bluuebunny/crossref_metadata_2025 huggingface dataset:
Maternal smoking during pregnancy and offspring intellectual disability: sibling analysis in an intergenerational Danish cohort
Authors: Madley-Dowd Paul , Kalkbrenner Amy E. , Heuvelman Hein , Heron Jon , Zammit Stanley , Rai Dheeraj , Schendel Diana
Published: October 2020

Background

Maternal smoking has known adverse effects on fetal development. However, research on the association between maternal smoking during pregnancy and offspring intellectual disability (ID) is limited, and whether any associations are due to a causal effect or residual confounding is unknown.

Method

Cohort study of all Danish births between 1995 and 2012 (1 066 989 persons from 658 335 families after exclusions), with prospectively recorded data for cohort members, parents and siblings. We assessed the association between maternal smoking during pregnancy (18.6% exposed, collected during prenatal visits) and offspring ID (8051 cases, measured using ICD-10 diagnosis codes F70–F79) using logistic generalised estimating equation regression models. Models were adjusted for confounders including measures of socio-economic status and parental psychiatric diagnoses and were adjusted for family averaged exposure between full siblings. Adjustment for a family averaged exposure allows calculation of the within-family effect of smoking on child outcomes which is robust against confounders that are shared between siblings.

Results

We found increased odds of ID among those exposed to maternal smoking in pregnancy after confounder adjustment (OR 1.35, 95% CI 1.28–1.42) which attenuated to a null effect following adjustment for family averaged exposure (OR 0.91, 95% CI 0.78–1.06).

Conclusions

Our findings are inconsistent with a causal effect of maternal smoking during pregnancy on offspring ID risk. By estimating a within-family effect, our results suggest that prior associations were the result of unmeasured genetic or environmental characteristics of families in which the mother smokes during pregnancy.
The structure of developing semantic networks: Evidence from single and multiple nominal word associations in young monolingual and bilingual readers
Authors: Spätgens Tessa , Schoonen Rob
Published: October 2020

The present study focuses on the effect of an important methodological choice in word association studies in children: the elicitation of single versus multiple responses. This choice has been shown to affect the numbers and types of associations adults produce, however, little is known about how it affects children’s word associations. A total of 11,725 associations to 80 nouns from 207 monolingual and bilingual minority children were classified according to a detailed coding system, and differences between the semantic characteristics of first, second, and third responses were examined. We show that in children as well, the multiple association task elicits more and qualitatively different responses, resulting in more diversified semantic networks surrounding the stimulus nouns. On the speaker level, reading comprehension scores were related differently to initial and later responses, suggesting a more complex measure of semantic knowledge emerges from the multiple word association task. No differences were found between monolingual and bilingual children’s associative preferences. We argue that the multiple association task produces more detailed data on language users’ semantic networks than the single association task, and suggest a number of ways in which this task could be employed in future research.
5-Alfa reductase type 2 (SRD5A2) gene rs523349 polymorphism is not associated with non-obstructive azoospermia in Turkish patients
Authors: Serdarogullari Munevver , Coban Onder , Yarkiner Zalihe , Gulec Yilmaz Seda , Akdeniz Tuba , Isbir Turgay
Published: October 2020

Spermatogenesis is an androgen-dependent event, and testosterone is the major androgen source. The enzyme 5-alpha reductase converts testosterone to dihydrotestosterone (DHT) in testicular and peripheral tissues. Polymorphisms in genes encoding 5-alpha reductase may be associated with impaired male fertility. The present study aimed to investigate the relationship between 5-alpha reductase type 2 (SRD5A2) gene rs523349 polymorphism and non-obstructive azoospermia (NOA) in Turkish patients. The study included 75 NOA patients and 43 fertile men from Turkey. No significant relationship was found between SRD5A2 gene rs523349 polymorphism and male infertility (P = 0.071). There was a statistically significant difference in total testosterone level and total testis volume between NOA patients and the control groups, however there was no significant difference between serum follicle-stimulating hormone and luteinizing hormone levels. Our results showed that SRD5A2 gene rs523349 polymorphism was not associated with NOA in Turkish patients.
Echocardiographic versus angiographic measurement of the aortic valve annulus in children undergoing balloon aortic valvuloplasty: method affects outcomes
Authors: Nicholson George T. , Goldstein Bryan H. , Gao Kevin , Sachdeva Ritu , Lang Sean M. , Gillespie Scott , Kim Sung-in H. , Petit Christopher J.
Published: October 2020

Objective:

Operators are mindful of the balloon-to-aortic annulus ratio when performing balloon aortic valvuloplasty. The method of measurement of the aortic valve annulus has not been standardised.

