bluuebunny/crossref_metadata_2025 huggingface dataset:
Closed-loop Neuroscience of brain rhythms: optimizing real-time quantification of narrow-band signals to expedite feedback delivery
Authors: Smetanin Nikolai , Belinskaya Anastasia , Lebedev Mikhail , Ossadtchi Alexei
Published: December 2019

Abstract

Closed-loop Neuroscience is based on the experimental approach where the ongoing brain activity is recorded, processed, and passed back to the brain as sensory feedback or direct stimulation of neural circuits. The artificial closed loops constructed with this approach expand the traditional stimulus-response experimentation. As such, closed-loop Neuroscience provides insights on the function of loops existing in the brain and the ways the flow of neural information could be modified to treat neurological conditions.

Neural oscillations, or brain rhythms, are a class of neural activities that have been extensively studied and also utilized in brain rhythm-contingent (BRC) paradigms that incorporate closed loops. In these implementations, instantaneous power and phase of neural oscillations form the signal that is fed back to the brain.

Here we addressed the problem of feedback delay in BRC paradigms. In many BRC systems, it is critical to keep the delay short. Long delays could render the intended modification of neural activity impossible because the stimulus is delivered after the targeted neural pattern has already completed. Yet, the processing time needed to extract oscillatory components from the broad-band neural signals can significantly exceed the period of oscillations, which puts a demand for algorithms that could minimize the delay.

We used EEG data collected in human subjects to systematically investigate the performance of a range of signal processing methods in the context of minimizing delay in BRC systems. We proposed a family of techniques based on the least-squares filter design – a transparent and simple approach, as it required a single parameter to adjust the accuracy versus latency trade-off. Our algorithm performed on par or better than the state-of the art techniques currently used for the estimation of rhythm envelope and phase in closed-loop EEG paradigms.
Computer-guided Binding Mode Identification and Affinity Improvement of an LRR Protein Binder without Structure Determination
Authors: Choi Yoonjoo , Jeong Sukyo , Choi Jung-Min , Ndong Christian , Bailey-Kellogg Chris , Griswold Karl E. , Kim Hak-Sung
Published: December 2019

Precise binding mode identification and subsequent affinity improvement without structure determination remain a challenge in the development of therapeutic proteins. However, relevant experimental techniques are generally quite costly, and purely computational methods have been unreliable. Here, we show that integrated computational and experimental epitope localization followed by full-atom energy minimization can yield an accurate complex model structure which ultimately enables effective affinity improvement and redesign of binding specificity. As proof-of-concept, we used a leucine-rich repeat (LRR) protein binder, called a repebody (Rb), that specifically recognizes human IgG1(hIgG1). We performed computationally-guided identification of the Rb:hIgG1binding mode and leveraged the resulting model to reengineer the Rb so as to significantly increase its binding affinity for hIgG1as well as redesign its specificity toward multiple IgGs from other species. Experimental structure determination verified that our Rb:hIgG1model closely matched the co-crystal structure. Using a benchmark of other LRR protein complexes, we further demonstrated that the present approach may be broadly applicable to proteins undergoing relatively small conformational changes upon target binding.

Author Summary

It is quite challenging for computational methods to determine how proteins interact and to design mutations to alter their binding affinity and specificity. Despite recent advances in computational methods, however,in silicoevaluation of binding energies has proven to be extremely difficult. We show that, in the case of protein-protein interactions where only small structural changes occur upon target binding, an integrated computational and experimental approach can identify a binding mode and drive reengineering efforts to improve binding affinity or specificity. Using as a model system a leucine-rich repeat (LRR) protein binder that recognizes human IgG1, our approach yielded a model of the protein complex that was very similar to the subsequently experimentally determined co-crystal structure, and enabled design of variants with significantly improved IgG1binding affinity and with the ability to recognize IgG1from other species.
SHAMAN: a user-friendly website for metataxonomic analysis from raw reads to statistical analysis
Authors: Volant Stevenn , Lechat Pierre , Woringer Perrine , Motreff Laurence , Malabat Christophe , Kennedy Sean , Ghozlane Amine
Published: December 2019

Comparing the composition of microbial communities among groups of interest (e.g., patients vs healthy individuals) is a central aspect in microbiome research. It typically involves sequencing, data processing, statistical analysis and graphical representation of the detected signatures. Such an analysis is normally obtained by using a set of different applications that require specific expertise for installation, data processing and in some case, programming skills. Here, we present SHAMAN, an interactive web application we developed in order to facilitate the use of (i) a bioinformatic workflow for metataxonomic analysis, (ii) a reliable statistical modelling and (iii) to provide among the largest panels of interactive visualizations as compared to the other options that are currently available. SHAMAN is specifically designed for non-expert users who may benefit from using an integrated version of the different analytic steps underlying a proper metagenomic analysis. The application is freely accessible athttp://shaman.pasteur.fr/, and may also work as a standalone application with a Docker container (aghozlane/shaman), conda and R. The source code is written in R and is available athttps://github.com/aghozlane/shaman. Using two datasets (a mock community sequencing and published 16S metagenomic data), we illustrate the strengths of SHAMAN in quickly performing a complete metataxonomic analysis.
Frequency- and state-dependent effects of hippocampal neural disinhibition on hippocampal local field potential oscillations in anaesthetised rats
Authors: Gwilt Miriam , Bauer Markus , Bast Tobias
Published: December 2019

