bluuebunny/crossref_metadata_2025 huggingface dataset:
Atypical relationships between neurofunctional features of print-sound integration and reading abilities in Chinese children with dyslexia
Authors: Xia Zhichao , Yang Ting , Cui Xin , Hoeft Fumiko , Liu Hong , Zhang Xianglin , Liu Xiangping , Shu Hua
Published: November 2021

Conquering print-sound mappings (e.g., grapheme-phoneme correspondence rules) is vital for developing fluent reading skills. In neuroimaging research, this ability can be indexed by activation differences between audiovisual congruent against incongruent conditions in brain areas such as the left superior temporal cortex. In line with it, individuals with dyslexia have difficulty in tasks requiring print-sound processing, accompanied by a reduced neural integration. However, existing evidence is almost restricted to alphabetic languages. Whether and how multisensory processing of print and sound is impaired in Chinese dyslexia remains underexplored. In this study, we applied a passive audiovisual integration paradigm with functional magnetic resonance imaging to investigate the possible dysfunctions in processing character-sound (opaque; semantics can be automatically accessed) and pinyin-sound associations (transparent; no particular meaning can be confirmed) in Chinese dyslexic children. Unexpectedly, the dyslexic group did not show reduced neural integration compared with typically developing readers in either character or pinyin experiment. However, the results revealed atypical correlations between neural integration and different reading abilities in dyslexia. Specifically, while the neural integration in the left inferior frontal cortex in processing character-sound pairs correlated with silent reading comprehension in both children with and without dyslexia, it was associated with morphological awareness (semantic-related) in controls but with rapid naming (phonological-related) in dyslexics. This result indicates Chinese dyslexic children may not use the same grapho-semantic processing strategy as their typical peers do. As for pinyin-sound processing, while a stronger neural integration in the direction of “congruent > incongruent” in the left occipito-temporal cortex and bilateral superior temporal cortices was associated with better oral reading fluency in the control group, an opposite pattern was found in dyslexia. This finding may reflect dyslexia’s dysfunctional recruitment of the regions in grapho-phonological processing, which further impedes character learning.

Highlights

Neurofunctional correlates of print-sound integration in Chinese children with and without dyslexia are investigated.

Dyslexic children show atypical relationships between neural audiovisual integration and reading abilities.

Chinese children with dyslexia are likely to use inefficient strategies to process characters and pinyin.
Clostridioides difficile phosphoproteomics shows an expansion of phosphorylated proteins in stationary growth phase
Authors: Smits Wiep Klaas , Mohammed Y. , de Ru Arnoud , Cordó Valentina , Friggen Annemieke , van Veelen Peter A. , Hensbergen Paul J.
Published: November 2021

Phosphorylation is a post-translational modification that can affect both house-keeping functions and virulence characteristics in bacterial pathogens. In the Gram-positive enteropathogen Clostridioides difficile the extent and nature of phosphorylation events is poorly characterized, though a protein-kinase mutant strain demonstrates pleiotropic phenotypes. Here, we used an immobilized metal affinity chromatography strategy to characterize serine, threonine and tyrosine phosphorylation in C. difficile. We find limited protein phosphorylation in the exponential growth phase but a sharp increase in the number of phosphopeptides after the onset of stationary growth phase. Among the overall more than 1500 phosphosites, our approach identifies expected targets and phosphorylation sites, including the protein kinase PrkC, the anti-sigma-F factor antagonist (SpoIIAA), the anti-sigma-B factor antagonist (RsbV) and HPr kinase/phosphorylase (HprK). Analysis of high-confidence phosphosites shows that phosphorylation on serine residues is most common, followed by threonine and tyrosine phosphorylation. This work forms the basis for a further investigation into the contributions of individual kinases to the overall phosphoproteome of C. difficile and the role of phosphorylation in C. difficile physiology and pathogenesis.

