasoning to generate a linear ranking of heights (e.g., "Matthew is taller than Thomas; Thomas is taller than Andrew; therefore Matthew is taller than Andrew"). During fMRI, participants recalled the approximate height of each individual based on these inferences. Using a predictive model based on the relative heights of the set of individuals, RSA revealed three brain regions in the right hemisphere that encoded this newly-learned representational space, located within the intraparietal sulcus, precuneus, and inferior frontal gyrus. These findings demonstrate the value of RSA for analyzing structure within patterns of activity and support theories asserting that logical reasoning recruits spatial processing mechanisms.

In depth comparative phenotyping of blood innate myeloid leukocytes from healthy humans and macaques using mass cytometry.

Comparative immune-profiling of innate responses in humans and non-human primates is important to understand the pathogenesis of infectious and chronic inflammatory diseases as well as for the preclinical development of vaccines and immune therapies. However, direct comparisons of the two species are rare and were never performed using mass cytometry. Here, whole-blood-derived leukocytes from healthy humans and cynomolgus macaques were analyzed with mass cytometry. Two similar panels of around 30 monoclonal antibodies targeting human markers associated with innate myeloid cells to stain fixed human and macaque leukocytes were constructed. To compare the circulating innate cells from the two primate species, an analysis pipeline combining a clustering analysis by the Spanning-tree Progression Analysis of Density-normalized Events (SPADE) algorithm with a two-step hierarchical clustering of cells nodes and markers was used. Identical SPADE settings were applied to both datasets, except for the 20 clustering markers which slightly differed. A correlation analysis designed to compare the phenotypes of human and macaque cell nodes and based on 16 markers, including 15 shared clustering markers and CD19 for humans or CD20 for macaques, revealed similarities and differences between staining patterns. This study unique by the number of individuals (26 humans and 5 macaques) and the use of mass cytometry certainly contributes to better assess the advantages and limits of the use of non-human primates in preclinical research. © 2017 International Society for Advancement of Cytometry.