bluuebunny/crossref_metadata_2025 huggingface dataset:
Disturbance of Information in Superior Parietal Lobe during Dual-task Interference in a Simulated Driving Task
Authors: Abbaszadeh Mojtaba , Hossein-Zadeh Gholam-Ali , Seyed-Allaei Shima , Vaziri-Pashkam Maryam
Published: July 2020

Performing a secondary task while driving causes a decline in driving performance. This phenomenon, called dual-task interference, can have lethal consequences. Previous fMRI studies have looked at the changes in the average brain activity to uncover the neural correlates of dual-task interference. From these results, it is unclear whether the overall modulations in brain activity result from general effects such as task difficulty, attentional modulations, and mental effort or whether it is caused by a change in the responses specific to each condition due to dual-task interference. To overcome this limitation, here, we used multi-voxel pattern analysis (MVPA) to interrogate the change in the information content in multiple brain regions during dual-task interference in simulated driving. Participants performed a lane change task in a simulated driving environment, along with a tone discrimination task with either short or long-time onset difference (Stimulus Onset Asynchrony, SOA) between the two tasks. Behavioral results indicated a robust dual-task effect on driving RT. MVPA revealed regions that carry information about the driving direction, including the superior parietal lobe (SPL), visual, and motor regions. Comparing the decoding accuracies across short and long SOA conditions, we showed lower accuracies in the SPL region in short than long SPA conditions. This change in accuracy was not observed in the visual and motor regions. In addition, the classification accuracy in the SPL was inversely correlated with participants’ reaction time in the driving task. These findings suggest that the dual-task interference in driving may be related to the disturbance of information processing in the SPL region.

Significance Statement

During real-world driving, when a driver wants to make a turn at an intersection and simultaneously respond to a cell phone call, his reaction time slows down. This effect is called dual-task interference. Here, we aimed to examine its neural mechanisms using a paradigm that consisted of a driving turn task and a tone discrimination task in a simulated environment. Results showed that the information for the driving turn was disturbed in the superior parietal lobe (SPL) during dual-task interference. We suggest that the driving performance decline in the presence of the secondary task might be related to the disturbance of information in the SPL.
Pseudomonas aeruginosareverse diauxie is an optimized, resource utilization strategy
Authors: McGill S. Lee , Yung Yeni , Hunt Kristopher A. , Henson Michael A. , Hanley Luke , Carlson Ross P.
Published: July 2020

Pseudomonas aeruginosais a globally-distributed bacterium often found in medical infections. The opportunistic pathogen uses a different, carbon catabolite repression (CCR) strategy than many, model microorganisms. It does not utilize a classic diauxie phenotype, nor does it follow common systems biology assumptions including preferential consumption of glucose with an ‘overflow’ metabolism. Despite these contradictions,P. aeruginosais competitive in many, disparate environments underscoring knowledge gaps in microbial ecology and systems biology. Physiological, omics, andin silicoanalyses were used to quantify theP. aeruginosaCCR strategy known as ‘reverse diauxie’. An ecological basis of reverse diauxie was identified using a genome-scale, metabolic model interrogated within vitroomics data. Reverse diauxie preference for lower energy, nonfermentable carbon sources, such as acetate or succinate over glucose, was predicted using a multidimensional strategy which minimized resource investment into central metabolism while completely oxidizing substrates. Application of a common,in silicooptimization criterion, which maximizes growth rate, did not predict the reverse diauxie phenotypes. This study quantifiesP. aeruginosametabolic strategies foundational to its wide distribution and virulence.
Impact of endotoxins in gelatine hydrogels on chondrogenic differentiation and inflammatory cytokine secretionin vitro
Authors: Groen Wilhelmina M.G.A.C. , Utomo Lizette , Castilho Miguel , Gawlitta Debby , Malda Jos , van Weeren Paul René , Levato Riccardo , Korthagen Nicoline M.
Published: July 2020

Gelatine methacryloyl (GelMA) hydrogels are widely used in studies aiming at cartilage regeneration. However, the endotoxin content of commercially available GelMAs and gelatines used in these studies is often overlooked, even though endotoxins may influence several cellular functions. Moreover, regulations for clinical use of biomaterials dictate a stringent endotoxin limit.

We determined the endotoxin level of five different GelMAs and evaluated the effect on the chondrogenic differentiation of equine mesenchymal stromal cells (MSCs). Cartilage-like matrix production was evaluated by biochemical assays and immunohistochemistry. Furthermore, equine peripheral blood mononuclear cells (PBMCs) were cultured on the hydrogels for 24 hours, followed by the assessment of tumour necrosis factor (TNF)-α and C-C motif chemokine ligand (CCL)2 as inflammatory markers.

The GelMAs were found to have widely varying endotoxin content (two with >1000 EU/ml and three with <10 EU/ml), however, this was not a critical factor determiningin vitrocartilage-like matrix production of embedded MSCs. PBMCs did produce significantly higher TNF-α and CCL2 in response to the GelMA with the highest endotoxin level compared to the other GelMAs.