Importance

In this manuscript, we present a comprehensive analysis of protein phosphorylation in the Gram-positive enteropathogen Clostridioides difficile. To date, only limited evidence on the role of phosphorylation in regulation in this organism has been published; the current study is expected to form the basis for research on this post-translational modification in C. difficile.
Apolipoprotein ε4 modifies obesity-related atrophy in the hippocampal formation of cognitively healthy adults
Authors: Coad Bethany M. , Ghomroudi Parisa A. , Sims Rebecca , Aggleton John P. , Vann Seralynne D. , Metzler-Baddeley Claudia
Published: November 2021

Characterizing age- and risk-related hippocampal vulnerabilities may inform about the neural underpinnings of cognitive decline. We studied the impact of three risk-factors, Apolipoprotein (APOE)-ε4, a family history of dementia, and central obesity, on CA1, CA2/3, dentate gyrus (DG) and subiculum in 158 cognitively healthy adults (38-71 years). Subfields were labelled with the Automatic Segmentation of Hippocampal Subfields (ASHS) and FreeSurfer (version 6) protocols. Volumetric and microstructural measurements from quantitative magnetization transfer and Neurite Orientation Density and Dispersion Imaging were extracted for each subfield and reduced to three principal components capturing apparent myelin/neurite packing, size/complexity, and metabolism. Aging was associated with an inverse U-shaped curve on myelin/neurite packing and affected all subfields. Obesity led to reductions in myelin/neurite packing and size/complexity regardless of APOE and FH status. However, amongst individuals with a healthy Waist-Hip-Ratio, APOE ε4 carriers showed lower size/complexity than non-carriers. Protocol type did not affect this risk pattern. These findings provide novel evidence for interactive effects between APOE and central obesity on the hippocampal formation of cognitively healthy adults.

Highlights

Age-related inverted U-shaped curve of hippocampal myelin/neurite packing

Obesity-related reductions of hippocampal myelin/neurite packing and size/complexity

APOE modifies the effects of obesity on hippocampal size/complexity

Age-related slowing of spatial navigation

No APOE, family history, or obesity effects on cognition
#COVIDisAirborne: AI-Enabled Multiscale Computational Microscopy of Delta SARS-CoV-2 in a Respiratory Aerosol
Authors: Dommer Abigail , Casalino Lorenzo , Kearns Fiona , Rosenfeld Mia , Wauer Nicholas , Ahn Surl-Hee , Russo John , Oliveira Sofia , Morris Clare , Bogetti Anthony , Trifan Anda , Brace Alexander , Sztain Terra , Clyde Austin , Ma Heng , Chennubhotla Chakra , Lee Hyungro , Turilli Matteo , Khalid Syma , Tamayo-Mendoza Teresa , Welborn Matthew , Christensen Anders , Smith Daniel G. A. , Qiao Zhuoran , Sirumalla Sai Krishna , O’Connor Michael , Manby Frederick , Anandkumar Anima , Hardy David , Phillips James , Stern Abraham , Romero Josh , Clark David , Dorrell Mitchell , Maiden Tom , Huang Lei , McCalpin John , Woods Christopher , Gray Alan , Williams Matt , Barker Bryan , Rajapaksha Harinda , Pitts Richard , Gibbs Tom , Stone John , Zuckerman Daniel , Mulholland Adrian , Miller Thomas , Jha Shantenu , Ramanathan Arvind , Chong Lillian , Amaro Rommie
Published: November 2021

We seek to completely revise current models of airborne transmission of respiratory viruses by providing never-before-seen atomic-level views of the SARS-CoV-2 virus within a respiratory aerosol. Our work dramatically extends the capabilities of multiscale computational microscopy to address the significant gaps that exist in current experimental methods, which are limited in their ability to interrogate aerosols at the atomic/molecular level and thus ob-scure our understanding of airborne transmission. We demonstrate how our integrated data-driven platform provides a new way of exploring the composition, structure, and dynamics of aerosols and aerosolized viruses, while driving simulation method development along several important axes. We present a series of initial scientific discoveries for the SARS-CoV-2 Delta variant, noting that the full scientific impact of this work has yet to be realized.

