bluuebunny/crossref_metadata_2025 huggingface dataset:
Safety and Immunogenicity of Heterologous and Homologous 2-Dose Regimens of Adenovirus Serotype 26– and Modified Vaccinia Ankara–Vectored Ebola Vaccines: A Randomized, Controlled Phase 1 Study
Authors: Goldstein Neil , Bockstal Viki , Bart Stephan , Luhn Kerstin , Robinson Cynthia , Gaddah Auguste , Callendret Benoit , Douoguih Macaya
Published: September 2020

Background

This phase 1 placebo-controlled study assessed the safety and immunogenicity of 2-dose regimens of Ad26.ZEBOV (adenovirus serotype 26 [Ad26]) and MVA-BN-Filo (modified vaccinia Ankara [MVA]) vaccines with booster vaccination at day 360.

Methods

Healthy US adults (N = 164) randomized into 10 groups received saline placebo or standard or high doses of Ad26 or MVA in 2-dose regimens at 7-, 14-, 28-, or 56-day intervals; 8 groups received booster Ad26 or MVA vaccinations on day 360. Participants reported solicited and unsolicited reactogenicity; we measured immunoglobulin G binding, neutralizing antibodies and cellular immune responses to Ebola virus glycoprotein.

Results

All regimens were well tolerated with no serious vaccine-related adverse events. Heterologous (Ad26,MVA [dose 1, dose 2] or MVA,Ad26) and homologous (Ad26,Ad26) regimens induced humoral and cellular immune responses 21 days after dose 2; responses were higher after heterologous regimens. Booster vaccination elicited anamnestic responses in all participants.

Conclusions

Both heterologous and homologous Ad26,MVA Ebola vaccine regimens are well tolerated in healthy adults, regardless of interval or dose level. Heterologous 2-dose Ad26,MVA regimens containing an Ebola virus insert induce strong, durable humoral and cellular immune responses. Immunological memory was rapidly recalled by booster vaccination, suggesting that Ad26 booster doses could be considered for individuals at risk of Ebola infection, who previously received the 2-dose regimen.
Soybean meal allergenic protein degradation and gut health of piglets fed protease-supplemented diets
Authors: Park Sangwoo , Lee Jung Wook , Cowieson Aaron J , Pappenberger Guenter , Woyengo Tofuko Awori
Published: September 2020

Two experiments were conducted to determine the effects of protease supplementation on degradation of soybean meal (SBM) allergenic proteins (glycinin and β-conglycinin) and gut health of weaned pigs fed soybean meal-based diets. In experiment 1, 2 SBM samples from 2 different sources were subjected to porcine in vitro gastric degradation to determine the effects of protease (at 15,000 U/kg of feedstuff) on degradation of the soybean allergenic proteins. In experiment 2, 48 weaned pigs (body weight = 6.66 kg) were obtained in 2 batches of 24 pigs each. Pigs were individually housed in metabolic crates and fed 4 diets (12 pigs/diet). The diets were corn-based diet with SBM 1 or SBM 2 without or with protease at 15,000 U/kg of diet in 2 × 2 factorial arrangement. Diets were fed for 10 d and pigs were sacrificed on day 10 for measurement of small intestinal histomorphology, permeability of small intestine mounted in Ussing chambers, and serum concentration of pro-inflammatory cytokines. Two SBM sources (SBM 1 and SBM 2) contained 46.9% or 47.7% CP, 14.0% or 14.6% glycinin, and 9.90% or 10.3% β-conglycinin, respectively. Protease and SBM source did not interact on any of the response criteria measured in the current study. Protease supplementation tended to increase (P = 0.069) the in vitro gastric degradation of glycinin. Protease supplementation tended to reduce (P = 0.099) fluorescein isothiocyanate dextran 4,000 Da (which is a marker probe for intestinal permeability) flow in jejunum, and reduced (P = 0.037) serum TNF-α concentration. Protease did not affect small intestinal histomorphology. In conclusion, protease tended to increase gastric degradation of glycinin and reduce gut permeability, and serum concentration of pro-inflammatory cytokines, indicating that the protease used in the current study can be added to SBM-based diets for weanling pigs to improve gut health.
Spiraling toward a New Cold War in the North? The Effect of Mutual and Multifaceted Securitization
Authors: Wilhelmsen Julie
Published: September 2020

Building on a discourse-theoretical reading of securitization theory, this article theorizes and examines how two political entities can become locked in a negative spiral of identification that may lead to a violent confrontation. Through mutual and multifaceted securitization, each party increasingly construes the other as a threat to itself. When this representation spreads beyond the military domain to other dimensions (trade, culture, diplomacy), the other party is projected as “different” and “dangerous” at every encounter: positive mutual recognition is gradually blocked out. Military means then become the logical, legitimate way of relating: contact and collaboration in other issue-areas are precluded. Drawing on official statements 2014–2018, this article investigates how Norwegian–Russian relations shifted from being a collaborative partnership to one of enmity in the High North. The emerging and mutual pattern of representing the other as a threat across issue-areas since 2014 has become an “autonomous” driver of conflict—regardless of whether either party might originally have had offensive designs on the other.
Formation of satellites in circumplanetary discs generated by disc instability
Authors: Inderbitzi C , Szulágyi J , Cilibrasi M , Mayer L
Published: September 2020