Methods and results:

Patients who underwent aortic valvuloplasty at two paediatric centres between 2007 and 2014 were included. The valve annulus measured by echocardiography and angiography was used to calculate the balloon-to-aortic annulus ratio and measurements were compared. The primary endpoint was an increase in aortic insufficiency by ≥2 degrees. Ninety-eight patients with a median age at valvuloplasty of 2.1 months (Interquartile range (IQR): 0.2–105.5) were included. The angiographic-based annulus was 8.2 mm (IQR: 6.8–16.0), which was greater than echocardiogram-based annulus of 7.5 mm (IQR: 6.1–14.8) (p < 0.001). This corresponded to a significantly lower angiographic balloon-to-aortic annulus ratio of 0.9 (IQR: 0.9–1.0), compared to an echocardiographic ratio of 1.1 (IQR: 1.0–1.1) (p < 0.001). The degree of discrepancy in measured diameter increased with smaller valve diameters (p = 0.041) and in neonates (p = 0.044). There was significant disagreement between angiographic and echocardiographic balloon-to-aortic annulus ratio measures regarding “High” ratio of >1.2, with angiographic ratio flagging only 2/12 (16.7%) of patients flagged by echocardiographic ratio as “High” (p = 0.012). Patients who had an increase in the degree of aortic insufficiency post valvuloplasty, only 3 (5.5%) had angiographic ratio > 1.1, while 21 (38%) had echocardiographic ratio >1.1 (p < 0.001). Patients with resultant ≥ moderate insufficiency more often had an echocardiographic ratio of >1.1 than angiographic ratio of >1.1 There was no association between increase in balloon-to-aortic annulus ratio and gradient reduction.

Conclusions:

Angiographic measurement is associated with a greater measured aortic valve annulus and the development of aortic insufficiency. Operators should use caution when relying solely on angiographic measurement when performing balloon aortic valvuloplasty.
A fully-textile wideband AMC-backed antenna for wristband WiMAX and medical applications
Authors: El Atrash Mohamed , Abdalla Mahmoud A. , Elhennawy Hadia M.
Published: October 2020

Proposed is a wideband, low profile, fully flexible, and all-textile-based slotted triangular antenna loaded with a 2 × 2 textile-inspired artificial magnetic conductor to be worn on the wrist. The integrated antenna design is designed to cover the frequency band from 3.1 to 6.5 GHz. The integrated design has two main resonances, where the first one is at 3.5 GHz, which can serve the WiMAX communication standard, while the second is at 5.8 GHz, which can serve the Industrial, Scientific and Medical (ISM)-band. The incorporated textile materials are composed of the conductive and dielectric fabrics that are realized by ShieldIt and Felt, respectively. When simulated against the human model wrist, the integrated antenna design displayed a realized gain of 6.71 dBi and radiation efficiency of 79.1%, at 3.5 GHz. Furthermore, at 5.8 GHz, it displayed a realized gain of 7.82 dBi and total efficiency performances of 66.1%. Moreover, it accomplished very low SAR levels within the antenna frequency band. Averaged over 1 g of tissue, it exhibited maximum SAR levels of 3.28 × 10−6 and 9.37 × 10−7 W/kg at 3.5 and 5.8 GHz, respectively. For the bent scenarios, the integrated antenna design displayed robustness when bent at an angle of 20 and 40°. Finally, measurement results are illustrated and analyzed. Based on the presented results, the suggested all-textile integrated antenna design might be designated for integration with the wristband to monitor the user health conditions through many possible frequency channels.
Indonesia's Position in Asia: Increasing Soft Power and Connectivity through the 2018 Asian Games
Authors: Trotier Friederike
Published: October 2020

Hosting a sports mega-event strengthens connectivity with the world and provides opportunities to establish or increase networks and to build soft power. These events operate as hubs for the global flow of capital, people, knowledge and technology, and they perform important rituals and symbolic functions. In particular, they become coveted opportunities to enrich the soft power portfolio of governments or individual leaders. Despite its regional character, the Asian Games have developed into such a mega-event. In 2018 – only for the second time in the history of the Asian Games – Indonesia staged the event in Jakarta and Palembang. This paper scrutinises the ways in which Indonesia used or failed to use the Asian Games as a platform to increase the country's soft power and reputation and to strengthen intra-Asian connectivity. Three aspects serve as examples to assess Indonesia's soft power initiatives: (1) the “spirit of 1962”, (2) the host country's emergence on the Asian stage and (3) Indonesia's cooperation with other countries and intra-Asia connections in the context of the sports event. Examining the prominence of domestic politics reveals shortcomings and untapped potential. The analysis shows that the inward-looking foreign policy approach of the Jokowi administration limited the initiatives to increase Indonesian soft power and to establish and address Asian themes and debates; consequently, this approach downgraded the sports event to a tool to generate political capital for domestic affairs.
Go East! 1905 as a Turning Point for the Transnational History of Vietnamese Education
Authors: Legrandjacques Sara
Published: October 2020

This paper discusses the year 1905 as an educational watershed in colonial Vietnam. It focuses on the development of student mobility that transcended colonial and imperial boundaries and gave new momentum to educational training on a transnational scale. In the mid-1900s, the anti-colonial mandarin Phan Bội Châu launched a new nationalist movement calledĐông Du, meaning ‘Going East.’ It centred on sending young men to Japan via Hong Kong to train them as effective anti-French activists. These students came from Tonkin, Annam, and Cochinchina and enrolled in a variety of curricula. Although this initiative collapsed in the late 1900s, it remained a watershed. Regional mobility did not disappear afterwards but mostly redirected itself towards China. This paper brings a great diversity of material face-to-face, including governmental archives and biographies, and challenges the colonial-based vision of Vietnamese education by highlighting its regional dimension, from the early twentieth century to the outset of the Second World War.
Comparison of aminocyclopyrachlor to standard herbicides for basal stem treatment of Eucalyptus benthamii
Authors: Minogue Patrick J. , Lorentz Kimberly A.
Published: October 2020