Although limited effects on chondrogenic differentiation were found in this study, caution with the use of commercial hydrogels is warranted in the translation fromin vitrotoin vivostudies because of regulatory constraints and potential inflammatory effects of the content of these hydrogels.
Density-dependent private benefit leads to bacterial mutualism
Authors: Jimenez Paul , Scheuring István
Published: July 2020

Microorganisms produce materials leaked from the cell which are beneficial for themselves and their neighbors. We modeled the situation when cells can produce different costly secretions which increase the carrying capacity of the population. Strains that lose the function of producing one or more secretions avoid the cost of production and can exhaust the producers. However, secreting substances provides a private benefit for the producers in a density-dependent way. We developed a model to examine the outcome of the selection among different type of producer strains from the non-producer strain to the partial producers, to the full producer one. We were particularly interested in circumstances under which selection maintains partners that produce complementary secreted materials thus forming an interdependent mutualistic interaction.

We show that interdependent mutualism is selected under broad range of conditions if private benefit decreases with density. Selection frequently causes the coexistence of more and less generalist cooperative strains, thus cooperation and exploitation co-occur. Interdependent mutual-ism is evolved under more specific circumstances if private benefit increases with density and these general observations are valid in a well-mixed and in a structured deme model. We show that the applied population structure supports cooperation in general, which, depending on the level of private benefit and intensity of mixing helps either the specialist or the generalist cooperators.
Brain age prediction in schizophrenia: does the choice of machine learning algorithm matter?
Authors: Lee Won Hee , Antoniades Mathilde , Schnack Hugo G , Kahn Rene S. , Frangou Sophia
Published: July 2020

Background

Schizophrenia has been associated with lifelong deviations in the normative trajectories of brain structure. These deviations can be captured using the brain-predicted age difference (brainPAD), which is the difference between the biological age of an individual’s brain, as inferred from neuroimaging data, and their chronological age. Various machine learning algorithms are currently used for this purpose but their comparative performance has yet to be systematically evaluated.

Methods

Six linear regression algorithms, ordinary least squares (OLS) regression, ridge regression, least absolute shrinkage and selection operator (Lasso) regression, elastic-net regression, linear support vector regression (SVR), and relevance vector regression (RVR), were applied to brain structural data acquired on the same 3T scanner using identical sequences from patients with schizophrenia (n=90) and healthy individuals (n=200). The performance of each algorithm was quantified by the mean absolute error (MAE) and the correlation (R) between predicted brain-age and chronological age. The inter-algorithm similarity in predicted brain-age, brain regional regression weights and brainPAD were compared using correlation analyses and hierarchical clustering.

Results

In patients with schizophrenia, ridge regression, Lasso regression, elastic-net regression, and RVR performed very similarly and showed a high degree of correlation in predicted brain-age (R>0.94) and brain regional regression weights (R>0.66). By contrast, OLS regression, which was the only algorithm without a penalty term, performed markedly worse and showed a lower similarity with the other algorithms. The mean brainPAD was higher in patients than in healthy individuals but varied by algorithm from 3.8 to 5.2 years although all analyses were performed on the same dataset.

Conclusions

Linear machine learning algorithms, with the exception of OLS regression, have comparable performance for age prediction on the basis of a combination of cortical and subcortical structural measures. However, algorithm choice introduced variation in brainPAD estimation, and therefore represents an important source of inter-study variability.
Genomic analyses of glycine decarboxylase neurogenic mutations, yield a large scale prediction model for prenatal disease
Authors: Farris Joseph D. , Alam Md. Suhail , MysoreRajashekara Arpitha , Haldar Kasturi
Published: July 2020

Glycine decarboxylase (GLDC) is a mitochondrial protein, hundreds of mutations in which cause a neurometabolic disorder Non-ketotic Hyperglycinemia (NKH), associated with elevation of plasma glycine. But why a mutation induces severe or attenuated neurological disease is poorly understood. We combined a human multiparametric mutation scale that separates severe from attenuated clinical, neurological disease, with newin silicotools to assess 238 of 255 NKH mutations in murine GLDC. We unified novel murine and human genome level-analyses across a linear scale of neurological severity, within vivoevidence from mice engineered with a top-ranking attenuated mutation and another mutation >10 times more pathogenic and integrated the data in a model of pre- and post-natal disease outcomes, relevant for over a hundred major and minor neurogenic mutations. Our findings suggest that highly severe neurogenic mutations predict fatal, prenatal disease that can be remedied by metabolic supplementation of dams, in absence of amelioration of persistent and age-dependent elevation of plasma glycine.
Relationship Between Neuroendocrine and Immune Gene Expression in Small Cell Lung Cancer
Authors: Cai Ling , Liu Hongyu , Huang Fang , Fujimoto Junya , Girard Luc , Chen Jun , Li Yongwen , Zhang Yuan , Deb Dhruba , Stastny Victor , Kuo Christin S. , Jia Gaoxiang , Yang Chendong , Zou Wei , Alomar Adeeb , Huffman Kenneth , Papari-Zareei Mahboubeh , Yang Lin , Drapkin Benjamin , Akbay Esra , Shames David S. , Wistuba Ignacio I. , Wang Tao , Xiao Guanghua , DeBerardinis Ralph J. , Minna John D. , Xie Yang , Gazdar Adi F.
Published: July 2020