ACM Reference Format

Abigail Dommer1†, Lorenzo Casalino1†, Fiona Kearns1†, Mia Rosenfeld1, Nicholas Wauer1, Surl-Hee Ahn1, John Russo,2Sofia Oliveira3, Clare Morris1, AnthonyBogetti4, AndaTrifan5,6, Alexander Brace5,7, TerraSztain1,8, Austin Clyde5,7, Heng Ma5, Chakra Chennubhotla4, Hyungro Lee9, Matteo Turilli9, Syma Khalid10, Teresa Tamayo-Mendoza11, Matthew Welborn11, Anders Christensen11, Daniel G. A. Smith11, Zhuoran Qiao12, Sai Krishna Sirumalla11, Michael O’Connor11, Frederick Manby11, Anima Anandkumar12,13, David Hardy6, James Phillips6, Abraham Stern13, Josh Romero13, David Clark13, Mitchell Dorrell14, Tom Maiden14, Lei Huang15, John McCalpin15, Christo- pherWoods3, Alan Gray13, MattWilliams3, Bryan Barker16, HarindaRajapaksha16, Richard Pitts16, Tom Gibbs13, John Stone6, Daniel Zuckerman2*, Adrian Mulholland3*, Thomas MillerIII11,12*, ShantenuJha9*, Arvind Ramanathan5*, Lillian Chong4*, Rommie Amaro1*. 2021. #COVIDisAirborne: AI-Enabled Multiscale Computational Microscopy ofDeltaSARS-CoV-2 in a Respiratory Aerosol. InSupercomputing ‘21: International Conference for High Perfor-mance Computing, Networking, Storage, and Analysis. ACM, New York, NY, USA, 14 pages.https://doi.org/finalDOI
“Addressing the core trait of bipolar disorder”: a concept analysis of mood stabilizing drugs
Authors: Estivalete Marchionatti Lauro , Blaya-Rocha Paula , Magalhães Pedro Vieira da Silva
Published: November 2021

Background

The term “mood stabilizer” is controversial in the literature. As there is no consensual meaning, its retirement has been suggested to avoid misuse. Nevertheless, it remains largely employed, and may carry an important meaning. This issue has not been approached using a validated qualitative inquiry.

Methods

We employed document analysis for reviewing definitions for mood stabilizer. Then, we used concept analysis as a qualitative methodology to clarify the meanings associated with the term. Based on its results, we built a theoretical model for a mood stabilizer, matching it with evidence for drugs used in the treatment of bipolar disorder.

Results

Concept analysis of documents defining the term unearthed four attributes of a mood stabilizer that were nested into the following ascending hierarchy: “not worsening”, “acute effects”, “prophylactic effects”, and “advanced effects”. To be considered a mood stabilizer, a drug had to reach the “prophylactic effects” tier, as this was discussed by authors as the core aspect of the class. After arranging drugs according to this scheme, “lithium” and “quetiapine” received the label, but only the former fulfilled all four attributes, as evidence indicates it has neuroprotective action.

Conclusion

The proposed model uses a hierarchy of attributes that take into account the complexity of the term and help to determine whether a drug is a mood stabilizer. Prophylaxis is pivotal to the concept, whose utility lies in implying a drug able to truly treat bipolar disorder, as opposed to merely targeting symptoms. This could modify long-term outcomes and illness trajectory.
Naloxone Buyers Club: Overlooked Critical Public Health Infrastructure for Preventing Overdose Deaths
Authors: Doe-Simkins Maya , Wheeler Eliza Jane , Figgatt Mary C. , Jones T. Stephen , Bell Alice , Davidson Peter J. , Dasgupta Nabarun
Published: November 2021

Background

Community-based naloxone distribution is an evidence-based pillar of overdose prevention. Since 2012, the naloxone Buyers Club facilitated purchase of low-cost naloxone by harm reduction and syringe service programs, the primary conduits for reaching people who use drugs. This innovative purchasing and mutual aid network has not been previously described.

Methods

We analyzed transactional records of naloxone orders (2017-2020, n=965), a survey of current Buyers Club members (2020, n=104), and mutual aid requests (2021, n=86).

Results

Between 2017 and 2020, annual orders for naloxone increased 2.6-fold. 114 unique harm reduction programs from 40 states placed orders for 3,714,110 vials of 0.4 mg/mL generic naloxone through the Buyers Club. States with most orders were: Arizona (600,000 vials), Illinois (576,800), Minnesota (347,450), California (317,200), North Carolina (315,040). Among programs that ordered naloxone in 2020, 52% (n=32) received no federal funding and ordered half as much as funded programs. During the 2021 shortage, mutual aid redistribution was common, with 80% participating as either a donor or recipient. Among 59 mutual aid requestors, 59% (n=35) were willing to accept expired naloxone; the clear preference was for generic injectable naloxone, 95% (n=56).