Eucalyptus species are grown for fiber, fuel, and other uses on more than 17.8 million ha worldwide, yet some species are considered invasive and may have adverse environmental or social impacts outside their native range. Aminocyclopyrachlor (AMCP) and standard applications of imazapyr and triclopyr herbicides were compared for eucalyptus control using a basal stem application method. At 6 and 12 mo after treatment (MAT), basal stem applications using 5% (vol/vol) AMCP (120 g ae L−1) in methylated soybean oil (MSO) resulted in 97% to 99% eucalyptus crown reduction and generally provided greater control across all diameter classes than standard treatments of 28% imazapyr (240 g ae L−1) or 75% triclopyr ester (480 g ae L−1). AMCP at 5% was as effective as 40% vol/vol. Increases in stem live height at 24 MAT suggest that the effect of triclopyr ester basal stem treatment may be impermanent. AMCP treated trees did not have regrowth by 24 MAT.
Angular Dependence and Spatial Distribution of Jupiter's Centimeter‐Wave Thermal Emission From Juno's Microwave Radiometer
Authors: Oyafuso Fabiano , Levin Steven , Orton Glenn , Brown Shannon T. , Adumitroaie Virgil , Janssen Michael , Wong Michael H. , Fletcher Leigh N. , Steffes Paul , Li Cheng , Gulkis Samuel , Atreya Sushil , Misra Sidharth , Bolton Scott
Published: October 2020

NASA's Juno spacecraft has been monitoring Jupiter in 53‐day orbits since 2016. Its six‐frequency microwave radiometer (MWR) is designed to measure black body emission from Jupiter over a range of pressures from a few tenths of a bar to several kilobars in order to retrieve details of the planet's atmospheric composition, in particular, its ammonia and water abundances. A key step toward achieving this goal is the determination of the latitudinal dependence of the nadir brightness temperature and limb darkening of Jupiter's thermal emission through a deconvolution of the measured antenna temperatures. We present a formulation of the deconvolution as an optimal estimation problem. It is demonstrated that a quadratic expression is sufficient to model the angular dependence of the thermal emission for the data set used to perform the deconvolution. Validation of the model and results from a subset of orbits favorable for MWR measurements is presented over a range of latitudes that cover up to 60° from the equator. A heuristic algorithm to mitigate the effects of nonthermal emission is also described.
Detectability of Artificial Ocean Alkalinization and Stratospheric Aerosol Injection in MPI‐ESM
Authors: Fröb Friederike , Sonntag Sebastian , Pongratz Julia , Schmidt Hauke , Ilyina Tatiana
Published: October 2020

To monitor the success of carbon dioxide removal (CDR) or solar radiation management (SRM) that offset anthropogenic climate change, the forced response to any external forcing is required to be detectable against internal variability. Thus far, only the detectability of SRM has been examined using both a stationary and nonstationary detection and attribution method. Here, the spatiotemporal detectability of the forced response to artificial ocean alkalinization (AOA) and stratospheric aerosol injection (SAI) as exemplary methods for CDR and SRM, respectively, is compared in Max Planck Institute Earth System Model (MPI‐ESM) experiments using regularized optimal fingerprinting and single‐model estimates of internal variability, while working under a stationary or nonstationary null hypothesis. Although both experiments are forced by emissions according to the Representative Concentration Pathway 8.5 (RCP8.5) and target the climate of the RCP4.5 scenario using AOA or SAI, detection timescales reflect the fundamentally different forcing agents. Moreover, detectability timescales are sensitive to the choice of null hypothesis. Globally, changes in the CO2 system in seawater are detected earlier than the response in temperature to AOA but later in the case of SAI. Locally, the detection time scales depend on the physical, chemical, and radiative impacts of CDR and SRM forcing on the climate system, as well as patterns of internal variability, which is highlighted for oceanic heat and carbon storage.
Influence of Inflow Density and Temperature Asymmetry on the Formation of Electron Jets during Magnetic Reconnection
Authors: Montag Peter , Egedal Jan , Daughton William
Published: October 2020

The structure of the electron diffusion region (EDR), fundamental to a comprehensive theory of magnetic reconnection, is highly sensitive to asymmetry in the plasma parameters across the reconnection current layer. Using known scaling laws for the inflow region electron pressure anisotropy, a model is developed to predict the formation of extended electron jets within the EDR. Confirmed by kinetic simulation, the analysis shows how embedded electron jets are driven for scenarios fulfilling a generalized symmetry conditions based on the marginal firehose condition.
Seafloor Depth of George VI Sound, Antarctic Peninsula, From Inversion of Aerogravity Data
Authors: Constantino Renata R. , Tinto Kirsty J. , Bell Robin E. , Porter David F. , Jordan Tom A.
Published: October 2020

George VI Sound is an ~600 km‐long curvilinear channel on the west coast of the southern Antarctic Peninsula separating Alexander Island from Palmer Land. The Sound is a geologically complex region presently covered by the George VI Ice Shelf. Here we model the bathymetry using aerogravity data. Our model is constrained by water depths from seismic measurements. We present a crustal density model for the region, propose a relocation for a major fault in the Sound, and reveal a dense body, ~200 km long, flanking the Palmer Land side. The southern half of the Sound consists of two distinct basins ~1,100 m deep, separated by a −650 m‐deep ridge. This constricting ridge presents a potential barrier to ocean circulation beneath the ice shelf and may account for observed differences in temperature‐salinity (T‐S) profiles.
Correlation Between Poroelastic Stress Perturbation and Multidisposal Wells Induced Earthquake Sequence in Cushing, Oklahoma
Authors: Deng Kai , Liu Yajing , Chen Xiaowei
Published: October 2020