We investigated the formation and evolution of satellite systems in a cold, extended circumplanetary disc (CPD) around a 10MJupiter gas giant, which was formed by gravitational instability at 50 au from its star. The disc parameters were from a 3D global smoothed particle hydrodynamics simulation. We used a population synthesis approach, where we placed satellite embryos in this disc, and let them accrete mass, migrate, collide until the gaseous disc is dissipated. In each run, we changed the initial dust-to-gas ratio, dispersion- and refilling time-scales within reasonable limits, as well as the number of embryos and their starting locations. We found that most satellites have mass similar to the Galilean ones, but very few can reach a maximum of 3MEarth due to the massive CPD. Large moons are often form as far as 0.5Rdisc. The migration rate of satellites are fast, hence during the disc lifetime, an average of 10MEarth worth of moons will be engulfed by the planet, increasing greatly its metallicity. We also investigated the effect of the planet’s semimajor axis on the resulting satellite systems by rescaling our model. This test revealed that for the discs closer to the star, the formed moons are lighter, and a larger amount of satellites are lost into the planet due to the even faster migration. Finally, we checked the probability of detecting satellites like our population, which resulted in a low number of ≤ 3 per cent even with upcoming powerful telescopes like E-ELT.
Reionization inference from the CMB optical depth and E-mode polarization power spectra
Authors: Qin Yuxiang , Poulin Vivian , Mesinger Andrei , Greig Bradley , Murray Steven , Park Jaehong
Published: September 2020

The Epoch of Reionization (EoR) depends on the complex astrophysics governing the birth and evolution of the first galaxies and structures in the intergalactic medium. EoR models rely on cosmic microwave background (CMB) observations, and in particular the large-scale E-mode polarization power spectra (EE PS), to help constrain their highly uncertain parameters. However, rather than directly forward-modelling the EE PS, most EoR models are constrained using a summary statistic – the Thompson scattering optical depth, τe. Compressing CMB observations to τe requires adopting a basis set for the EoR history. The common choice is the unphysical, redshift-symmetric hyperbolic tangent (tanh) function, which differs in shape from physical EoR models based on hierarchical structure formation. Combining public EoR and CMB codes, 21cmfast and class, here we quantify how inference using the τe summary statistic impacts the resulting constraints on galaxy properties and EoR histories. Using the last Planck 2018 data release, we show that the marginalized constraints on the EoR history are more sensitive to the choice of the basis set (tanh versus physical model) than to the CMB likelihood statistic (τe versus PS). For example, EoR histories implied by the growth of structure show a small tail of partial reionization extending to higher redshifts. However, biases in inference using τe are negligible for the Planck 2018 data. Using EoR constraints from high-redshift observations including the quasar dark fraction, galaxy UV luminosity functions, and CMB EE PS, our physical model recovers $\tau _\mathrm{ e} = 0.0569_{-0.0066}^{+0.0081}$.
Tracking the year-to-year variation in the spectral energy distribution of the narrow-line Seyfert 1 galaxy Mrk 335
Authors: Tripathi S , McGrath K M , Gallo L C , Grupe D , Komossa S , Berton M , Kriss G , Longinotti A L
Published: September 2020

Multiwavelength monitoring of Mrk 335 with Swift between 2007 and 2019 are used to construct annual spectral energy distributions (SEDs) and track year-to-year changes. Non-contemporaneous archival data prior to 2007 are used to build a bright state SED. In this work, the changes are examined and quantified to build the foundation for future SED modelling. The yearly SEDs trace a downward trend on the average, with the X-ray portion varying significantly and acquiring further lower values in the past two years when compared to the optical/UV portion of SED. The bolometric Eddington ratios derived using optical/UV to X-ray SEDs and the calculated X-ray luminosities show a gradual decrease over the monitoring period. Changes in the parameters over time are examined. Principal component analysis suggests that the primary variability is in the X-ray properties of Mrk 335. When looking at the broader picture of Mrk 335 and its behaviour, the X-rays, accounting most of the variability in the 13-yr data, are possibly driven by physical processes related to the corona or absorption whereas the modest optical–UV variations suggest their origin within the accretion disc. These results are consistent with the previous interpretation of Mrk 335 using the timing analyses on the monitoring data and spectral modelling of deep observations.
Probing the circumstellar medium 2.8 Gyr after the big bang: detection of Bowen fluorescence in the Sunburst arc
Authors: Vanzella E , Meneghetti M , Pastorello A , Calura F , Sani E , Cupani G , Caminha G B , Castellano M , Rosati P , D’Odorico V , Cristiani S , Grillo C , Mercurio A , Nonino M , Brammer G B , Hartman H
Published: September 2020