Small cell lung cancer (SCLC) is classified as a high-grade neuroendocrine (NE) tumor, but a subset of SCLC has been termed “variant” due to the loss of NE characteristics. In this study, we computed NE scores for patient-derived SCLC cell lines and xenografts, as well as human tumors. We aligned NE properties with transcription factor-defined molecular subtypes. Then we investigated the different immune phenotypes associated with high and low NE scores. We found repression of immune response genes as a shared feature between classic SCLC and pulmonary neuroendocrine cells of the healthy lung. With loss of NE fate, variant SCLC tumors regain cell-autonomous immune gene expression and exhibit higher tumor-immune interactions. Pan-cancer analysis revealed this NE lineage-specific immune phenotype in other cancers. Additionally, we observed MHC I re-expression in SCLC upon development of chemoresistance. These findings provide a new framework to guide design of treatment regimens in SCLC.
Elucidation of tumor-stromal heterogeneity and the ligand-receptor interactome by single cell transcriptomics in real-world pancreatic cancer biopsies
Authors: Lee Jaewon J. , Bernard Vincent , Semaan Alexander , Monberg Maria E. , Huang Jonathan , Stephens Bret M. , Lin Daniel , Weston Brian R. , Bhutani Manoop S. , Haymaker Cara L. , Bernatchez Chantale , Taniguchi Cullen M. , Maitra Anirban , Guerrero Paola A.
Published: July 2020

Precision medicine approaches in pancreatic ductal adenocarcinoma (PDAC) are imperative for improving disease outcomes. However, the long-term fidelity of recently deployedex vivopreclinical platforms, such as patient-derived organoids (PDOs) remains unknown. Through single-cell RNA sequencing (scRNA-seq), we identify substantial transcriptomic evolution of PDOs propagated from the parental tumor, which may alter predicted drug sensitivity. In contrast, scRNA-seq is readily applicable to limited biopsies from human primary and metastatic PDAC and identifies most cancers as being an admixture of previously described epithelial transcriptomic subtypes. Integrative analyses of our data provide an in-depth characterization of the heterogeneity within the tumor microenvironment, including cancer-associated fibroblast (CAF) subclasses, and predicts for a multitude of ligand-receptor interactions, revealing potential targets for immunotherapy approaches. While PDOs continue to enable prospective therapeutic prediction, our analysis also demonstrates the complementarity of using orthogonalde novobiopsies from PDAC patients paired with scRNA-seq to inform clinical decision-making.

Statement of Significance

The application of single-cell RNA sequencing to diagnostic pancreatic cancer biopsies provides in-depth transcriptomic characterization of the tumor epithelium and microenvironment, while minimizing potential artifacts introduced by an interveningex vivopassaging step. Thus, this approach can complement the use of patient-derived organoids in implementing precision oncology.
Effects of osteogenic ambulatory mechanical stimulation on early stages of BMP-2 mediated bone repair
Authors: Klosterhoff Brett S. , Vantucci Casey E. , Kaiser Jarred , Ong Keat Ghee , Wood Levi B. , Weiss Jeffrey A. , Guldberg Robert E. , Willett Nick J.
Published: July 2020

Mechanical loading of bone defects through rehabilitation is a promising therapeutic approach to stimulate repair and reduce the risk of non-union; however, little is known about how therapeutic mechanical stimuli modulate early stages of repair before mineralized bone formation. In a previous study, we established an osteogenic mechanical loading protocol using early ambulatory rehabilitation and a compliant, load-sharing fixator in a rat model of BMP-2 mediated bone defect repair. The objective of this study was to investigate the early effects of osteogenic loading on cytokine expression, tissue composition, and angiogenesis during the first 3 weeks of repair in this model. Using a wireless implantable strain sensor for local measurements of mechanical boundary conditions, finite element simulations showed that osteogenic mechanical loading increased mean compressive strain in defect soft tissue during rehabilitative ambulation at 1 week (load-sharing: −1.54 ± 0.17% vs. load-shielded: −0.76 ± 0.06%), and that strain was amplified in remaining soft tissue regions at 3 weeks as mineralization progressed (load-sharing: −1.89 ± 0.35% vs. load-shielded: −1.38 ± 0.35%). Multivariate analysis of multiplex cytokine arrays revealed that loading significantly altered cytokine expression profiles in the defect tissue at 2 weeks compared to load-shielded defects. Specifically, loading reduced VEGF and increased CXCL5 (LIX) levels. Subsequently, vascular volume in loaded defects was reduced relative to load-shielded defects but similar to intact bone at 3 weeks. Endochondral bone repair was also observed histologically in loaded defects only at 3 weeks. Together, these results demonstrate that moderate ambulatory strains previously shown to stimulate functional bone regeneration significantly alter early angiogenic and cytokine signaling and may promote endochondral ossification in large segmental bone defects.