Over 100 small‐ to moderate‐sized earthquakes, including an Mw 5.0 event, were detected during September 2015 to November 2016 near the town of Cushing, Oklahoma. The seismic sequence was spatial‐temporally linked to four wastewater disposal wells within 4 km. We calculate pore pressure and stress perturbations caused by fluid injection at multiple wells and analyze seismic risk in a Coulomb failure stress framework. Despite being more than an order of magnitude smaller than the pore pressure perturbation, the sign of shear stress change, in the sense of assumed right‐lateral fault motion, dictates where earthquakes are induced. Most of the relocated earthquakes are located within areas of positive shear stress changes. Our results suggest that poroelastic stress changes also play an essential role in the wastewater disposal environment, and a strategic design of well locations with respect to fault orientation and direction of motion can help mitigate induced seismic hazard.
Minimal Climate Impacts From Short‐Lived Climate Forcers Following Emission Reductions Related to the COVID‐19 Pandemic
Authors: Weber James , Shin Youngsub M. , Staunton Sykes John , Archer‐Nicholls Scott , Abraham N. Luke , Archibald Alex T.
Published: October 2020

We present an assessment of the impacts on atmospheric composition and radiative forcing of short‐lived pollutants following a worldwide decrease in anthropogenic activity and emissions comparable to what has occurred in response to the COVID‐19 pandemic, using the global composition‐climate model United Kingdom Chemistry and Aerosols Model (UKCA). Emission changes reduce tropospheric hydroxyl radical and ozone burdens, increasing methane lifetime. Reduced SO2 emissions and oxidizing capacity lead to a decrease in sulfate aerosol and increase in aerosol size, with accompanying reductions to cloud droplet concentration. However, large reductions in black carbon emissions increase aerosol albedo. Overall, the changes in ozone and aerosol direct effects (neglecting aerosol‐cloud interactions which were statistically insignificant but whose response warrants future investigation) yield a radiative forcing of −33 to −78 mWm−2. Upon cessation of emission reductions, the short‐lived climate forcers rapidly return to pre‐COVID levels; meaning, these changes are unlikely to have lasting impacts on climate assuming emissions return to pre‐intervention levels.
A Local Particle Filter Using Gamma Test Theory for High‐Dimensional State Spaces
Authors: Wang Zhenwu , Hut Rolf , Van de Giesen Nick
Published: October 2020

Particle filters are non‐Gaussian filters, which means that the assumption that the error distribution of the ensemble should be Gaussian is unnecessary. Like the ensemble Kalman filter, particle filters are based on the Monte Carlo approximation to represent the distribution of model states. It requires a substantial number of particles to approximate the probability density function of states in high‐dimensional models, which is prohibitive for real applications. In order to overcome problems with high dimensionality, localization was applied in an Ensemble‐type data assimilation system. This study combines the localization in LETKF (Local Ensemble Transformation Kalman Filter) with particle filters and proposes a new local particle filter with the model state space correction using Gamma test theory for high‐dimensional models. A series of tests with various parameter settings, including different the numbers of particles, observation intervals, localization scale, inflation factors, and observation operators, were used to evaluate the performance of this new method using a Lorenz model with 40 variables. Besides, the proposed filter was applied in the Lorenz model with 1,000 variables to evaluate its performance in the model with higher dimensions. The results show that this approach can deal with the issue of dimensionality, which otherwise leads to the collapse of the particle filters in high‐dimensional systems. The local particle filter is stable and has considerable potential for complex higher‐dimensional models.
Structural Evolution of Orogenic Wedges: Interplay Between Erosion and Weak Décollements
Authors: Dal Zilio Luca , Ruh Jonas , Avouac Jean‐Philippe
Published: October 2020

Orogenic wedges commonly display an inner wedge, where crystalline units have been exhumed, and an outer wedge formed by imbricated sedimentary units detached from the basement. Analog experiments have shown that similar structures can emerge naturally in the presence of weak décollements due to the interplay between erosion and deformation. In this study, we further investigate this hypothesis using two‐dimensional, visco‐elasto‐plastic numerical models. Our experiments assume a basal and an intermediate décollement within the wedge. Experiments with a frictional strength of the basal décollement lower or equal to that of the intermediate décollement show a structural evolution of fold‐and‐thrust belts dominated by out‐of‐sequence thrusting. Conversely, when the intermediate décollement is weaker than the basal décollement, distinct outer and inner wedges are formed. This process leads to episodic migration of midcrustal ramps, tectonic underplating, and antiformal stacking facilitated by erosion. Comparison between our models and the Himalayan wedge suggests a low effective friction (∼0.10), which is probably due to dynamic weakening during large (M8+) Himalayan earthquakes. The deeper décollement, along which the lower plate thrusts beneath the High Himalaya, must be a thermally activated ductile shear zone with an apparent friction of ∼0.18. Fold‐and‐thrust belts worldwide exhibit various architectures in which different décollement levels might be activated. Thus, our study provides a framework to help assess under which conditions a variety of structures observed in orogenic systems can arise.
Evogliptin, a dipeptidyl peptidase-4 inhibitor, attenuates pathological retinal angiogenesis by suppressing vascular endothelial growth factor-induced Arf6 activation
Authors: Seo Songyi , Kim Mi-Kyung , Kim Ryul-I , Yeo Yeongju , Kim Koung Li , Suh Wonhee
Published: October 2020