Conclusions

The naloxone Buyers Club is a critical element of overdose prevention infrastructure. Yet, barriers from corporate compliance officers and federal prescription-only status impede access. These barriers can be reduced by FDA removing the prescription requirement for naloxone and government funding for harm reduction programs.
Safety and immunogenicity of anti-SARS CoV-2 vaccine SOBERANA 02 in homologous or heterologous scheme
Authors: Eugenia-Toledo-Romani Maria , Verdecia-Sánchez Leslihana , Rodriguez-González Meybis , Rodríguez-Noda Laura , Valenzuela-Silva Carmen , Paredes-Moreno Beatriz , Sanchez-Ramirez Belinda , Perez-Nicado Rocmira , González-Mugica Raul , Hernández-Garcia Tays , Bergado-Baez Gretchen , Pi-Estopiñán Franciscary , Cruz-Sui Otto , Fraga-Quintero Anitza , García-Montero Majela , Palenzuela-Diaz Ariel , Baro-Roman Gerardo , Mendosa-Hernández Ivis , Fernandez-Castillo Sonsire , Climent-Ruiz Yanet , Santana-Mederos Darielys , Gonzalez Ubel Ramírez , García-Vega Yanelda , Perez-Massón Beatriz , Guang-Wu-Chen  , Boggiano-Ayo Tammy , Ojito-Magaz Eduardo , Rivera Daniel G. , Valdés-Balbín Yury , García-Rivera Dagmar , Vérez-Bencomo Vicente ,   SOBERANA Research Group
Published: November 2021

Background

SOBERANA 02 is a COVID-19 conjugate vaccine candidate based on SARS-CoV-2 recombinant RBD conjugated to tetanus toxoid. SOBERANA Plus antigen is dimeric-RBD. Here we report safety, reactogenicity and immunogenicity from phase I and IIa clinical trials using two-doses SOBERANA 02 (homologous protocol) and three-doses (homologous) or heterologous (with SOBERANA Plus) protocols.

Method

We performed an open-label, monocentric, sequential and adaptive phase I for evaluating safety, reactogenicity and exploring immunogenicity of SOBERANA 02 in two formulations (15 and 25 μg) in 40 subjects, 19–59 years old. Phase IIa was open-label including 100 volunteers 19–80 years, receiving two doses of SOBERANA 02-25 μg. In both trials, half of volunteers received a third dose of SOBERANA 02, half received a heterologous dose of SOBERANA Plus-50 μg. Primary outcomes were safety and reactogenicity. The secondary outcome was vaccine immunogenicity evaluated by anti-RBD IgG ELISA, molecular neutralization test of RBD:hACE2 interaction, live-virus neutralization test and specific T-cells response.

Results

The most frequent AE was local pain, other AEs had frequencies ≤ 5%. No serious related AEs were reported. Phase IIa confirmed the safety results in 60–80 years subjects. In phase-I SOBERANA 02-25µg elicited higher immune response than SOBERANA 02-15 µg; in consequence, the higher dose progressed to phase IIa. Phase IIa results confirmed the immunogenicity of SOBERANA 02-25 μg even in 60–80 age range. Two doses of SOBERANA02-25 μg elicited an immune response similar to that of the Cuban Convalescent Serum Panel; it was higher after both the homologous and heterologous third doses; the heterologous scheme showing a higher immunological response.

Conclusions

SOBERANA 02 was safe and immunogenic in persons aged 19–80 years, eliciting neutralizing antibodies and specific T cell response. Highest immune responses were obtained in the heterologous three doses protocol. Trial registry: https://rpcec.sld.cu/trials/RPCEC00000340 and https://rpcec.sld.cu/trials/RPCEC00000347
Comparison and aggregation of event sequences across ten cohorts to describe the consensus biomarker evolution in Alzheimer’s disease
Authors: Khatami Sepehr Golriz , Salimi Yasamin , Hofmann-Apitius Martin , Oxtoby Neil P. , Birkenbihl Colin ,   for the Alzheimer’s Disease Neuroimaging Initiative,   the Japanese Alzheimer’s Disease Neuroimaging Initiative,   the Alzheimer’s Disease Repository Without Borders Investigators
Published: November 2021

Background

Previous models of Alzheimer’s disease (AD) progression were primarily hypothetical or based on data originating from single cohort studies. However, cohort datasets are subject to specific inclusion and exclusion criteria that influence the signals observed in their collected data. Furthermore, each study measures only a subset of AD relevant variables. To gain a comprehensive understanding of AD progression, the heterogeneity and robustness of estimated progression patterns must be understood, and complementary information contained in cohort datasets be leveraged.