Reduced inhibitory GABA function, so-called neural disinhibition, has been implicated in cognitive disorders, including schizophrenia and age-related cognitive decline. We previously showed in rats that hippocampal disinhibition by local microinfusion of the GABA-A antagonist picrotoxin disrupted memory and attention and enhanced hippocampal multi-unit burst firing recorded around the infusion site under isoflurane anaesthesia. Here, we analysed the hippocampal LFP recorded alongside the multi-unit data. We predicted frequency-specific LFP changes, based on previous studies implicating GABA in hippocampal oscillations, with the weight of evidence suggesting that disinhibition would facilitate theta and disrupt gamma oscillations. Using a new semi-automated method based on the kurtosis of the LFP peak-amplitude distribution as well as on amplitude envelope thresholding, we separated three distinct hippocampal LFP states under isoflurane anaesthesia: ‘burst’ and ‘suppression’ states – high-amplitude LFP-spike bursts and the interspersed low-amplitude periods – and a medium-amplitude ‘continuous’ state. The burst state showed greater overall power than suppression and continuous states and higher relative delta/theta power, but lower relative beta/gamma power. The burst state also showed reduced functional connectivity across the hippocampal recording area, especially around theta and beta frequencies. Overall neuronal firing was higher in the burst than the other two states, whereas the proportion of burst firing was higher in burst and continuous states than the suppression state. Disinhibition caused state- and frequency-dependent LFP changes, tending to increase power at lower frequencies (<20Hz), but to decrease power and connectivity at higher frequencies (>20Hz) in burst and suppression states. The disinhibition-induced enhancement of multi-unit bursting was also state-dependent, tending to be more pronounced in burst and suppression states than the continuous state. Overall, we characterized three distinct hippocampal LFP states in isoflurane-anaesthetized rats. Disinhibition changed hippocampal LFP oscillations in a state- and frequency-dependent way. Moreover, the disinhibition-induced enhancement of multi-unit bursting was also LFP-state dependent.
Cellular state determines the multimodal signaling response of single cells
Authors: Kramer Bernhard A. , Pelkmans Lucas
Published: December 2019

Numerous fundamental biological processes require individual cells to correctly interpret and accurately respond to incoming cues. How intracellular signaling networks achieve the integration of complex information from various contexts remains unclear. Here we quantify epidermal growth factor-induced heterogeneous activation of multiple signaling proteins, as well as cellular state markers, in the same single cells across multiple spatial scales. We find that the acute response of each node in a signaling network is tightly coupled to the cellular state in a partially non-redundant manner. This generates a multimodal response that senses the diversity of cellular states better than any individual response alone and allows individual cells to accurately place growth factor concentration in the context of their cellular state. We propose that the non-redundant multimodal property of signaling networks in mammalian cells underlies specific and context-aware cellular decision making in a multicellular setting.
Scavenging dicarbonyls with 5’-O-pentyl-pyridoxamine increases HDL net cholesterol efflux capacity and attenuates atherosclerosis and insulin resistance
Authors: Huang Jiansheng , Tao Huan , Yancey Patricia G. , Leuthner Zoe , May-Zhang Linda S. , Jung Ju-Yang , Zhang Youmin , Ding Lei , Amarnath Venkataraman , Liu Dianxin , Collins Sheila , Davies Sean S. , Linton MacRae F.
Published: December 2019

Objective

Oxidative stress contributes to the development of insulin resistance (IR) and atherosclerosis. Peroxidation of lipids produces reactive dicarbonyls such as Isolevuglandins (IsoLG) and malondialdehyde (MDA) that covalently bind plasma/cellular proteins, phospholipids, and DNA leading to altered function and toxicity. We examined whether scavenging reactive dicarbonyls with 5’-O-pentyl-pyridoxamine (PPM) protects against the development of IR and atherosclerosis inLdlr-/-mice.

Methods

Male or femaleLdlr-/-mice were fed a western diet (WD) for 16 weeks and treated with PPM versus vehicle alone. Plaque extent, dicarbonyl-lysyl adducts, efferocytosis, apoptosis, macrophage inflammation, and necrotic area were measured. Plasma MDA-LDL adducts and the in vivo and in vitro effects of PPM on the ability of HDL to reduce macrophage cholesterol were measured. Blood Ly6Chimonocytes and ex vivo 5-ethynyl-2’-deoxyuridine (EdU) incorporation into bone marrow CD11b+ monocytes and CD34+ hematopoietic stem and progenitor cells (HSPC) were also examined. IR was examined by measuring fasting glucose/insulin levels and tolerance to insulin/glucose challenge.