Dipeptidyl peptidase-4 (DPP-4) inhibitors are used for the treatment of type 2 diabetes mellitus (DM). Recent studies have shown that beyond their effect in lowing glucose, DPP-4 inhibitors mitigate DM-related microvascular complications, such as diabetic retinopathy. However, the mechanism by which pathological retinal neovascularization, a major clinical manifestation of diabetic retinopathy, is inhibited is unclear. This study sought to examine the effects of evogliptin, a potent DPP-4 inhibitor, on pathological retinal neovascularization in mice and elucidate the mechanism by which evogliptin inhibits angiogenesis mediated by vascular endothelial growth factor (VEGF), a key factor in the vascular pathogenesis of proliferative diabetic retinopathy (PDR). In a murine model of PDR, an intravitreal injection of evogliptin significantly suppressed aberrant retinal neovascularization. In human endothelial cells, evogliptin reduced VEGF-induced angiogenesis. Western blot analysis showed that evogliptin inhibited the phosphorylation of signaling molecules associated with VEGF-induced cell adhesion and migration. Moreover, evogliptin substantially inhibited the VEGF-induced activation of adenosine 5′-diphosphate ribosylation factor 6 (Arf6), a small guanosine 5′-triphosphatase (GTPase) that regulates VEGF receptor 2 signal transduction. Direct activation of Arf6 using a chemical inhibitor of Arf-directed GTPase-activating protein completely abrogated the inhibitory effect of evogliptin on VEGF-induced activation of the angiogenic signaling pathway, which suggests that evogliptin suppresses VEGF-induced angiogenesis by blocking Arf6 activation. Our results provide insights into the molecular mechanism of the direct inhibitory effect of the DPP-4 inhibitor evogliptin on pathological retinal neovascularization. In addition to its glucose-lowering effect, the antiangiogenic effect of evogliptin could also render it beneficial for individuals with PDR.
Impact of angiotensin receptor blocker product recalls on antihypertensive prescribing in Germany
Authors: Rudolph Ulrike Maria , Enners Salka , Kieble Marita , Mahfoud Felix , Böhm Michael , Laufs Ulrich , Schulz Martin
Published: October 2020

In Germany, ~8 million patients take angiotensin receptor blockers (ARBs) and 2.25 million of them valsartan. In 2018, contamination of generic ARBs with probable carcinogenic nitrosamines resulted in more than 30 recalls. The impact of such a huge recall has never been explored in Europe. We analyzed the utilization of valsartan, all ARBs, and other alternative antihypertensive drugs in Germany. We used our database of anonymized dispensing data from >80% of community pharmacies at the expense of the statutory health insurance (SHI) funds from January 2017 to December 2019. We analyzed 290.8 million prescriptions, including all oral mono- and fixed-dose combinations of ARBs and plausible alternatives, i.e. ACE inhibitors (ACEi), beta-blockers (BB), and calcium channel blockers (CCB). Utilization was calculated by defined daily doses per 1000 SHI-insured persons per day (DID). Valsartan use decreased substantially after the recalls in July 2018 from 39.0 to 14.2 DID (−64%) in the second quarter of 2019 and to 16.9 DID (−57%) in the fourth quarter of 2019. Simultaneously, the use of alternative ARBs increased from 77.7 DID in the second quarter of 2018 to 121.9 DID (+57%) in the fourth quarter of 2019, mainly due to an increase of candesartan dispensing to 99.8 DID (+73%). There were no changes in the utilization of ACEi, BB, or CCB. The majority of recalled generic valsartan products were replaced by other ARBs, predominantly candesartan, despite documented drug shortages. In contrast to previous safety warnings/recalls, our data do not suggest an under-prescription of antihypertensives during this period.
Safety review of hydroxyprogesterone caproate in women with a history of spontaneous preterm birth
Authors: Sibai Baha , Saade George R. , Das Anita F. , Gudeman Jennifer
Published: October 2020

17-alpha-hydroxyprogesterone caproate (17P) has been in use for prevention of recurrent preterm birth since 2003 when the Meis trial was published. A requirement for Food and Drug Administration approval of 17P was a confirmatory trial, called “PROLONG”, which was recently completed, but did not replicate the efficacy demonstrated in the Meis trial. This review analyzes the safety data from each trial, as well as integrated data from the two trials. The relative risks (95% CI) with 17P versus placebo in the integrated dataset were 0.66 (0.25–1.78) for miscarriage, 1.83 (0.68–4.91) for stillbirth, and 0.86 (0.53–1.41) for all fetal and neonatal death. The rate of gestational diabetes in the integrated dataset was 3.6% for 17P vs. 3.8% for placebo. Similar findings with low and comparable rates between 17P and placebo were also found for other adverse events. The integrated safety data demonstrate a favorable safety profile that was comparable to placebo.
Correction: Precision weighting of cortical unsigned prediction error signals benefits learning, is mediated by dopamine, and is impaired in psychosis
Authors: Haarsma J. , Fletcher P. C. , Griffin J. D. , Taverne H. J. , Ziauddeen H. , Spencer T. J. , Miller C. , Katthagen T. , Goodyer I. , Diederen K. M. J. , Murray G. K.
Published: October 2020