We discovered Bowen emission arising from a strongly lensed (i.e. with magnification factor μ > 20) source hosted in the Sunburst arc at z = 2.37. We claim this source is plausibly a transient stellar object and study the unique ultraviolet lines emerging from it. In particular, narrow (σv ≃ 40 km s−1) ionization lines of Fe fluoresce after being exposed to Ly α (1216 Å) radiation that pumps selectively their atomic levels. Data from VLT/MUSE, X-Shooter, and ESPRESSO observations (the latter placed at the focus of the four UTs) at increasing spectral resolution of R = 2500, 11 400, and 70 000, respectively, confirm such fluorescent lines are present since at least 3.3 yr (≃1 yr rest frame). Additional Fe forbidden lines have been detected, while C and Si doublets probe an electron density ne ≳ 106 cm−3. Similarities with the spectral features observed in the circumstellar Weigelt blobs of Eta Carinae probing the circumstellar dense gas condensations in radiation-rich conditions are observed. We discuss the physical origin of the transient event, which remains unclear. We expect such transient events (including also supernova or impostors) will be easily recognized with ELTs thanks to high angular resolution provided by adaptive optics and large collecting area, especially in modest (μ < 3) magnification regime.
Complex Evolution of Light-Dependent Protochlorophyllide Oxidoreductases in Aerobic Anoxygenic Phototrophs: Origin, Phylogeny, and Function
Authors: Chernomor Olga , Peters Lena , Schneidewind Judith , Loeschcke Anita , Knieps-Grünhagen Esther , Schmitz Fabian , von Lieres Eric , Kutta Roger Jan , Svensson Vera , Jaeger Karl-Erich , Drepper Thomas , von Haeseler Arndt , Krauss Ulrich
Published: September 2020

Light-dependent protochlorophyllide oxidoreductase (LPOR) and dark-operative protochlorophyllide oxidoreductase are evolutionary and structurally distinct enzymes that are essential for the synthesis of (bacterio)chlorophyll, the primary pigment needed for both anoxygenic and oxygenic photosynthesis. In contrast to the long-held hypothesis that LPORs are only present in oxygenic phototrophs, we recently identified a functional LPOR in the aerobic anoxygenic phototrophic bacterium (AAPB) Dinoroseobacter shibae and attributed its presence to a single horizontal gene transfer event from cyanobacteria. Here, we provide evidence for the more widespread presence of genuine LPOR enzymes in AAPBs. An exhaustive bioinformatics search identified 36 putative LPORs outside of oxygenic phototrophic bacteria (cyanobacteria) with the majority being AAPBs. Using in vitro and in vivo assays, we show that the large majority of the tested AAPB enzymes are genuine LPORs. Solution structural analyses, performed for two of the AAPB LPORs, revealed a globally conserved structure when compared with a well-characterized cyanobacterial LPOR. Phylogenetic analyses suggest that LPORs were transferred not only from cyanobacteria but also subsequently between proteobacteria and from proteobacteria to Gemmatimonadetes. Our study thus provides another interesting example for the complex evolutionary processes that govern the evolution of bacteria, involving multiple horizontal gene transfer events that likely occurred at different time points and involved different donors.
Gender-Based Evaluations Of Integrity Failures Women Leaders Judged Worse
Authors: Thomas Benjamin J , Petrow Gregory A
Published: September 2020

Although research indicates that men and women enjoy similar electoral success, individual-level studies reveal subtle differences in how voters evaluate male and female candidates. Stereotype effects have received a great deal of scholarly attention, with mixed results. However, less studied have been the effects of gender-specific expectations resulting from broadly held social roles, as described by Social Role Theory, and how the moral role expectations of men and women may lead to different evaluative standards and consequences for female candidates (cf. male candidates). Our experiment tested how evaluations of male and female candidates for high-level political office vary as a result of the candidates’ integrity level. In a mixed factorial design, we tested the effects of multiple reports of a candidate’s integrity, to determine how candidate gender and integrity level operate together to affect evaluations of political candidates. As hypothesized, in the absence of actual information concerning a candidate’s character, participants believe female candidates possess greater integrity than their male counterparts. More interestingly, women face a greater evaluative penalty for instances of low integrity, but only when respondents are exposed to multiple reports of a political candidate’s poor integrity. Male candidates are not as severely penalized as female candidates for repeated integrity failings.
A comparison of sleep, depressive symptoms, and parental perceptions between U.S. and Taiwan adolescents with self-reported sleep problems
Authors: Yang Ya-Ting , Kaplan Katherine A , Zeitzer Jamie M
Published: September 2020

Study Objectives

Inadequate sleep is pervasive among teens worldwide, resulting in daytime sleepiness and, in some cases, depressive symptoms. In addition to their own behavioral choices, parent perceptions may also play a role in adolescent sleep. This study conducted a preliminary evaluation of the antecedents and consequences of sleep factors among adolescents in the United States and Taiwan.

Methods

Participants were adolescents with self-reported sleep concerns from academically similar schools in Taiwan (n = 548) and northern California, United States (n = 128). Questionnaires on sleep and mood were administered to both the teens and parents.

Results

While Taiwanese students’ self-reported sleep behavior was generally better than U.S. students (p < .01), Taiwanese students had higher overall self-reported sleepiness (p < .01). Furthermore, Taiwanese parents reported teen sleep durations of 6.53 ± .827 hours per night during the week (with 45% perceiving this as sufficient), while U.S. parents reported teen sleep durations of 7.22 ± .930 hours (with 27% perceiving this as sufficient). Adolescents in both cohorts had high levels of symptoms consistent with depression (Taiwan: 70%, United States: 62%), which was associated with shorter sleep times for both cohorts and evening chronotype in the Taiwanese, but not U.S., adolescents.