Authors’ Contributions

B.S.K., N.J.W., and R.E.G. designed the research and performed surgeries; B.S.K., C.E.V., and J.K. performed experiments; B.S.K., C.E.V., J.K., and L.B.W., analyzed data; B.S.K., C.E.V., N.J.W., and R.E.G. wrote the manuscript; All authors interpreted data, critically edited, and have read and approved the final manuscript.
The genetic architecture and evolution of life history divergence among perennials in theMimulus guttatusspecies complex
Authors: Coughlan Jenn M. , Brown Maya Wilson , Willis J.H.
Published: July 2020

Ecological divergence is a main source of trait divergence between closely related species. Despite its importance in generating phenotypic diversity, the genetic architecture of most ecologically relevant traits is poorly understood. Differences in elevation can impose substantial selection for phenotypic divergence of both complex, correlated suites of traits (such as life history), as well as novel adaptations. Here, we use theMimulus guttatusspecies complex to assess if divergence in elevation is accompanied by trait divergence in a group of closely related perennial species, and determine the genetic architecture of this divergence. We find that divergence in elevation is associated with differences in multivariate quantitative life history traits, as well as a unique trait; the production of rhizomes, which may play an important role in overwintering survival. However, the extent of phenotypic divergence among species depended on ontogeny, suggesting that species also diverged in investment strategies across development. Lastly, we show that the genetic architecture of life history divergence between two species is simple, involving few mid to large effect Quantitative Trait Loci (QTLs), and that the genetic architecture of the ability to produce rhizomes changes through development, which has potential implications for hybrid fitness in the wild.
A White Noise Approach to Evolutionary Ecology
Authors: Week Bob , Nuismer Scott L. , Harmon Luke J. , Krone Stephen M.
Published: July 2020

Although the evolutionary response to random genetic drift is classically modelled as a sampling process for populations with fixed abundance, the abundances of populations in the wild fluctuate over time. Furthermore, since wild populations exhibit demographic stochasticity, it is reasonable to consider the evolutionary response to demographic stochasticity and its relation to random genetic drift. Here we close this gap in the context of quantitative genetics by deriving the dynamics of the distribution of a quantitative character and the abundance of a biological population from a stochastic partial differential equation driven by space-time white noise. In the process we develop a useful set of heuristics to operationalize the powerful, but abstract theory of white noise and measure-valued stochastic processes. This approach allows us to compute the full implications of demographic stochasticity on phenotypic distributions and abundances of populations. We demonstrate the utility of our approach by deriving a quantitative genetic model of diffuse coevolution mediated by exploitative competition for a continuum of resources. In addition to trait and abundance distributions, this model predicts interaction networks defined by rates of interactions, competition coefficients, or selection gradients. Analyzing the relationship between selection gradients and competition coefficients reveals independence between linear selection gradients and competition coefficients. In contrast, absolute values of linear selection gradients and quadratic selection gradients tend to be positively correlated with competition coefficients. That is, competing species that strongly affect each other’s abundance tend to also impose selection on one another, but the directionality is not predicted. This approach contributes to the development of a synthetic theory of evolutionary ecology by formalizing first principle derivations of stochastic models that underlie rigorous investigations of the relationship between feedbacks of biological processes and the patterns of diversity they produce.
Characterization of the gut DNA and RNA viromes in a cohort of Chinese residents and visiting Pakistanis
Authors: Yan Qiulong , Wang Yu , Chen Xiuli , Jin Hao , Wang Guangyang , Guan Kuiqing , Zhang Yue , Zhang Pan , Ayaz Taj , Liang Yanshan , Wang Junyi , Cui Guangyi , Sun Yuanyuan , Xiao Manchun , Zhang Aiqin , Li Peng , Liu Xueyang , Ma Yufang , Li Shenghui , Ma Tonghui
Published: July 2020

Background

Trillions of viruses inhabit the gastrointestinal tract. Some of them have been well-studied on their roles in infection and human health, but the majority remain unsurveyed. It has been established that the composition of the gut virome is highly variable based on the changes of diet, physical state, and environmental factors. However, the effect of host genetic factors, e.g. ethnic origin, on the gut virome is rarely investigated.

Methods and Results

Here, we characterized and compared the gut virome in a cohort of local Chinese residents and visiting Pakistani individuals, each group containing 24 healthy adults and 6 children. Using metagenomic shotgun sequencing and assembly of fecal samples, a huge number of viral operational taxonomic units (vOTUs) were identified for profiling the DNA and RNA viromes. National background contributed a primary variation to individuals’ gut virome. Compared with the Chinese adults, the Pakistan adults showed higher macrodiversity and different compositional and functional structures in their DNA virome and lower diversity and altered composition in their RNA virome. The virome variations of Pakistan children were inherited from the that of the adults but also tended to share similar characteristics with the Chinese cohort. We also analyzed and compared the bacterial microbiome between two cohorts and further revealed numerous connections between virus and bacterial host. Statistically, the gut DNA and RNA viromes were covariant to some extent (p<0.001), and they both influenced the holistic bacterial composition and vice versa.

Conclusions

This study provides an overview of gut viral community in Chinese and visiting Pakistanis and proposes a considerable role of ethnic origin in shaping the virome.
Zinc Sulfide-Based Hybrid Exosome-Coated Nanoplatform for Targeted Treatment of Glioblastoma in an Orthotopic Mouse Glioblastoma Model
Authors: Mo Jingxin , Li Meiying , Tang Edith K.Y. , Li Shaoyuan , Zhao Wei , Gooding J. Justin
Published: July 2020