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
A multistate model of survival prediction and event monitoring in prefibrotic myelofibrosis
Authors: Carobbio Alessandra , Guglielmelli Paola , Rumi Elisa , Cavalloni Chiara , De Stefano Valerio , Betti Silvia , Rambaldi Alessandro , Finazzi Maria Chiara , Thiele Juergen , Vannucchi Alessandro M. , Tefferi Ayalew , Barbui Tiziano
Published: October 2020

Among 382 patients with WHO-defined prefibrotic myelofibrosis (pre-PMF) followed for a median of 6.9 years, fibrotic or leukemic transformation or death accounts for 15, 7, and 27% of cases, respectively. A multistate model was applied to analyze survival data taking into account intermediate states that are part of the clinical course of pre-PMF, including overt PMF and acute myeloid leukemia (AML). Within this multistate framework, multivariable models disclosed older age (>65 years) and leukocytosis (>15 × 109/L) as predictors of death and leukemic transformation. The risk factors for fibrotic progression included anemia and grade 1 bone marrow fibrosis. The outcome was further affected by high molecular risk (HMR) but not driver mutations. Direct transition to overt PMF, AML, or death occurred in 15.2, 4.7, and 17.3% of patients, respectively. The risk of AML was the highest in the first 5 years (7%), but leveled off thereafter. Conversely, the probability of death from overt PMF or AML increased more rapidly over time, especially when compared to death in the pre-PMF state without disease progression. The probability of being alive with pre-PMF status decreased to 70 and 30% at 10 and 20 years, respectively. This study highlights the aspects of the clinical course and estimates of disease progression in pre-PMF.
The quality of life index: a pilot study integrating treatment efficacy and quality of life in oncology
Authors: Basu A. , Philip E. J. , Dewitt B. , Hanmer J. , Chattopadhyay A. , Yau C. , Melisko M. E. , Esserman L. J.
Published: October 2020

The majority of women diagnosed with breast cancer will experience some form of drug-related toxicity and subsequent impairments in Health-related Quality of Life (HRQoL). Despite this, HRQoL is assessed inconsistently and there is no validated method to integrate HRQoL data into the assessment of therapeutic agents. This proof of concept study utilizes data from the neoadjuvant I-SPY 2 clinical trial to describe the development of the Quality of Life Index (QoLI) measure. The QoLI represents a single composite score that incorporates validated longitudinal measures of clinical efficacy and QoL and one that permits a more comprehensive, direct comparison of individual therapeutic agents. Preliminary data suggest the QoLI is able to distinguish between agents based on their efficacy and toxicity; with further validation, the QoLI has the potential to provide more patient-centered evaluations in clinical trials and help guide treatment decision making in breast cancer and other oncologic diseases.
Impact of mixed biofilm formation with environmental microorganisms on E. coli O157:H7 survival against sanitization
Authors: Chitlapilly Dass Sapna , Bosilevac Joseph M. , Weinroth Maggie , Elowsky Christian G. , Zhou You , Anandappa Angela , Wang Rong
Published: October 2020

Biofilm formation by foodborne pathogens is a serious threat to food safety and public health. Meat processing plants may harbor various microorganisms and occasional foodborne pathogens; thus, the environmental microbial community might impact pathogen survival via mixed biofilm formation. We collected floor drain samples from two beef plants with different E. coli O157:H7 prevalence history and investigated the effects of the environmental microorganisms on pathogen sanitizer tolerance. The results showed that biofilm forming ability and bacterial species composition varied considerably based on the plants and drain locations. E. coli O157:H7 cells obtained significantly higher sanitizer tolerance in mixed biofilms by samples from the plant with recurrent E. coli O157:H7 prevalence than those mixed with samples from the other plant. The mixed biofilm that best protected E. coli O157:H7 also had the highest species diversity. The percentages of the species were altered significantly after sanitization, suggesting that the community composition affects the role and tolerance level of each individual species. Therefore, the unique environmental microbial community, their ability to form biofilms on contact surfaces and the interspecies interactions all play roles in E. coli O157:H7 persistence by either enhancing or reducing pathogen survival within the biofilm community.
The structural role of osteocalcin in bone biomechanics and its alteration in Type-2 Diabetes
Authors: Tavakol Mahdi , Vaughan Ted J.
Published: October 2020

This study presents an investigation into the role of Osteocalcin (OC) on bone biomechanics, with the results demonstrating that the protein’s α-helix structures play a critical role in energy dissipation behavior in healthy conditions. In the first instance, α-helix structures have high affinity with the Hydroxyapatite (HAp) mineral surface and provide favorable conditions for adsorption of OC proteins onto the mineral surface. Using steered molecular dynamics simulation, several key energy dissipation mechanisms associated with α-helix structures were observed, which included stick–slip behavior, a sacrificial bond mechanism and a favorable binding feature provided by the Ca2+ motif on the OC protein. In the case of Type-2 Diabetes, this study demonstrated that possible glycation of the OC protein can occur through covalent crosslinking between Arginine and N-terminus regions, causing disruption of α-helices leading to a lower protein affinity to the HAp surface. Furthermore, the loss of α-helix structures allowed protein deformation to occur more easily during pulling and key energy dissipation mechanisms observed in the healthy configuration were no longer present. This study has significant implications for our understanding of bone biomechanics, revealing several novel mechanisms in OC’s involvement in energy dissipation. Furthermore, these mechanisms can be disrupted following the onset of Type-2 Diabetes, implying that glycation of OC could have a substantial contribution to the increased bone fragility observed during this disease state.
Infants’ gaze exhibits a fractal structure that varies by age and stimulus salience
Authors: Stallworthy Isabella C. , Sifre Robin , Berry Daniel , Lasch Carolyn , Smith Tim J. , Elison Jed T.
Published: October 2020