Conclusions

Some differences exist between Taiwanese and U.S. adolescents, with generally better sleep and less sleepiness reported among students in the United States, and Taiwanese students’ sleep influenced more strongly by chronotype. Furthermore, Taiwanese parents reported less concern about their child’s insufficient sleep, despite the fact that inadequate sleep is strongly associated with depressive symptoms for both cohorts.
Involvement of a Novel TetR-Like Regulator (BdtR) of Bradyrhizobium diazoefficiens in the Efflux of Isoflavonoid Genistein
Authors: Han Fang , He Xueqian , Chen Wenwen , Gai Haoyu , Bai Xuemei , He Yongxing , Takeshima Keisuke , Ohwada Takuji , Wei Min , Xie Fang
Published: September 2020

A wide variety of leguminous plant-released (iso)flavonoids, such as genistein, are potential inducers of the nodulation (nod) genes of endosymbiotic rhizobia for the production of Nod factors, which are vital signaling molecules for triggering the symbiotic process. However, these (iso)flavonoids are generally thought to be toxic to the bacterial partner to varying degrees. Here, a novel TetR-like regulator gene of the soybean symbiont Bradyrhizobium diazoefficiens USDA110, bdtR (systematic designation blr7023), was characterized. It was found to be rapidly and preferentially induced by genistein, and its mutation resulted in significantly increased expression of the neighboring bll7019-bll7021 genes, encoding a multidrug resistance efflux pump system, in the absence of this isoflavonoid. Then, the transcriptional start site of BdtR was determined, and it was revealed that BdtR acted as a transcriptional repressor of the above efflux system through the binding of an AT-rich operator, which could be completely prevented by genistein. In addition, the ΔbdtR deletion mutant strain showed higher accumulation of extracellular genistein and became less susceptible to the isoflavonoid. In contrast, the inactivation of BdtR led to the significantly decreased induction of a nodulation gene (nodY) independent of the expression of nodD1 and nodW and to much weaker nodulation competitiveness. Taken together, the results show that BdtR plays an early sensing role in maintaining the intracellular homeostasis of genistein, helping to alleviate its toxic effect on this bacterium by negatively regulating neighboring genes encoding an efflux pump system while being essentially required for nodule occupancy competitiveness.

[Formula: see text] Copyright © 2020 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license .
The Prevalence of Incontinence-Associated Dermatitis in Hospitalized Patients in China
Authors: Wei Min , Yang Dongliang , Wu Ling , Chen Wenyue , Chen Yan , Fu Qiaomei
Published: September 2020

OBJECTIVE

To determine the prevalence and characteristics of incontinence-associated dermatitis (IAD) among hospitalized Chinese patients.

DATA SOURCES

Authors searched Chinese (China National Knowledge Infrastructure, Wanfang Data, VIP Data, Chinese Biomedicine) and English (PubMed, Web of Science) electronic databases for articles published from 1987 through February 2019.

STUDY SELECTION

The preliminary search identified 558 studies. After removal of duplicates (n = 202), application of exclusion criteria, and screening titles and abstracts (n = 346), 10 studies met the inclusion criteria.

DATA EXTRACTION

A standardized form was constructed to extract data from eligible studies, and this information was extracted by two independent authors.

DATA SYNTHESIS

A pooled analysis of the 10 studies (total sample size, 40,039) showed the prevalence of IAD in hospitalized Chinese patients was 1.44% (95% confidence interval, 1.10%–1.79%). Subgroup analysis indicated no significant association between sex and IAD. Patients older than 90 years had the highest incidence of IAD (8.64%). The most common type was mild IAD (1.00%). Fecal incontinence (48.02%) led to more cases of IAD than urinary incontinence (11.35%) or both (25.78%). The most common types of IAD were perineal (0.92%) and perianal (0.90%).

CONCLUSIONS

Incontinence-associated dermatitis is a global health problem that requires more attention. Understanding the prevalence and characteristics of IAD is helpful in the formulation of IAD prevention and treatment programs in China.
Vasopressor-Refractory Shock From Clozapine Overdose Treated With Synthetic Angiotensin II Infusion
Authors: Wieruszewski Patrick M. , Nelson Sarah , Wittwer Erica D. , Leung Jonathan G.
Published: September 2020

Background:

Clozapine is an atypical antipsychotic with potent alpha-adrenergic blocking properties when administered at high dosages, resulting in vasodilatory shock in overdose settings.

Case Summary:

A 39-year-old man presented with profound catecholamine- and vasopressin-refractory vasodilatory shock following massive clozapine ingestion. Angiotensin II was initiated when the patient was requiring 2.2 µg/kg/min norepinephrine equivalents of vasopressor support, resulting in a prompt increase in the perfusion pressure. All vasopressors were liberated within 18 hours of angiotensin II initiation, and the patient was discharged with no deficits.

Conclusions:

Synthetic angiotensin II may represent a therapeutic option for refractory hypotension resulting from high dosages of clozapine or other potent alpha-adrenergic blocking medications.
Quantitative evaluation of electrical conductivity inside stress corrosion crack with electromagnetic NDE methods
Authors: Cai Wenlu , Jomdecha Cherdpong , Zhao Yingsong , Wang Li , Xie Shejuan , Chen Zhenmao
Published: September 2020

This paper presents a comparison of studies on the local distributed electrical conductivity in stress corrosion crack (SCC) from signals of eddy current testing (ECT) and direct current potential drop (DCPD) aiming to improve SCC sizing accuracy when using electromagnetic non-destructive testing (NDT) methods. Experimental setups of ECT and DCPD were established, respectively, to collect measurement signals due to artificial SCCs in a plate of austenitic stainless steel. The local conductivity in the SCC region was reconstructed from the feature parameters extracted from the measured ECT and DCPD signals through inverse analyses. The inversion strategies for ECT and DCPD, each including an efficient forward simulation and an optimization scheme, were introduced from the viewpoint of conductivity reconstruction. Inversion results obtained from the measured ECT and DCPD signals showed the consistent trend which proved the validity of the predicted electrical conductivity indirectly. It is clarified that the electrical conductivity in a SCC is relatively high at the crack tip area and may become as high as 17% of that of the base material. These results provide a good reference to enhance the sizing accuracy of SCC with an electromagnetic NDT method such as ECT by updating the conductive crack model based on the results of this work.