Core-hybrid shell hydroxychloroquine (HCQ) loaded zinc sulfide (ZnS) nanoparticles were synthesized, characterized and evaluated for the treatment of glioblastoma cellsin vitroandin vivo. These particles, denoted as HCQ@ZnS@exo@iRGD, consist of hollow ZnS nanoparticles loading with the autophagic inhibitor of hydroxychloroquine and covered by a hybrid shell containing exosomes (exo) and phosphatidylserine derived pH- and redox-responsive pegylated iRGD peptide, a gliomablastoma-homing and penetrating peptide. The hybrid exosomes enable HCQ@ZnS with good permeability across the blood-brain barrier and targeting ability to glioblastoma cells in orthotopic mouse glioblastoma model. ZnS acts as a photosensitizer for reactive oxygen species (ROS) production to inflict damage to organelles within glioblastoma cells. Hydroxychloroquine inhibits autophagic flux, which can subsequently lead to the accumulation of impaired organelles caused by the ROS. As a result, substantial selective damage to glioblastoma cells was realized owing to the hybrid exosomes guiding the anti-tumour effects of hydroxychloroquine and ZnS under light irradiation. The results provide evidence for the utility of HCQ@ZnS@exo@iRGD as a therapeutic strategy for glioblastoma.
Vision affects gait speed but not patterns of muscle activation during inclined walking – a virtual reality study
Authors: Benady Amit , Zadik Sean , Ben-Gal Oran , Cano-Porras Desiderio , Wenkert Atalia , Gilaie-Dotan Sharon , Plotnik Meir
Published: July 2020

While walking, our locomotion is affected by and adapts to the environment based on vision-based and body-based (vestibular and proprioception) cues, all contributing to an “Internal Model of Gravity”. During surface inclination transitions, we modulate gait to counteract gravitational forces by braking during downhill walking to avoid uncontrolled acceleration or by exerting effort to avoid deceleration while walking uphill. In this study, we investigated the role of vision in gait modulation during surface inclination transitions by using an immersive large-scale Virtual Reality (VR) system equipped with a self-paced treadmill and projected visual scenes that allowed us to modulate physical-visual inclinations congruence parametrically. Gait speed and leg muscle electromyography (EMG) were measured in 12 healthy young adults. In addition, the magnitude of subjective visual misperception of verticality was measured by the rod and frame test. During virtual (non-veridical) inclination transitions, vision modulated gait speed after transitions by (i) slowing down to counteract the excepted gravitational ‘boost’ in virtual downhill inclinations and by (ii) speeding up to counteract the expected gravity resistance in virtual uphill inclinations. These gait speed modulations were reflected in muscle activation intensity changes and associated with subjective visual verticality misperception. However, temporal patterns of muscle activation, which are significantly affected by real gravitational inclination transitions, were not affected by virtual (visual) inclination transitions. Our results delineate the contribution of vision to functional locomotion on uneven surfaces and may lead to enhanced rehabilitation strategies for neurological disorders affecting movement.

Significance statement

A crucial component of successful locomotion is maintaining balance and speed while walking on uneven surfaces. In order to reach successful locomotion, an individual must utilize multisensory integration of visual, gravitational, and proprioception cues. The contribution of vision to this process is still unclear, thus we used a fully immersive virtual reality treadmill setup allowing us to manipulate visual (virtual) and gravitational (real) surface inclinations independently during locomotion of healthy adults. While vision modulated gait speed for a short period after inclination transitions and this was predictive of individual’s visual dependency, muscle activation patterns were only affected by gravitational surface inclinations, not by vision. Understanding the vision’s contribution to successful locomotion may lead to improved rehabilitation for movement disorders.
Simplexviruses successfully adapt to their host by fine-tuning immune responses
Authors: Mozzi Alessandra , Cagliani Rachele , Pontremoli Chiara , Forni Diego , Saulle Irma , Saresella Marina , Pozzoli Uberto , Clerici Mario , Biasin Mara , Sironi Manuela
Published: July 2020

Primate herpes simplex viruses are relatively harmless to their natural hosts, whereas cross-species transmission can result in severe disease. We performed a genome-wide scan for signals of adaptation of simplexviruses to hominins. We found evidence of positive selection in three glycoproteins, with selected sites located in antigenic determinants. Positively selected non-core proteins were involved in different immune-escape mechanisms. By expressing mutants of one of these proteins (ICP47), we show that the amino acid status at the positively selected sites is sufficient to induce HLA-G. HSV-1/HSV-2 ICP47 induced HLA-G when mutated to recapitulate residues in B virus, whereas the mutated version of B virus ICP47 failed to determine HLA-G expression. Thus, the evolution of ICP47 in HSV-1/HSV-2 determined the loss of an immunosuppressive effect, suggesting that simplexviruses tune immune responses to promote successful co-existence with their hosts. These results also help explain the high pathogenicity of B virus in humans.
Determinants of SARS-CoV-2 infection in Italian healthcare workers: a multicenter study
Authors: Boffetta Paolo , Violante Francesco , Durando Paolo , Palma Giuseppe De , Pira Enrico , Vimercati Luigi , Cristaudo Alfonso , Icardi Giancarlo , Sala Emma , Coggiola Maurizio , Tafuri Silvio , Gattini Vittorio , Apostoli Pietro , Spatari Giovanna ,   Working Group on SARS-CoV-2 infection in Italian healthcare workers.
Published: July 2020

Background

Healthcare workers (HCW) are at increased risk of being infected with SARS-CoV-2, yet limited information is available on risk factors of infection.