The development of selective visual attention is critical for effectively engaging with an ever-changing world. Its optimal deployment depends upon interactions between neural, motor, and sensory systems across multiple timescales and neurocognitive loci. Previous work illustrates the spatio-temporal dynamics of these processes in adults, but less is known about this emergent phenomenon early in life. Using data (n = 190; 421 visits) collected between 3 and 35 months of age, we examined the spatio-temporal complexity of young children’s gaze patterns as they viewed stimuli varying in semantic salience. Specifically, we used detrended fluctuation analysis (DFA) to quantify the extent to which infants’ gaze patterns exhibited scale invariant patterns of nested variability, an organizational feature thought to reflect self-organized and optimally flexible system dynamics that are not overly rigid or random. Results indicated that gaze patterns of even the youngest infants exhibited fractal organization that increased with age. Further, fractal organization was greater when children (a) viewed social stimuli compared to stimuli with degraded social information and (b) when they spontaneously gazed at faces. These findings suggest that selective attention is well-organized in infancy, particularly toward social information, and indicate noteworthy growth in these processes across the first years of life.
Hypervirulent pneumococcal serotype 1 harbours two pneumolysin variants with differential haemolytic activity
Authors: Panagiotou Stavros , Chaguza Chrispin , Yahya Reham , Audshasai Teerawit , Baltazar Murielle , Ressel Lorenzo , Khandaker Shadia , Alsahag Mansoor , Mitchell Tim J. , Prudhomme Marc , Kadioglu Aras , Yang Marie
Published: October 2020

Streptococcus pneumoniae is a devastating global pathogen. Prevalent in sub-Saharan Africa, pneumococcal serotype 1 is atypical in that it is rarely found as a nasopharyngeal coloniser, yet is described as one of the most common causes of invasive pneumococcal disease. Clonal sequence type (ST)-306 and ST615 are representative of the two major serotype 1 lineages A and C, respectively. Here we investigated the virulence properties and haemolytic activities of these 2 clonal types using in vivo mouse models and in vitro assays. A lethal dose of ST615 administered intranasally to mice led to the rapid onset of disease symptoms and resulted in 90% mortality. In contrast, mice exposed to the same infection dose of ST306 or a pneumolysin (Ply)-deficient ST615 failed to develop any disease symptoms. Interestingly, the 2 strains did not differ in their ability to bind the immune complement or to undergo neutrophil-mediated phagocytosis. Upon comparative genomic analysis, we found higher within-ST sequence diversity in ST615 compared with ST306 and determined that ZmpA, ZmpD proteins, and IgA protease, were uniquely found in ST615. Using cell fractionation and cell contact-dependent assay, we made the unexpected finding that ST615 harbours the expression of two haemolytic variants of Ply: a cell-wall restricted fully haemolytic Ply, and a cytosolic pool of Ply void of any detectable haemolytic activity. This is the first time such a phenomenon has been described. We discuss the biological significance of our observation in relation to the aptitude of the pneumococcus for sustaining its human reservoir.
Skin hydration dynamics investigated by electrical impedance techniques in vivo and in vitro
Authors: Morin Maxim , Ruzgas Tautgirdas , Svedenhag Per , Anderson Christopher D. , Ollmar Stig , Engblom Johan , Björklund Sebastian
Published: October 2020

Skin is easily accessible for transdermal drug delivery and also attractive for biomarker sampling. These applications are strongly influenced by hydration where elevated hydration generally leads to increased skin permeability. Thus, favorable transdermal delivery and extraction conditions can be easily obtained by exploiting elevated skin hydration. Here, we provide a detailed in vivo and in vitro investigation of the skin hydration dynamics using three techniques based on electrical impedance spectroscopy. Good correlation between in vivo and in vitro results is demonstrated, which implies that simple but realistic in vitro models can be used for further studies related to skin hydration (e.g., cosmetic testing). Importantly, the results show that hydration proceeds in two stages. Firstly, hydration between 5 and 10 min results in a drastic skin impedance change, which is interpreted as filling of superficial voids in skin with conducting electrolyte solution. Secondly, a subtle impedance change is observed over time, which is interpreted as leveling of the water gradient across skin leading to structural relaxation/changes of the macromolecular skin barrier components. With respect to transdermal drug delivery and extraction of biomarkers; 1 h of hydration is suggested to result in beneficial and stable conditions in terms of high skin permeability and extraction efficiency.
Multi-gene metabolic engineering of tomato plants results in increased fruit yield up to 23%
Authors: Vallarino José G. , Kubiszewski-Jakubiak Szymon , Ruf Stephanie , Rößner Margit , Timm Stefan , Bauwe Hermann , Carrari Fernando , Rentsch Doris , Bock Ralph , Sweetlove Lee J. , Fernie Alisdair R.
Published: October 2020