Results

PPM reduced the proximal aortic atherosclerosis by 48% and by 46% in female and maleLdlr-/-mice, respectively. PPM also decreased IR and hepatic fat and inflammation in maleLdlr-/-mice. Importantly, PPM decreased plasma MDA-LDL adducts and prevented the accumulation of plaque MDA- and IsoLG-lysyl adducts inLdlr-/-mice. In addition, PPM increased the net cholesterol efflux capacity of HDL fromLdlr-/-mice and prevented both the in vitro impairment of HDL net cholesterol efflux capacity and apoAI crosslinking by MPO generated hypochlorous acid. Moreover, PPM decreased features of plaque instability including decreased proinflammatory M1-like macrophages, IL-1β expression, myeloperoxidase, apoptosis, and necrotic core. In contrast, PPM increased M2-like macrophages, Tregs, fibrous cap thickness, and efferocytosis. Furthermore, PPM reduced inflammatory monocytosis as evidenced by decreased blood Ly6Chimonocytes and proliferation of bone marrow monocytes and HSPC fromLdlr-/-mice.

Conclusions

PPM has pleotropic atheroprotective effects in a murine model of familial hypercholesterolemia, supporting the therapeutic potential of reactive dicarbonyl scavenging in the treatment of IR and atherosclerotic cardiovascular disease.
Does previous work experience matter in students’ learning in higher project management education?
Authors: Sharma Keshav Kumar , Israel D. , Bhalla Bhavna
Published: December 2019

Purpose

In view of the substantial gaps between desirable and actual competencies of project practitioners, there is a genuine and continual need to improve approaches towards project management education. The purpose of this paper is to empirically examine whether previous work experience of students pursuing a master’s programme in project management plays a role in their understanding and learning from the programme.

Design/methodology/approach

Survey data were collected from 282 respondents, who included working project professionals along with first-year (junior) and second-year (senior) students of a two-year postgraduate programme in project management. Considering the responses of working project professionals as the benchmark, the paper employs exploratory factor analysis and multiple comparisons to examine differences in the perceived importance given to factor groupings of critical success factors (CSFs) of construction projects by different respondent groups.

Findings

Results of the study suggest that irrespective of students’ seniority in the postgraduate programme, responses of students with previous project work experience more closely match the responses of project professionals, in contrast to students without such experience. The results indicate that students’ previous project work experience does play a role in their understanding and learning. In addition, the paper also identifies four factor groupings of CSFs and, diverging from past studies, conceptualises “alignment” as a new factor grouping.

Practical implications

Findings support the view that adequate previous work experience may be included as an essential qualifying requirement for pursuing higher education in project management.

Originality/value

To the best of the authors’ knowledge, this is one of the first empirical studies that investigate the requirement of students’ previous work experience and reveals its significance in higher project management education.
Determining the level of development for BIM implementation in large-scale projects
Authors: Alshorafa Raif , Ergen Esin
Published: December 2019

Purpose

Proper definition of level of development (LOD) is one of the significant issues in building information modeling (BIM) applications; however, it is still not adequately addressed during BIM implementations. The purpose of this paper is to investigate and describe the current practice in defining the LOD in large-scale BIM-based projects and identify the challenges and solutions that were provided.

Design/methodology/approach

Four case studies were performed at four different types of large-scale projects to depict the current practice in determining the LOD and the required properties of elements that are going to be included in a BIM model. Semi-structured face-to-face interviews were performed to collect information from six professionals from four international firms.

Findings

The findings of the case studies revealed that defining LOD is an ambiguous process and requires high-cumulated experience. The results provide the challenges, adopted solutions and lessons learned. It was highlighted that the cost of including an element or related information in the model should be compared to the benefit of having that information in the model from the perspective of defined BIM uses.

Research limitations/implications

The findings are based on the projects that were performed in three developing countries. However, the main contractors were international companies and the construction management firms were well-known companies in the USA. In the future, additional case studies can be performed in other countries to identify similarities and regional differences.

Practical implications

The results of this study can be used to highlight the current needs in determining the LOD and guide the efforts for developing standards and policies in the AEC sector to streamline BIM adoption process in practice. The practitioners can utilize the findings of this study to increase their efficiency in adopting BIM and to decrease the time loss and cost overruns.

Originality/value

Most of the previous studies investigated the benefits and challenges when adopting BIM, and few of them considered LOD definition as a core part of this process. This study specifically investigated the current practice in determining the LOD and the required properties of elements that are going to be included in a BIM model. It also described the applied solutions and lessons learned in the case studies.
Is there a Ramadhan effect on Sharia mutual funds? Evidence from Indonesia and Malaysia
Authors: Rokhim Rofikoh , Octaviani Irma
Published: December 2019

Purpose

This paper aims to examine whether Sharia mutual fund managers are able to gain abnormal returns from what is called the Ramadhan effect.

Design/methodology/approach

The authors use GARCH regression on daily data of domestic Sharia mutual fund performance in Indonesia and Malaysia over the period of 2007-2017.