This article is part of the theme issue ‘Advanced electromagnetic non-destructive evaluation and smart monitoring’.
Physic perspective fusion of electromagnetic acoustic transducer and pulsed eddy current testing in non-destructive testing system
Authors: Guo Wei , Gao Bin , Yun Tian Gui , Si Dan
Published: September 2020

Comprehensive non-destructive testing (NDT) for pipelines is a critical and challenging task. This paper proposes a novel physic perspective fusion NDT method of electromagnetic acoustic transducer (EMAT) and pulsed Eddy current testing (PECT) for detecting hybrid defects. This transceiver-integrated fusion sensor structure can simultaneously excite ultrasound and pulsed eddy current. Therefore, the generated ultrasound is applied to detect deep defects, while the eddy current detects surface defects. The theoretical derivation of EMAT and PECT fusion mechanism has been developed for analysis and interpretation of the results. In addition, numerical simulation on the detection of hybrid defects including surface defects with different width, depth and multiple bottom-thinning defects has been conducted. Experiments on both ferromagnetic and non-ferromagnetic material verify the feasibility of composite detection. Finally, tests have been validated on pipeline with weld defects, and the results show that the composite inspection method is capable of monitoring thickness variations and inspecting surface defects.

This article is part of the theme issue ‘Advanced electromagnetic non-destructive evaluation and smart monitoring’.
An invasive infection with an unusual spaB-possessing Erysipelothrix rhusiopathiae in a human
Authors: Taguchi Yudai , Shiraiwa Kazumasa , Ogawa Yohsuke , Oi Tomoki , Nakamura Shigeo , Okumura Junichiro , Shimoji Yoshihiro
Published: September 2020

Erysipelothrix rhusiopathiae

is a zoonotic pathogen that causes erysipelas in a variety of animals. In humans, in contrast to the cutaneous form called erysipeloid, which is an occupational disease and common in individuals who handle raw meat and fish, invasive systemic infections are unusual.

E. rhusiopathiae

expresses an immunogenic surface protein, Spa (surface protective antigen), which is involved in virulence. Among the antigenically different Spa proteins (SpaA, B and C), which are mostly associated with serovars, SpaA is by far the most prevalent in

E. rhusiopathiae

isolates from diseased animals. However, the Spa type has not been examined for human isolates, and it is unknown whether SpaB- or SpaC-possessing isolates can cause disease in humans. A Gram-positive, rod-shaped bacterium isolated from a case of human pyogenic spondylitis was analysed. The bacterium was identified as

E. rhusiopathiae

by a routine biochemical test and MS, and ultimately confirmed by an

E. rhusiopathiae

-specific PCR assay. Spa typing by sequencing revealed the SpaB type, and the serovar of the strain was identified as untypeable by a conventional agar gel precipitation test, but determined to be serovar 6 by a serotyping PCR assay. Sequence analysis of the serovar-defining chromosomal region revealed that the isolate displayed the same gene organization as the serovar 6 reference strain, but the region was disrupted by an insertion sequence element, suggesting that the isolate originated from a serovar 6 strain. These results highlight that unusual, spaB-possessing

E. rhusiopathiae

strains can potentially pose serious risks to humans.
Health-related effects of education level: a Mendelian randomization study
Authors: Yuan Shuai , Xiong Ying , Michaëlsson Madeleine , Michaëlsson Karl , Larsson Susanna C.
Published: September 2020

Background

A deeper understanding of the causal links from education level to health outcomes may shed a light for disease prevention at a novel and efficient perspective.

Methods

We conducted a wide-angled Mendelian randomization to disentangle the causal role of education level from intelligence for 31 health outcomes and explore to what extent body mass index and smoking mediate the associations. Univariable and multivariable Mendelian randomization analyses were performed.

Results

Genetically higher education level was associated with lower risk of major mental disorders and most somatic diseases independent of intelligence. The intelligence-adjusted odds ratios for each additional standard deviation of education (4.2 years) were 0.48 (0.37, 0.62) for suicide attempts, 0.50 (0.36, 0.68) for large artery stroke, 0.51 (0.42, 0.63) for heart failure, 0.52 (0.42, 0.65) for lung cancer, 0.45 (0.33,0.61) for rheumatoid arthritis, and 0.48 (0.43, 0.55) for type 2 diabetes. Higher education level adjusted for intelligence was additionally associated with lower risk of insomnia, major depressive disorder, stroke, coronary artery disease, breast cancer, ovarian cancer and gout but with higher risk of obsessive-compulsive disorder, anorexia nervosa, bipolar disorder and prostate cancer. Moreover, higher education level was associated with modifiable health-related risk factors in a favorable manner. Adjustment for body mass index and smoking attenuated the associations between education level and several outcomes, especially for type 2 diabetes and heart failure. High education level exerts causal protective effects on major somatic diseases.