Methods

We pooled data on occupational surveillance of 10,654 HCW who were tested for SARS-CoV-2 infection in six Italian centers. Information was available on demographics, job title, department of employment, source of exposure, use of personal protective equipment (PPE), and COVID-19-related symptoms. We fitted multivariable logistic regression models to calculate odds ratios (OR) and 95% confidence intervals (CI).

Findings

The prevalence of infection varied across centers and ranged from 3.0% to 22.0%, being strongly correlated with that of the respective areas. Women were at lower risk of infection compared to men. Fever, cough, dyspnea and malaise were the symptoms most strongly associated with infection, together with anosmia and ageusia. No differences in the risk of infection were detected between job titles, or working in a COVID-19 designated department. Reported contact with a patient inside or outside the workplace was a risk factor. Use of a mask was strongly protective against risk of infection as was use of gloves. The use of a mask by the source of exposure (patient or colleague) had an independent effect in reducing infection risk.
Trans-ethnic analysis of the human leukocyte antigen region for ulcerative colitis reveals shared but also ethnicity-specific disease associations
Authors: Degenhardt Frauke , Mayr Gabriele , Wendorff Mareike , Boucher Gabrielle , Ellinghaus Eva , Ellinghaus David , ElAbd Hesham , Rosati Elisa , Hübenthal Matthias , Juzenas Simonas , Abedian Shifteh , Vahedi Homayon , BK Thelma , Yang Suk-Kyun , Ye Byong Duk , Cheon Jae Hee , Datta Lisa Wu , Daryani Naser Ebrahim , Ellul Pierre , Esaki Motohiro , Fuyuno Yuta , McGovern Dermot PB , Haritunians Talin , Hong Myhunghee , Juyal Garima , Jung Eun Suk , Kubo Michiaki , Kugathasan Subra , Lenz Tobias L. , Leslie Stephen , Malekzadeh Reza , Midha Vandana , Motyer Allan , Ng Siew C , Okou David T , Raychaudhuri Soumya , Schembri John , Schreiber Stefan , Song Kyuyoung , Sood Ajit , Takahashi Atsushi , Torres Esther A , Umeno Junji , Alizadeh Behrooz Z. , Weersma Rinse K , Wong Sunny H , Yamazaki Keiko , Karlsen Tom H , Rioux John D , Brant Steven R ,   for the MAAIS Recruitment Center, Franke Andre ,   for the International IBD Genetics Consortium
Published: July 2020

Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the gut. Genetic association studies have identified the highly variable human leukocyte antigen (HLA) region as the strongest susceptibility locus for IBD, and specifically DRB1*01:03 as a determining factor for ulcerative colitis (UC). However, for most of the association signal such a delineation could not be made due to tight structures of linkage disequilibrium within the HLA. The aim of this study was therefore to further characterize the HLA signal using a trans-ethnic approach. We performed a comprehensive fine mapping of single HLA alleles in UC in a cohort of 9,272 individuals with African American, East Asian, Puerto Rican, Indian and Iranian descent and 40,691 previously analyzed Caucasians, additionally analyzing whole HLA haplotypes. We computationally characterized the binding of associated HLA alleles to human self-peptides and analysed the physico-chemical properties of the HLA proteins and predicted self-peptidomes. Highlighting alleles of the HLA-DRB1*15 group and their correlated HLA-DQ-DR haplotypes, we identified consistent associations across different ethnicities but also identified population-specific signals. We observed that DRB1*01:03 is mostly present in individuals of Western European descent and hardly present in non-Caucasian individuals. We found peptides predicted to bind to risk HLA alleles to be rich in positively charged amino acids such. We conclude that the HLA plays an important role for UC susceptibility across different ethnicities. This research further implicates specific features of peptides that are predicted to bind risk and protective HLA proteins.
Evidence favouring the efficacy of convalescent plasma for COVID-19 therapy
Authors: Joyner Michael J. , Klassen Stephen A. , Senefeld Jonathon W. , Johnson Patrick W. , Carter Rickey E. , Wiggins Chad C. , Shoham Shmuel , Grossman Brenda J. , Henderson Jeffrey P. , Musser James , Salazar Eric , Hartman William R. , Bouvier Nicole M. , Liu Sean T. H. , Pirofski Liise-anne , Baker Sarah E. , van Helmond Noud , Wright R. Scott , Fairweather DeLisa , Bruno Katelyn A. , Paneth Nigel S. , Casadevall Arturo
Published: July 2020

To determine the effect of COVID-19 convalescent plasma on mortality, we aggregated patient outcome data from randomized clinical trials, matched control, case series, and case report studies. Fixed-effects analyses demonstrated that hospitalized COVID-19 patients transfused with convalescent plasma exhibited a ~57% reduction in mortality rate (10%) compared to matched-patients receiving standard treatments (22%; OR: 0.43,P< 0.001). These data provide evidence favouring the efficacy of human convalescent plasma as a therapeutic agent in hospitalized COVID-19 patients.
Deep skin dysbiosis in vitiligo patients: link with mitochondrial and immune changes
Authors: Bzioueche Hanene , Simonyté Sjödin Kotryna , West Christina E , Khemis Abdallah , Rocchi Stéphane , Passeron Thierry , Tulic Meri K
Published: July 2020

Rationale

Vitiligo is an autoimmune-disease characterized by patchy, white skin due to melanocyte loss. Commensal cutaneous or gut dysbiosis have been linked to various dermatological disorders. Here, we studied skin and gut microbiota of vitiligo patients compared to healthy controls.