Findings

The authors find that the Ramadhan effect is not a strong predictor of Sharia fund excess return in Indonesia and Malaysia, and they identify a positive Ramadhan abnormal return on the Malaysia Sharia Equity Fund. This result shows there is size effect on sharia fund excess return in Indonesia and value effect on Sharia Balanced Fund in both markets. It is suggested that the effect of market excess return in Indonesia is stronger than in Malaysia.

Research limitations/implications

The samples are limited to Sharia Funds over the period 2007-2017.

Practical implications

The authors suggest that size and value effect could be considered to develop the selection and timing strategies to explore the Ramadhan effect.

Originality/value

This study focuses on Indonesia and Malaysia, the two largest Islamic Stock Markets in Southeast Asia and examines specific on Sharia Mutual Fund (equity and balanced fund). It also compares differences in total performance measures between the Ramadhan period and non-Ramadhan period.
Mapping literacies
Authors: Zimmerman Margaret S.
Published: December 2019

Purpose

Information literacy and health literacy skills are positively correlated with indicators of quality of life. Assessing these literacies, however, can be daunting – particularly with people that may not respond well to prose-based tools. The purpose of this paper is to use information horizons methodology as a metric that may be reflective of literacies.

Design/methodology/approach

Following a power analysis to insure statistical significance, a sample of 161 participants was recruited from a university population and given formal, vetted measures of information literacy and health literacy and then was asked to create an information horizons map within a health-related context. The information horizons maps were evaluated in two different ways. First, the number of sources was counted. Then, the quality of sources was factored in. Multiple regression analysis was applied to both metrics as independent variables with the other assessments as dependent variables. Anker, Reinhart, and Feeley’s model provided the conceptual framework for the study.

Findings

Information horizons mapping was not found to have a significant relationship with measures of information literacy. However, there were strong, statistically significant relationships with the measures of health literacy employed in this study.

Originality/value

Employing information horizons methodology as a means of providing a metric to assess literacies may be helpful in providing a more complete picture of a person’s abilities. While the current assessment tools have value, this method has the potential to provide important information about the health literacy of people who are not traditionally well represented by prose-based measures.
Examining the relationship between the price, the characteristics and the visitor evaluation of attributes of Italian farmhouses with an educational farm
Authors: Fanelli Rosa Maria
Published: December 2019

Purpose

The purpose of this paper is to examine the relationship between the price charged for a guest room in a farmhouse with an educational farm, the farmhouse characteristics and the visitor evaluation of the principal external and internal farmhouse attributes.

Design/methodology/approach

A large sample of 10,880 visitor reviews, extrapolated from the websites of 399 Italian farmhouses with an educational farm (FEF), was analyzed. Principal component analysis (PCA) was performed to identify the main latent dimensions of the farmhouses (visitor satisfaction with farmhouse attributes, farmhouse dimensions, visitor frequency, farmhouse services, types of accommodation and altitude) that affect the price charged for a guest room. Subsequently, multivariate regression was applied to measure the impact of these new latent factors on the price.

Findings

Overall, the results indicate that the price of a farmhouse with an educational farm – in the context of this niche of the Italian agritourism sector – reflects the visitor evaluation of the farmhouse attributes (especially activities and facilities available in the surrounding countryside), the farmhouse dimensions, the types of accommodation, the number of services on offer and the presence of connectivity (WI-FI). In addition, the results reveal that the price represents an important driver that guides guests in their choice of a farmhouse and that it affects visitor satisfaction with farmhouse attributes.

Research limitations/implications

Because of the sample chosen, the data gathered are limited to one type of organization – Italian FEF. Furthermore, it may be important to investigate in more depth some issues that remain partly unanswered that concern this niche of the Italian agritourism sector.

Practical implications

Thanks to the identification of latent dimensions by PCA and the examination of their impact on the farmhouse price, farmhouse operators can understanda priorithe main determinants on which to focus to improve the quality of activities and facilities available in the farmhouse location to better satisfy visitor expectations.

Originality/value

This study provides new and practical insights into the farmhouse experience in Italian municipalities, an area where very limited research has been conducted. Indeed, this is one of the few studies to focus on online reviews to evaluate more than two farmhouse attributes and their impact on pricing.
Separation of multi‐mode surface waves by supervised machine learning methods
Authors: Li Jing , Chen Yuqing , Schuster Gerard T.
Published: December 2019

Logistic regression, neural networks and support vector machines are tested for their effectiveness in isolating surface waves in seismic shot records. To distinguish surface waves from other arrivals, we train the algorithms on three distinguishing features of surface‐wave dispersion curves in the domain: spectrum coherency of the trace's magnitude spectrum, local dip and the frequency range for a fixed wavenumber k in the spectrum. Numerical tests on synthetic data show that the kernel‐based support vector machines algorithm gives the highest accuracy in predicting the surface‐wave window in the domain compared to neural networks and logistic regression. This window is also used to automatically pick the fundamental dispersion curve. The other two methods correctly pick the low‐frequency part of the dispersion curve but fail at higher frequencies where there is interference with higher‐order modes.
Habitat predicts local prevalence of migratory behaviour in an alpine ungulate
Authors: Spitz Derek B. , Hebblewhite Mark , Stephenson Thomas R.
Published: December 2019

The resource hierarchy hypothesis predicts that the most important factors limiting a species’ distribution act at the coarsest spatial scales. However, resource selection behaviour affords mobile organisms the opportunity to adopt a range of tactics for navigating spatial trade‐offs between competing biotic and abiotic constraints. Throughout the animal kingdom, partial migration (where some individuals migrate, and others remain resident year round) offers a pervasive example of such behavioural polymorphism. Identifying the differences between these behaviours is therefore central to understanding the conditions (habitat) needed to sustain migrant and resident populations.