Conclusions

These findings emphasize the importance of education to reduce the burden of common diseases.
Does pericentral mu-rhythm “power” corticomotor excitability? – a matter of EEG perspective
Authors: Karabanov Anke Ninija , Madsen Kristoffer Hougaard , Krohne Lærke Gebser , Siebner Hartwig Roman
Published: September 2020

Background

Electroencephalography (EEG) and single-pulse transcranial magnetic stimulation (spTMS) of the primary motor hand area (M1-HAND) have been combined to explore whether the instantaneous expression of pericentral mu-rhythm drives fluctuations in corticomotor excitability, but this line of research has yielded diverging results.

Objectives

To re-assess the relationship between the mu-rhythm power expressed in left pericentral cortex and the amplitude of motor potentials (MEP) evoked with spTMS in left M1-HAND.

Methods

15 non-preselected healthy young participants received spTMS to the motor hot spot of left M1-HAND. Regional expression of mu-rhythm was estimated online based on a radial source at motor hotspot and informed the timing of spTMS which was applied either during epochs belonging to the highest or lowest quartile of regionally expressed mu-power. Using MEP amplitude as dependent variable, we computed a linear mixed-effects model, which included mu-power and mu-phase at the time of stimulation and the inter-stimulus interval (ISI) as fixed effects and subject as a random effect. Mu-phase was estimated by post-hoc sorting of trials into four discrete phase bins. We performed a follow-up analysis on the same EEG-triggered MEP data set in which we isolated mu-power at the sensor level using a Laplacian montage centered on the electrode above the M1-HAND.

Results

Pericentral mu-power traced as radial source at motor hot spot did not significantly modulate the MEP, but mu-power determined by the surface Laplacian did, showing a positive relation between mu-power and MEP amplitude. In neither case, there was an effect of mu-phase on MEP amplitude.

Conclusion

The relationship between cortical oscillatory activity and cortical excitability is complex and minor differences in the methodological choices may critically affect sensitivity.
Chronic Exposure to Glucocorticoids Induces Suboptimal Decision-Making in Mice
Authors: Cabeza Lidia , Ramadan Bahrie , Giustiniani Julie , Houdayer Christophe , Pellequer Yann , Gabriel Damien , Fauconnet Sylvie , Haffen Emmanuel , Risold Pierre-Yves , Fellmann Dominique , Belin David , Peterschmitt Yvan
Published: September 2020

Anxio-depressive symptoms as well as severe cognitive dysfunction including aberrant decision-making (DM) are documented in neuropsychiatric patients with hypercortisolaemia. Yet, the influence of the hypothalamo-pituitary-adrenal (HPA) axis on DM processes remains poorly understood. As a tractable mean to approach this human condition, adult male C57BL/6JRj mice were chronically treated with corticosterone (CORT) prior to behavioural, physiological and neurobiological evaluation. The behavioural data indicate that chronic CORT delays the acquisition of contingencies required to orient responding towards optimal DM performance in a mouse Gambling Task (mGT). Specifically, CORT-treated animals show a longer exploration and a delayed onset of the optimal DM performance. Remarkably, the proportion of individuals performing suboptimally in the mGT is increased in the CORT condition. This variability seems to be better accounted for by variations in sensitivity to negative rather than to positive outcome. Besides, CORT-treated animals perform worse than control animals in a spatial working memory (WM) paradigm and in a motor learning task. Finally, Western blotting neurobiological analyses show that chronic CORT downregulates glucocorticoid receptor expression in the medial Prefrontal Cortex (mPFC). Besides, corticotropin-releasing factor signalling in the mPFC of CORT individuals negatively correlates with their DM performance. Collectively, this study describes how chronic exposure to glucocorticoids induces suboptimal DM under uncertainty in a mGT, hampers WM and motor learning processes, thus affecting specific emotional, motor, cognitive and neurobiological endophenotypic dimensions relevant for precision medicine in biological psychiatry.
PSA-targeted Alpha-, Beta- and Positron Emitting Immuno-Theranostics in Murine Prostate Cancer Models and Non-Human Primates
Authors: Veach Darren R. , Storey Claire M. , Lückerath Katharina , Braun Katharina , von Bodman Christian , Lamminmäki Urpo , Kalidindi Teja , Strand Sven-Erik , Strand Joanna , Altai Mohamed , Damoiseaux Robert , Zanzonico Pat , Benabdallah Nadia , Pankov Dmitry , Scher Howard I. , Scardino Peter , Larson Steven M. , Lilja Hans , McDevitt Michael R. , Thorek Daniel L. J. , Ulmert David
Published: September 2020

Purpose

Most prostate cancer (PCa) patients treated with androgen receptor (AR)-signaling inhibitors develop therapeutic resistance due to restoration of AR-functionality. Thus, there is a critical need for novel treatment approaches. Here we investigate the theranostic potential of hu5A10, a humanized monoclonal antibody specifically targeting free prostate-specific antigen (KLK3).