Methods

We recruited 20 subjects and obtained swabs and biopsies from lesional and non-lesional skin, stool and blood from each individual (total 100 samples).

Results

We detected reduced richness and distribution of microbiota in stool of vitiligo subjects compared to controls (P<0.01). Skin swabs had greater alpha-diversity than skin biopsies (P<0.001), however only trends were seen between groups when examining microbiota at the skin surface. This was in contrast to sampling deeper layers of skin from the same patients which showed decreased richness and distribution of species (P<0.01) but greater phylogenetic diversity (P<0.01) in lesional compared to non-lesional sites. Biopsy microbiota from the lesional skin had distinct microbiota composition which was depleted of protective Bifidobacterium and enriched in Terenicutes, Streptococcus, Mycoplasma and mitochondrial DNA (P<0.001); the latter was linked with increased innate immunity and stress markers in the blood of the same patients (P<0.05).

Conclusion

These data describe vitiligo-specific cutaneous and gut microbiota and, for the first time in humans, a link between mitochondrial alteration, innate immunity and skin microbiota.
Readmission Rates and Medication Selection for Patients with Heart Failure Preserved Ejection Fraction
Authors: Kramer Troy , Vogler Carrie , Robinson Robert , Bhattarai Mukul
Published: July 2020

Purpose

Heart failure with preserved ejection fraction (HFpEF) has less guideline driven treatment options due to a lack of trials demonstrating medications with improved clinical outcomes for this patient population. The primary objective of this study is to determine which medications and dosages are related to high readmission rates for HFpEF patients.

Methods

A retrospective, single center, chart review was performed on patients with HFpEF at an academic medical center. Heart failure patients ages between 18-89 with an ejection fraction ≥45% from a transthoracic echocardiogram (TTE) were included. Primary outcomes include 30-day all cause readmission rates, prescribing patterns, and avoidance of potentially harmful medications. Descriptive statistics and multivariate logistic regression were used to assess potential risk factors.

Results

This study analyzed 455 patient admissions. Univariate analysis shows patients who were not readmitted were more likely to be on furosemide (54% vs 42%; p = 0.019). Conversely, readmitted patients were more likely to be taking bumetanide (4% vs 1%; p = 0.039). Lisinopril was the only angiotensin converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) associated with lower readmission rates (p = 0.036). Multivariate logistic regression showed bumetanide on admission (OR 14.6, p = 0.001), discharged on rosuvastatin (OR 6.29, p = 0.003) and meloxicam therapy (OR 6.33, p = 0.003) to be independent predictors of hospital readmission.

Conclusion

Three independent pharmacologic predictors for 30-day readmissions for patients with HFpEF were therapy with bumetanide, meloxicam, or rosuvastatin. Further research is needed to clarify the significance of these results.
Efficacy and safety of treating symptomatic, primary focal osteochondral lesions of the patella with a combination of intra-articular injection of hyaluronic acid (HAi) and radial extracorporeal shock wave therapy (rESWT) or HAi alone: a retrospective two-cohort study
Authors: Cao Jin , Huang Heqin , Zhang Changgui , Yang Liu , Schmitz Christoph , Duan Xiaojun
Published: July 2020

Background

This study tested the hypothesis that a combination of intra-articular injection of hyaluronic acid (HAi) and radial extracorporeal shock wave therapy (rESWT) is more effective than HAi alone in the treatment of symptomatic, primary focal osteochondral lesions of the patella (sPFOLP).

Methods

We performed a retrospective analysis of n=81 subjects with unilateral sPFOLP who were treated with respectively HAi+rESWT (n=36) or HAi alone (n=45) at the outpatient department of our hospital between January 1st, 2014 and January 31th, 2018. Subjects in both cohorts also received education with special attention to reduction of going up and down the stairs, squatting and specific activities, as well as non-opioid analgesics if necessary. Efficacy was assessed using the pain visual analogue scale (VAS) and the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score, which were examined at baseline (BL) and six weeks (W6), three months (M3) and six months (M6) after BL, as well as during a last follow-up examination (LE) which was performed at 37.6 ± 1.7 (mean ± standard error of the mean) months after BL (range, 12-59 months). In addition, measurements of the area of the patellar bone marrow edema (PBME) on sagittal, fat suppression sequence magnetic resonance imaging (MRI) scans of the knee were performed at BL, M3, M6 and LE.

Results

Subjects who were treated with HAi+rESWT showed significantly smaller mean VAS pain scores at W6, M3 and M6, significantly smaller mean WOMAC scores at W6, M3 and LE and significantly smaller mean PBME areas at M3, M6 and LE than subjects who were treated with HAi alone. No severe adverse events were observed.

Discussion

The results of this study suggest that HAi+rESWT is safe and more effective than HAi alone in the treatment of sPFOLP. This result should be verified in adequate randomized controlled trials.