Here we test an extension of the resource hierarchy hypothesis. We hypothesized that rather than responding to a single limiting factor, migration and residency represent contrasting scale‐specific approaches to managing trade‐offs between forage, predation risk and severe winter conditions. Furthermore, we predicted that the distribution of habitat selected by migrants and residents is predictive of the local prevalence of migratory behaviour.

To test these hypotheses, we quantified migratory status‐ (resident/migrant) and season‐specific (winter/summer) differences in resource selection by eight populations of federally endangered Sierra Nevada bighorn sheep Ovis canadensis sierrae across three spatial scales: population range, individual range and within individual range. We then integrated these spatial predictions to produce separate spatial predictions of migrant and resident winter habitat.

As predicted, model selection provided strong evidence for the importance of status‐specific differences in resource selection. Residents showed stronger coarse‐scale selection for terrain associated with predator avoidance and stronger fine‐scale selection for greenness, while in migrants this pattern was reversed. Availability of migrant habitat predicted the local prevalence of migration (top model pseudo R2 of .87).

Our ability to respond to global declines of migratory species depends on improving our understanding of the conditions required to maintain migratory behaviour. Through explicitly contrasting migrant and resident behaviour, our results illustrate seasonal differences in migrant and resident habitat and how these two behaviours represent responses to different limiting conditions. Our analyses provides a novel empirical basis for assessing the local prevalence of migratory behaviour across large landscapes.
Sesquiterpenes in grapes and wines: Occurrence, biosynthesis, functionality, and influence of winemaking processes
Authors: Li Zizhan , Howell Kate , Fang Zhongxiang , Zhang Pangzhen
Published: December 2019

Grapes are an important global horticultural product, and are mainly used for winemaking. Typically, grapes and wines are rich in various phytochemicals, including phenolics, terpenes, pyrazines, and benzenoids, with different compounds responsible for different nutritional and sensory properties. Among these compounds, sesquiterpenes, a subcategory of the terpenes, are attracting increasing interest as they affect aroma and have potential health benefits. The characteristics of sesquiterpenes in grapes and wines in terms of classification, biosynthesis pathway, and active functions have not been extensively reviewed. This paper summarizes 97 different sesquiterpenes reported in grapes and wines and reviews their biosynthesis pathways and relevant bio‐regulation mechanisms. This review further discusses the functionalities of these sesquiterpenes including their aroma contribution to grapes and wines and potential health benefits, as well as how winemaking processes affect sesquiterpene concentrations.
Esomeprazole vs pantoprazole effects on cyclosporine levels in kidney transplantation: A randomized clinical trial
Authors: El‐Bohy Doaa , El Sharkawy Magdy , Abo‐Elazm Soheir , Shahin Sara , Bchari Waleed , Mancy Azza , El Hamamsy Manal
Published: December 2019

Renal allograft survival requires multiple immunosuppressive drugs. This strategy may lead to gastric complications that necessitate gastro‐protective medications, notably, proton pump inhibitors (PPI). This study aimed to compare the influence of pantoprazole and esomeprazole on serum cyclosporine trough levels (C0) in renal transplant recipients (RTR). A prospective, parallel, open‐label trial was conducted on 47 adult RTR receiving cyclosporine doses adjusted to attain trough concentrations of 100 to 150 μg/L, mycophenolate mofetil (MMF) 750 mg q12 hour and prednisolone at 5 mg daily at Nasser Institute, Cairo, Egypt from January to September 2016. Patients were randomized into the esomeprazole group (25) or pantoprazole group (22) receiving the same dose (40 mg once daily). The study outcomes included clinical signs of rejection and renal function decline, assessed by elevations in serum creatinine, caused by cyclosporine level variations in either of the two study groups. Renal function, C0 and CBC measurements were measured at baseline and monthly for 6 months. The mean C0 values were higher in the pantoprazole group than in the esomeprazole group in the sixth month only (P = .007). Serum creatinine level was lower in the sixth month than at baseline in the esomeprazole group (P = .004). There were no signs of rejection biochemical or clinical in any of the study groups. In conclusion, PPIs should be used with caution and doses should be titrated to reach the C0 targets in RTR, which is of more importance in pantoprazole than esomeprazole to avoid C0 level elevation or decline affecting the allograft function.
Interaction Between Alcohol Use and Metabolic Risk Factors for Liver Disease: A Critical Review of Epidemiological Studies
Authors: Åberg Fredrik , Färkkilä Martti , Männistö Ville
Published: December 2019