Experimental Design

LNCaP-AR xenografts (NSG mice) andKLK3_Hi-Myctransgenic mice were imaged with89Zr- or treated with90Y- or225Ac-labeled hu5A10; biodistribution and subcellular localization were analyzed by gamma-counting, positron emission tomography (PET), autoradiography and microscopy. Therapeutic efficacy of [225Ac]hu5A10 and [90Y]hu5A10 in LNCaP-AR tumors was assessed by tumor volume measurements, time to nadir (TTN), time to progression (TTP), and survival. Pharmacokinetics of [89Zr]hu5A10 in non-human primates (NHP) were determined using PET.

Results

Biodistribution of radiolabeled hu5A10-constructs was comparable in different mouse models. Specific tumor uptake increased over time and correlated with PSA expression. Treatment with [90Y]/[225Ac]hu5A10 effectively reduced tumor burden and prolonged survival (p≤0.0054). Effects of [90Y]hu5A10 were more immediate than [225Ac]hu5A10 (TTN, p<0.0001) but less sustained (TTP, p<0.0001). Complete responses were observed in 7/18 [225Ac]hu5A10 and 1/9 mice [90Y]hu5A10. Pharmacokinetics of [89Zr]hu5A10 were consistent between NHPs and comparable to those in mice. [89Zr]hu5A10-PET visualized the NHP-prostate over the 2-week observation period.

Conclusions

We present a complete preclinical evaluation of radiolabeled hu5A10 in mouse PCa models and NHPs, and establish hu5A10 as a new theranostic agent that allows highly specific and effective downstream targeting of AR in PSA-expressing tissue. Our data support the clinical translation of radiolabeled hu5A10 for treating PCa.
Inequality in access to health and care services during lockdown – Findings from the COVID-19 survey in five UK national longitudinal studies
Authors: Topriceanu Constantin-Cristian , Wong Andrew , Moon James C , Hughes Alun D , Bann David , Chaturvedi Nish , Patalay Praveetha , Conti Gabriella , Captur Gabriella
Published: September 2020

Background

Access to health services and adequate care is influenced by sex, ethnicity, socio-economic position (SEP) and burden of co-morbidities. However, it is unknown whether the COVID-19 pandemic further deepened these already existing health inequalities.

Methods

Participants were from five longitudinal age-homogenous British cohorts (born in 2001, 1990, 1970, 1958 and 1946). A web and telephone-based survey provided data on cancelled surgical or medical appointments, and the number of care hours received during the UK COVID-19 national lockdown. Using binary or ordered logistic regression, we evaluated whether these outcomes differed by sex, ethnicity, SEP and having a chronic illness. Adjustment was made for study-design, non-response weights, psychological distress, presence of children or adolescents in the household, keyworker status, and whether participants had received a shielding letter. Meta-analyses were performed across the cohorts and meta-regression evaluated the effect of age as a moderator.

Findings

14891 participants were included. Females (OR 1·40, 95% confidence interval [1·27,1·55]) and those with a chronic illness (OR 1·84 [1·65-2·05]) experienced significantly more cancellations during lockdown (all p<0·0001). Ethnic minorities and those with a chronic illness required a higher number of care hours during the lockdown (both OR ≈2·00, all p<0·002). Age was not independently associated with either outcome in meta-regression. SEP was not associated with cancellation or care hours.

Interpretation

The UK government’s lockdown approach during the COVID-19 pandemic appears to have deepened existing health inequalities, impacting predominantly females, ethnic-minorities and those with chronic illnesses. Public health authorities need to implement urgent policies to ensure equitable access to health and care for all in preparation for a second wave.
Economic implications of polypharmacy in Nepal: Multicenter community-based study
Authors: Sapkota Binaya , Shakya Suraj , Sah Saroj , Chaudhary Narendra , Tamang Bijendra , Karki Saugat Singh
Published: September 2020

Objective

Improper management of polypharmacy in community and hospital pharmacies may lead to adverse effects and drug interactions in patients of all age groups, especially children and the elderly. This study aimed to determine the scenario of polypharmacy in multiple communities in Nepal and the costs associated with them.

Design

Cross-sectional study

Setting

Local communities of nine districts in Nepal

Participants

Total 400 patients of all age groups, who were consuming medicines and who fulfilled inclusion criteria from May 2017 to August 2018

Primary and secondary outcome measures

A semi-structured questionnaire, based on the prescription optimization method, was used for data collection. Multinomial logistic regression was performed to analyze the statistical significance of polypharmacy with the predictor variables (e.g., age, education level, occupation, diagnosis, total cost of medicines). The p-value < 0.05 was considered statistically significant at 95% confidence interval. Polypharmacy cases and their economic implications were reported.

Results

Eighty-one patients (20.3%) with an age group of 22-31 years with female patients (219, 54.8%) reported more polypharmacy events. There were 216 patients (54%) with prescriptions of five medicines i.e., moderate polypharmacy. Total number of medicines consumed by all 400 patients was 2269, with a mean±SD 5.67 ±1.08. Total expenditure by all 400 patients was USD 3409.54 during the study period, with a mean±SD8.66±6.04. Both moderate and severe polypharmacy cases were non-significantly related with age, gender and total cost of medications. They had significant relationship in almost all levels of education and occupation and showed mixed type of significance and non-significance with the diagnosis of the respondents.