Level of evidence

Level III; retrospective two-cohort study.
Performance of Abbott Architect, Ortho Vitros, and Euroimmun Assays in Detecting Prior SARS-CoV-2 Infection
Authors: Mahajan Shiwani , Redlich Carrie A. , Wisnewski Adam V. , Fazen Louis E. , Rao Lokinendi V. , Kuppusamy Karthik , Ko Albert I. , Krumholz Harlan M.
Published: July 2020

Background

Several serological assays have been developed to detect anti-SARS-CoV-2 IgG antibodies, but evidence about their comparative performance is limited. We sought to assess the sensitivity of four anti-SARS-CoV-2 IgG enzyme-linked immunosorbent assays (ELISA) in individuals with evidence of prior SARS-CoV-2 infection.

Methods

We obtained sera from 36 individuals with PCR-confirmed SARS-CoV-2 infection between March and May 2020. We evaluated samples collected at around 21 days (±14 days) after their initial PCR test using 3 commercially available ELISA assays, two anti-spike (Ortho- Clinical Diagnostics Vitros, and Euroimmun) and one anti-nucleocapsid (Abbott Architect), and a Yale-developed anti-spike ELISA test. We determined the sensitivity of the tests and compared their results. The Euroimmun and Yale ELISA had an equivocal and indeterminate category, which were considered as both negative and positive.

Results

Among the 36 individuals with SARS-CoV-2 infection, mean age was 43 (±13) years and 19 (53%) were female. The sensitivities of the tests were not significantly different (Abbott Architect, Ortho Vitros, Euroimmmun, and Yale assays: 86% (95% confidence interval [CI], 71– 95), 94% (95% CI, 81–99), 86% (95% CI, 71–95), and 94% (95% CI, 81–99), respectively; p- value=0.464). The sensitivities of the Euroimmun and Yale ELISA tests increased when the equivocal/indeterminate results were considered positive (97% [95% CI, 85–100] and 100% [95% CI, 90–100], respectively), but were not significantly different from other tests (p=0.082). The cross-correlation coefficient ranged from 0.85–0.98 between three anti-spike protein assays (Ortho Vitros, Euroimmun, Yale) and was 0.58–0.71 between the three anti-spike protein assays and the anti-nucleocapsid assay (Abbott).

Conclusion

The sensitivities of four anti-SARS-CoV-2 protein assays did not significantly differ, although the sample size was small. Sensitivity also depended on the interpretation of equivocal and indeterminate results. The strongest correlations were present for the three anti- spike proteins assays. These findings suggest that individual test characteristics and the correlation between different tests should be considered when comparing or aggregating data across different populations studies for serologic surveillance of past SARS-CoV-2 infection.
Eye-tracking for low vision with virtual reality (VR): testing status quo usability of the HTC Vive Pro Eye
Authors: Sipatchin Alexandra , Wahl Siegfried , Rifai Katharina
Published: July 2020

Background

Adding an eye tracker inside a head-mounted display (HMD) can offer a variety of novel functions in virtual reality (VR). Promising results point towards its usability as a flexible and interactive tool for low vision assessments and research of low vision functional impairment. Visual field (VF) perimetry performed using VR methodologies evidenced a correlation between the reliability of visual field testing in VR and the Humphrey test. The simulation of visual loss in VR is a powerful method used to investigate the impact and the adaptation to visual diseases. The present study presents a preliminary assessment of the HTC Vive Pro Eye for its potential use for these applications.

Methods

We investigated data quality over a wide visual field and tested the effect of head motion. An objective direct end-to-end temporal precision test simulated two different scenarios: the appearance of a pupil inside the eye tracker and a shift in pupil position, known as artificial saccade generator. The technique is low-cost thanks to a Raspberry Pi system and automatic.

Results

The target position on the screen and the head movement limit the HTC Vive Pro Eye’s usability. All the simulated scenarios showed a system’s latency of 58.1 milliseconds (ms).

Conclusion

These results point towards limitations and improvements of the HTC Vive Pro Eye’s status quo for visual loss simulation scenarios and visual perimetry testing.
Estradiol Action at the Median Preoptic Nucleus is Necessary and Sufficient for Sleep Suppression in Female Rats
Authors: Smith Philip C. , Cusmano Danielle M. , Viechweg Shaun S. , Schwartz Michael D. , Mong Jessica A.
Published: July 2020

To further our understanding of how gonadal steroids impact sleep biology, we sought to address the mechanism by which proestrus levels of cycling ovarian steroids, particularly estradiol (E2), suppress sleep in female rats. We showed that steroid replacement of proestrus levels of E2 to ovariectomized female rats, suppressed sleep to similar levels as those reported by endogenous ovarian hormones. We further showed that this suppression is due to the high levels of E2 alone, and that progesterone did not have a significant impact on sleep behavior. We found that E2 action within the Median Preoptic Nucleus (MnPO), which contains estrogen receptors (ERs), is necessary for this effect; antagonism of ERs in the MnPO attenuated the E2-mediated suppression of both non-Rapid Eye Movement (NREM) and Rapid Eye Movement (REM) sleep. Finally, we found E2 action at the MnPO is also sufficient for sleep suppression, as direct infusion of E2 into the MnPO suppressed sleep. Based on our findings, we predict proestrus levels of E2 alone, acting at the MnPO, mediate sex-hormone driven suppression of sleep in female rats.

Competing Interest Statement

MDS is now an employee of Jazz Pharmaceuticals; the views expressed in this manuscript are solely the authors’ and do not reflect the views, policies or procedures of Jazz Pharmaceuticals.