Coexistence of alcohol use and metabolic risk—the 2 commonest population risk factors for nonviral chronic liver disease—is a growing concern. Clinical evidence and mechanistic evidence point to considerable supraadditive interaction effects for the development and progression of chronic liver disease between hazardous alcohol use and metabolic abnormalities including obesity, diabetes, and the metabolic syndrome (MetS). Intermittent binge drinking once monthly or more often seems to be associated with progression of liver disease even when average alcohol intake is within the currently allowed limits for a diagnosis of nonalcoholic fatty liver disease (NAFLD), and supraadditive interaction between binge drinking and the MetS has been reported. There are contradictory findings regarding the association between low alcohol use and liver steatosis, but, clearly, the mechanisms of alcoholic hepatotoxicity extend beyond simple fat accumulation. The presence of liver steatosis seems to amplify alcoholic hepatotoxicity. Recent longitudinal studies of NAFLD subjects report low alcohol use associated with both increased fibrosis progression and an elevated risk for liver cancer and severe liver disease. There is no clear safe limit of alcohol intake in the presence of NAFLD or metabolic risk. The interaction effects between alcohol and metabolic dysfunction merit increased attention in public health policy, individual counseling, and risk stratification. Based on current evidence, a strict dichotomization of liver disease into either pure alcoholic or nonalcoholic may be inappropriate.
A novel mutation combining with rs66612022 in a Chinese pedigree suggests a new pathogenesis to osteogenesis imperfecta via whole genome sequencing
Authors: Li Yanjiao , Liang Hongsuo , Yuan Dekai , Liu Baoling , Liu Ling , Zhang Yongfa , Hou Kaiyu , Zhang Yunchao , Chen Bin , Ding Jing , Li Yunxia , Wang Qilin , Wu Haiying , Shi Hong , Hu Min
Published: December 2019

Osteogenesis imperfecta (OI) is a rare heritable disease with systemic connective tissue disorder. Most of the patients represent autosomal dominant form of OI, and are usually resulting from the mutations in type I collagen genes. However, the gene mutations reported previously only account for ∼70% of the OI cases. Here, in a Chinese OI family, we examined seven patients and nine normal individuals using the whole genome sequencing and molecular genetic analysis. The mutation of rs66612022 (COL1A2:p.Gly328Ser) related to glycine substitution was found in the seven patients. Moreover, we identified a novel missense mutation (HMMR:p.Glu2Gln). Interestingly, the individuals of this family with both the mutations were suffering from OI, while the others carried one or none of them are normal. The mutations of COL1A2 and HMMR and their combined effect on OI would further expand the genetic spectrum of OI.
Recent advances in the genetics of preterm birth
Authors: Wadon Megan , Modi Neena , Wong Hilary S. , Thapar Anita , O'Donovan Michael C.
Published: December 2019

Preterm birth is associated with short‐ and long‐term impairments affecting physical, cognitive, and neuropsychiatric health. These sequelae, together with a rising preterm birth rate and increased survival, make prematurity a growing public health issue because of the increased number of individuals with impaired health throughout the life span. Although a major contribution to preterm birth comes from environmental factors, it is also modestly heritable. Little is known about the architecture of this genetic contribution. Studies of common and of rare genetic variation have had limited power, but recent findings implicate variation in both the maternal and fetal genome. There is some evidence risk alleles in mothers may be enriched for processes related to immunity and inflammation, and in the preterm infant, processes related to brain development. Overall genomic discoveries for preterm birth lag behind progress for many other multifactorial diseases and traits. Investigations focusing on gene–environment interactions may also provide insights, but these studies still have a number of limitations. Adequately sized genetic studies of preterm birth are a priority for the future especially given the breadth of its negative health impacts across the life span and the current interest in newborn genome sequencing.
Short‐term and long‐term outcomes of oesophagogastric surgery for cancer in obese and normal weight patients
Authors: Glatz Torben , Kulemann Birte , Kuvendjiska Jasmina , Fichtner‐Feigl Stefan , Hoeppner Jens
Published: December 2019

Background

Obesity is generally considered to be associated with worse surgical outcome and impaired oncological prognosis. The impact of pre‐therapeutic body mass index (BMI) in patients with oesophagogastric cancer on the surgical outcome is controversially discussed.

Methods

We retrospectively examined 730 patients who had undergone curative treatment for oesophagogastric cancer at the Medical Center of the University of Freiburg (1996–2015). Patients were divided in groups according to pre‐therapeutic BMI (underweight (UW): <18.5 kg/m2; normal weight (NW): 18.5–25 kg/m2; overweight (OW): 25–30 kg/m2; and obese (OB): >30 kg/m2).