Conclusion

Polypharmacy cases can be minimized, considering adverse drug reactions and drug interactions. Further studies are warranted in medication utilization and avoidable polypharmacy along with detailed pharmacoeconomic evaluation.
A new model of decision processing in instrumental learning tasks
Authors: Miletić Steven , Boag Russell J. , Trutti Anne C. , Forstmann Birte U. , Heathcote Andrew
Published: September 2020

Learning and decision making are interactive processes, yet cognitive modelling of error-driven learning and decision making have largely evolved separately. Recently, evidence accumulation models (EAMs) of decision making and reinforcement learning (RL) models of error-driven learning have been combined into joint RL-EAMs that can in principle address these interactions. However, we show that the most commonly used combination, based on the diffusion decision model (DDM) for binary choice, consistently fails to capture crucial aspects of response times observed during reinforcement learning. We propose a new RL-EAM based on an advantage racing diffusion (ARD) framework for choices among two or more options that not only addresses this problem but captures stimulus difficulty, speed-accuracy trade-off, and stimulus-response-mapping reversal effects. The RL-ARD avoids fundamental limitations imposed by the DDM on addressing effects of absolute values of choices, as well as extensions beyond binary choice, and provides a computationally tractable basis for wider applications.
Prolonged low-dose dioxin exposure impairs metabolic adaptability to high-fat diet feeding in female but not male mice
Authors: Matteo Geronimo , Hoyeck Myriam P , Blair Hannah L , Zebarth Julia , Rick Kayleigh RC , Williams Andrew , Gagné Rémi , Buick Julie K , Yauk Carole L , Bruin Jennifer E
Published: September 2020

Objective

Human studies consistently show an association between exposure to persistent organic pollutants, including 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, aka “dioxin”), and increased diabetes risk, but rarely consider potential sex differences. We previously showed that a single high-dose TCDD exposure (20 µg/kg) decreased plasma insulin levels in both male and female micein vivo, but effects on glucose homeostasis were sex-dependent. The purpose of the current study was to determine whether prolonged exposure to a physiologically relevant low-dose of TCDD impacts glucose homeostasis and/or the islet phenotype in a sex-dependent manner in either chow-fed or high fat diet (HFD)-fed mice.

Methods

Male and female mice were exposed to 20 ng/kg/d TCDD 2x/week for 12 weeks and simultaneously fed standard chow or a 45% HFD. Glucose homeostasis was assessed by glucose and insulin tolerance tests, and glucose-induced plasma insulin levels were measuredin vivo. Histological analysis was performed on pancreas from male and female mice, and islets were isolated from females at 12 weeks for Tempo-Seq® analysis.

Results

Low-dose TCDD exposure did not lead to adverse metabolic consequences in chow-fed male or female mice, or in HFD-fed males. However, TCDD accelerated the onset of HFD-induced hyperglycemia and impaired glucose-induced plasma insulin levels in female mice. TCDD caused a modest increase in islet area in males irrespective of diet, but reduced % beta cell area within islets in females. RNAseq analysis of female islets also revealed abnormal changes to endocrine and metabolic pathways in TCDD-exposed HFD-fed females compared chow-fed females.

Conclusions

Our data suggest that prolonged low-dose TCDD exposure has minimal effects on glucose homeostasis and islet morphology in chow-fed male and female mice, but promotes maladaptive metabolic responses in HFD-fed females.
Rapid development of cloud-native intelligent data pipelines for scientific data streams using the HASTE Toolkit
Authors: Blamey Ben , Toor Salman , Dahlö Martin , Wieslander Håkan , Harrison Philip J , Sintorn Ida-Maria , Sabirsh Alan , Wählby Carolina , Spjuth Ola , Hellander Andreas
Published: September 2020

This paper introduces theHASTE Toolkit, a cloud-native software toolkit capable of partitioning data streams in order to prioritize usage of limited resources. This in turn enables more efficient data-intensive experiments. We propose a model that introduces automated, autonomous decision making in data pipelines, such that a stream of data can be partitioned into a tiered or ordereddata hierarchy. Importantly, the partitioning is online and based on data content rather thana priorimetadata. At the core of the model areinterestingness functionsandpolicies. Interestingness functions assign a quantitative measure of interestingness to a single data object in the stream, an interestingness score. Based on this score, a policy guides decisions on how to prioritize computational resource usage for a given object. The HASTE Toolkit is a collection of tools to adapt data stream processing to this pipeline model. The result is smart data pipelines capable of effective or even optimal use of e.g. storage, compute and network bandwidth, to support experiments involving rapid processing of scientific data characterized by large individual data object sizes. We demonstrate the proposed model and our toolkit through two microscopy imaging case studies, each with their own interestingness functions, policies, and data hierarchies. The first deals with a high content screening experiment, where images are analyzed in an on-premise container cloud with the goal of prioritizing the images for storage and subsequent computation. The second considers edge processing of images for upload into the public cloud for a real-time control loop for a transmission electron microscope.

Key Points

We propose a pipeline model for building intelligent pipelines for streams, accounting for actual information content in data rather thana priorimetadata, and present the HASTE Toolkit, a cloud-native software toolkit for supporting rapid development according to the proposed model.

We demonstrate how the HASTE Toolkit enables intelligent resource optimization in two image analysis case studies based on a) high-content imaging and b) transmission electron microscopy.

We highlight the challenges of storage, processing and transfer in streamed high volume, high velocity scientific data for both cloud and cloud-edge use cases.