The capacity to assimilate carbon and nitrogen, to transport the resultant sugars and amino acids to sink tissues, and to convert the incoming sugars and amino acids into storage compounds in the sink tissues, are key determinants of crop yield. Given that all of these processes have the potential to co-limit growth, multiple genetic interventions in source and sink tissues, plus transport processes may be necessary to reach the full yield potential of a crop. We used biolistic combinatorial co-transformation (up to 20 transgenes) for increasing C and N flows with the purpose of increasing tomato fruit yield. We observed an increased fruit yield of up to 23%. To better explore the reconfiguration of metabolic networks in these transformants, we generated a dataset encompassing physiological parameters, gene expression and metabolite profiling on plants grown under glasshouse or polytunnel conditions. A Sparse Partial Least Squares regression model was able to explain the combination of genes that contributed to increased fruit yield. This combinatorial study of multiple transgenes targeting primary metabolism thus offers opportunities to probe the genetic basis of metabolic and phenotypic variation, providing insight into the difficulties in choosing the correct combination of targets for engineering increased fruit yield.
Small-scaled association between ambient temperature and campylobacteriosis incidence in Germany
Authors: Oberheim Julia , Höser Christoph , Lüchters Guido , Kistemann Thomas
Published: October 2020

Campylobacteriosis is the leading bacterial cause of human diarrheal illness worldwide. Campylobacteriosis incidence exhibits seasonality and has been attributed to ambient temperature. However, the role of ambient temperature on campylobacteriosis remains poorly understood. To examine the impact of ambient temperature on local campylobacteriosis in Germany, weekly incidences on NUTS-3 level were analysed using a novel small-scaled approach, regression and time lags. Campylobacteriosis incidence correlated positively with temperatures between − 5 and 28 °C. The sigmoid regression model estimated an incidence increase of 0.52 per 5 °C temperature rise in the observation period. The weekly average of daily minimum temperature was most significant at a time lag of two weeks and showed the steepest incidence increase of 0.13 per 1 °C temperature increase in a temperature corridor of 5.1 to 12.2 °C. The impact of average minimum temperatures on campylobacteriosis incidence is crucial, likely to be indirect and especially relevant in the recent part of the infection chain. Vectors or human behaviour are presumably more directly linked with temperature than the pathogen’s microbiology and should be examined. These variables outweigh the direct temperature-pathogen relationship when the whole chain of infection is considered. In the context of climate change, campylobacteriosis is likely to increase in Germany due to an increased temperature effect.
Motif 1 Binding Protein suppresses wingless to promote eye fate in Drosophila
Authors: Raj Akanksha , Chimata Anuradha Venkatakrishnan , Singh Amit
Published: October 2020

The phenomenon of RNA polymerase II (Pol II) pausing at transcription start site (TSS) is one of the key rate-limiting steps in regulating genome-wide gene expression. In Drosophila embryo, Pol II pausing is known to regulate the developmental control genes expression, however, the functional implication of Pol II pausing during later developmental time windows remains largely unknown. A highly conserved zinc finger transcription factor, Motif 1 Binding Protein (M1BP), is known to orchestrate promoter-proximal pausing. We found a new role of M1BP in regulating Drosophila eye development. Downregulation of M1BP function suppresses eye fate resulting in a reduced eye or a “no-eye” phenotype. The eye suppression function of M1BP has no domain constraint in the developing eye. Downregulation of M1BP results in more than two-fold induction of wingless (wg) gene expression along with robust induction of Homothorax (Hth), a negative regulator of eye fate. The loss-of-eye phenotype of M1BP downregulation is dependent on Wg upregulation as downregulation of both M1BP and wg, by using wgRNAi, shows a significant rescue of a reduced eye or a “no-eye” phenotype, which is accompanied by normalizing of wg and hth expression levels in the eye imaginal disc. Ectopic induction of Wg is known to trigger developmental cell death. We found that upregulation of wg as a result of downregulation of M1BP also induces apoptotic cell death, which can be significantly restored by blocking caspase-mediated cell death. Our data strongly imply that transcriptional regulation of wg by Pol II pausing factor M1BP may be one of the important regulatory mechanism(s) during Drosophila eye development.
Plant secondary metabolites induced electron flux in microbial fuel cell: investigation from laboratory-to-field scale
Authors: Nath Dibyojyoty , Ghangrekar M. M.
Published: October 2020

Wastewater treatment coupled with electricity recovery in microbial fuel cell (MFC) prefer mixed anaerobic sludge as inoculum in anodic chamber than pure stain of electroactive bacteria (EAB), due to robustness and syntrophic association. Genetic modification is difficult to adopt for mixed sludge microbes for enhancing power production of MFC. Hence, we demonstrated use of eco-friendly plant secondary metabolites (PSM) with sub-lethal concentrations to enhance the rate of extracellular electron transfer between EAB and anode and validated it in both bench-scale as well as pilot-scale MFCs. The PSMs contain tannin, saponin and essential oils, which are having electron shuttling properties and their addition to microbes can cause alteration in cell morphology, electroactive behaviour and shifting in microbial population dynamics depending upon concentrations and types of PSM used. Improvement of 2.1-times and 3.8-times in power densities was observed in two different MFCs inoculated withEucalyptus-extract pre-treated mixed anaerobic sludge and pure culture ofPseudomonas aeruginosa, respectively, as compared to respective control MFCs operated without addingEucalyptus-extract to inoculum. WhenEucalyptus-extract-dose was spiked to anodic chamber (125 l) of pilot-scale MFC, treating septage, the current production was dramatically improved. Thus, PSM-dosing to inoculum holds exciting promise for increasing electricity production of field-scale MFCs.