Results

Median BMI was 24.7 kg/m2. Forty‐two patients were UW, 337 NW, 263 OW and 84 OB. No significant differences between the groups (UW/NW/OW/OB) in operating time, hospital stay, perioperative complication rate and in‐hospital mortality were found. Pre‐therapeutic BMI was significantly associated with 5‐year survival (UW: 22%, NW: 37%, OW: 51%, OB: 50%, P < 0.001). Multivariate analysis identified UW/NW (BMI <25 kg/m2) as an independent risk factor for poor survival (relative risk 1.38, P = 0.001) among high American Society of Anesthesiologists score, old age, positive resection margin and high cancer stage according to the Union Internationale Contre le Cancer (UICC).

Conclusion

In oesophagogastric cancer, OW and OB patients can be treated surgically without impaired perioperative outcome and expect improved long‐term survival compared to patients with a BMI <25 kg/m2.
Atypical glandular lesions of the cervix and risk of cervical cancer
Authors: Graue Renate , Lönnberg Stefan , Skare Gry B. , Sæther Solbjørg M. M. , Bjørge Tone
Published: December 2019

Introduction

Cytology screening has been effective in reducing risks for cervical squamous cell carcinoma but less so for adenocarcinoma. We explored the association of atypical glandular cells or absence of glandular cells in cytology, and subsequent histological diagnoses and cancer risk.

Material and methods

All women in Norway with atypical glandular cells of undetermined significance (AGUS), adenocarcinoma in situ (ACIS) and normal/benign cells, but absence of endocervical or metaplastic cells (NC‐NEC) in their first cytology during 1992‐2014 (NC‐NEC; 2005‐2014), recorded in the Cancer Registry of Norway, were included (n = 142 445). Histology diagnoses (stratified by age) within 1 and 3 years after cytology were examined. The Nelson‐Aalen cumulative hazard function for gynecological cancer risk was displayed.

Results

The majority of AGUS and particularly ACIS were followed with histology within 1 and 3 years. Cervical intraepithelial neoplasia (CIN) lesions were more common in women <35 than in women ≥35 years. Cervical adenocarcinoma followed 13% of ACIS after 1 and 3 years. After ACIS and AGUS, cervical adenocarcinoma was the most frequent cancer subtype. Cumulative risks of cervical adenocarcinoma following ACIS, AGUS and NC‐NEC were 3.5%, 0.9% and 0.05%, respectively, after 22, 22 and 9 years of follow‐up.

Conclusions

There was a high‐risk of glandular malignancies after AGUS and ACIS in cytology. If effective treatment of pre‐cancer and early cancer is available, cytology screening provides some level of prevention of adenocarcinoma. Lack of glandular cells did not entail a higher cancer risk.
Impact of renal impairment and human organic anion transporter inhibition on pharmacokinetics, safety and tolerability of relebactam combined with imipenem and cilastatin
Authors: Bhagunde Pratik , Colon‐Gonzalez Francheska , Liu Yang , Wu Jin , Xu Shiyao Sherrie , Garrett Graigory , Jumes Patricia , Lasseter Kenneth , Marbury Thomas , Rizk Matthew L. , Lala Mallika , Rhee Elizabeth G. , Butterton Joan R. , Boundy Keith
Published: December 2019

Aims

Two phase 1, open‐label studies were conducted to investigate the effect of renal impairment (RI) and organic anion transporter (OAT) inhibition on pharmacokinetics (PK) and safety of relebactam (REL) plus imipenem/cilastatin (IMI).

Methods

Study PN005 evaluated the PK of REL (125 mg) plus IMI (250 mg) in participants with RI vs healthy controls. Study PN019 evaluated the PK of REL (250 mg) and imipenem (500 mg; dosed as IMI) with/without probenecid (1 g; OAT inhibitor) in healthy adults.

Results

Geometric mean ratios (RI/healthy matched controls) of area under the concentration–time curve from time 0 to infinity (AUC0‐∞; 90% confidence interval) for REL, imipenem and cilastatin increased as RI increased from mild (1.6 [1.1, 2.4], 1.4 [1.1, 1.8] and 1.6 [1.0, 2.5], respectively) to severe (4.9 [3.4, 7.0], 2.5 [1.9, 3.3] and 5.6 [3.6, 8.6], respectively). For all 3 analytes, plasma and renal clearance decreased and corresponding plasma apparent terminal half‐life increased with increasing RI. Geometric mean ratios ([probenecid+IMI/REL]/[IMI/REL]) of plasma exposure for REL and imipenem were 1.24 (1.19, 1.28) and 1.16 (1.13, 1.20), respectively. The dose fraction excreted (fe) in the urine decreased progressively from mild to severe RI. Probenecid reduced renal clearance of REL and imipenem by 25 and 31%, respectively. Compared with IMI/REL, coadministration of IMI/REL with probenecid yielded lower fe for REL and imipenem. In both studies, treatment was well tolerated; there were no serious adverse events or discontinuations due to adverse events.

Conclusion

RI increased plasma exposure and similarly decreased clearance of REL, imipenem and cilastatin; IMI/REL dose adjustment (fixed‐ratio) will be required for patients with RI. Probenecid had no clinically meaningful impact on the PK of REL or imipenem.
A multilevel mixed effects varying coefficient model with multilevel predictors and random effects for modeling hospitalization risk in patients on dialysis
Authors: Li Yihao , Nguyen Danh V. , Kürüm Esra , Rhee Connie M. , Chen Yanjun , Kalantar‐Zadeh Kamyar , Şentürk Damla
Published: December 2019

For patients on dialysis, hospitalizations remain a major risk factor for mortality and morbidity. We use data from a large national database, United States Renal Data System, to model time‐varying effects of hospitalization risk factors as functions of time since initiation of dialysis. To account for the three‐level hierarchical structure in the data where hospitalizations are nested in patients and patients are nested in dialysis facilities, we propose a multilevel mixed effects varying coefficient model (MME‐VCM) where multilevel (patient‐ and facility‐level) random effects are used to model the dependence structure of the data. The proposed MME‐VCM also includes multilevel covariates, where baseline demographics and comorbidities are among the patient‐level factors, and staffing composition and facility size are among the facility‐level risk factors. To address the challenge of high‐dimensional integrals due to the hierarchical structure of the random effects, we propose a novel two‐step approximate EM algorithm based on the fully exponential Laplace approximation. Inference for the varying coefficient functions and variance components is achieved via derivation of the standard errors using score contributions. The finite sample performance of the proposed estimation procedure is studied through simulations.
Bimodal stimulation in children with inner ear malformation: One side cochlear implant and contralateral auditory brainstem implant
Authors: Batuk Merve Ozbal , Cinar Betul Cicek , Yarali Mehmet , Aslan Filiz , Ozkan Hilal Burcu , Sennaroglu Gonca , Yucel Esra , Bajin Munir Demir , Bilginer Burcak , Sennaroglu Levent
Published: December 2019

Objective

To determine audiological outcomes of children who use a cochlear implant (CI) in one ear and an auditory brainstem implant (ABI) in the contralateral ear.

Design

Retrospective case review.

Setting

Tertiary referral hospital.

Participants

Twelve children followed with CI and contralateral auditory brainstem implant (ABI) by Hacettepe University Department of Otorhinolaryngology and Audiology in Turkey. All children were diagnosed with different inner ear malformations with cochlear nerve aplasia/hypoplasia. CI was planned in the ear with better sound detection during behavioural testing with inserted ear phones and with better CN as seen on MRI. Due to the limited auditory and speech progress with the cochlear implant, ABI was performed on the contralateral ear in all subjects.

Main outcome measures

Audiological performance and auditory perception skills of children with cochlear nerve deficiency (CND) who use bimodal electrical stimulation with CI and contralateral ABI.

Results

Mean age of the subjects was 84.00 ± 33.94 months. Age at CI surgery and ABI surgery was 25.00 ± 10.98 months and 41.50 ± 16.14 months, respectively. However, hearing thresholds only with CI and only with ABI did not reveal significant difference, and auditory perception scores improved with bimodal stimulation. The MAIS scores were significantly improved from unilateral CI to bimodal stimulation (P = .002). Pattern perception and word recognition scores were significantly higher with the bimodal condition when compared to CI only and ABI only conditions.

Conclusion

Children with CND showed better performance with CI and contralateral ABI combined. Depending on the audiological and radiological results, bimodal stimulation should be advised for children with CND.
Effects of bioenergy on biodiversity arising from land‐use change and crop type
Authors: Núñez‐Regueiro Mauricio M. , Siddiqui Sharmin F. , Fletcher Robert J.
Published: December 2019

Understanding how the world's flora and fauna will respond to bioenergy expansion is critical. This issue is particularly pronounced considering bioenergy's potential role as a driver of land‐use change, the variety of production crops being considered and currently used for biomass, and the diversity of ecosystems that can potentially supply land for bioenergy across the planet. We conducted 2 global meta‐analyses to determine how 8 of the most commonly used bioenergy crops may affect site‐level biodiversity. One search was directed at finding data on biodiversity in different production land uses and the other at extracting energy‐yield estimates of potential bioenergy crops. We used linear mixed‐effect models to test whether effects on biodiversity varied with different individual bioenergy crop species, estimated energy yield, first‐ or second‐generation crops, type of reference ecosystem considered, and magnitude of vertical change in habitat structure between any given crop and the reference ecosystem. Species diversity and abundance were generally lower in crops considered for bioenergy relative to the natural ecosystems they may replace. First‐generation crops, derived from oils, sugars, and starches, tended to have greater effects than second‐generation crops, derived from lignocellulose, woody crops, or residues. Crop yield had nonlinear effects on abundance and, to a lesser extent, overall biodiversity; biodiversity effects were driven by negative yield effects for birds but not other taxa. Our results emphasize that replacing natural ecosystems with bioenergy crops across the planet will largely be detrimental for biodiversity, with first generation and high‐yield crops having the strongest negative effects. We argue that meeting energy goals with bioenergy using existing marginal lands or biomass extraction within existing production landscapes may provide more biodiversity‐friendly alternatives than conversion of natural ecosystems for biofuel production.