Methods

We compared ten event-based models that we fit to ten independent AD cohort datasets. Additionally, we designed and applied a novel rank aggregation algorithm that combines partially overlapping, individual event sequences into a meta-sequence containing the complementary information from each cohort.

Results

We observed overall consistency across the ten event-based model sequences (Kendall’s tau correlation coefficient of 0.78±0.13), despite variance in the positioning of mainly imaging variables. The changes described in the aggregated meta-sequence are broadly consistent with current understanding of AD progression, starting with cerebrospinal fluid amyloid beta, followed by memory impairment, tauopathy, FDG-PET, and ultimately brain deterioration and impairment of visual memory.

Conclusion

Overall, the event-based models demonstrated similar and robust disease cascades across independent AD cohorts. Aggregation of data-driven results can combine complementary strengths and information of patient-level datasets. Accordingly, the derived meta-sequence draws a more complete picture of AD pathology compared to models relying on single cohorts.
Should we Mitigate or Suppress the next Pandemic? Time-Horizons and Costs shape optimal Social Distancing Strategies
Authors: Nowak Sarah , de Lima Pedro Nascimento , Vardavas Raffaele
Published: November 2021

The COVID-19 pandemic has called for swift action from local governments, which have instated Nonpharmaceutical Interventions (NPIs) to curb the spread of SARS-Cov-2. The quick and decisive decision to save lives through blunt instruments has raised questions about the conditions under which decision-makers should employ mitigation or suppression strategies to tackle the COVID-19 pandemic. More broadly, there are still debates over which set of strategies should be adopted to control different pandemics, and the lessons learned for SARS-Cov-2 may not apply to a new pathogen. While curbing SARS-Cov-2 required blunt instruments, it is unclear whether a less-transmissible and less-deadly emerging pathogen would justify the same response. This paper illuminates this question using a parsimonious transmission model by formulating the social distancing lives vs. livelihoods dilemma as a boundary value problem. In this setup, society balances the costs and benefits of social distancing contingent on the costs of reducing transmission relative to the burden imposed by the disease. To the best of our knowledge, our approach is distinct in the sense that strategies emerge from the problem structure rather than being imposed a priori. We find that the relative time-horizon of the pandemic (i.e., the time it takes to develop effective vaccines and treatments) and the relative cost of social distancing influence the choice of the optimal policy. Unsurprisingly, we find that the appropriate policy response depends on these two factors. We discuss the conditions under which each policy archetype (suppression vs. mitigation) appears to be the most appropriate.
Higher Vaccination Rate Predicts Reduction in SARS-CoV-2 Transmission across the United States
Authors: Au Jacky
Published: November 2021

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) began proliferating widely throughout the world in late 2019/early 2020, creating a global pandemic and health crisis. Although vaccines became available to the public approximately one year after the onset of the pandemic, there still remains much hesitancy surrounding vaccination even two years into the pandemic. One key concern comes from reports of breakthrough infections among the vaccinated that show comparable levels of peak viral load as the unvaccinated, calling into question the ability of vaccines to slow or prevent transmission. Therefore young, healthy individuals who are at low risk of serious complications themselves have little incentive to receive a vaccine that they are not convinced will protect others around them. To address this important concern, this article analyzes COVID-19 incidence in the United States as a function of each state’s vaccination rate. Results show that states with higher percentages of fully vaccinated individuals report fewer new cases among the remaining unvaccinated population. These data add to accumulating evidence that COVID-19 vaccinations can indeed slow the spread of SARS-CoV-2, and are an important tool in society’s arsenal to put this pandemic behind us.
Viral E Protein Neutralizes BET Protein-Mediated Post-Entry Antagonism of SARS-CoV-2
Authors: Chen Irene P. , Longbotham James E. , McMahon Sarah , Suryawanshi Rahul K. , Carlson-Stevermer Jared , Gupta Meghna , Zhang Meng Yao , Soveg Frank W. , Hayashi Jennifer M. , Taha Taha Y. , Lam Victor L. , Li Yang , Yu Zanlin , Titus Erron W. , Diallo Amy , Oki Jennifer , Holden Kevin ,   QCRG Structural Biology Consortium, Krogan Nevan , Galonić Fujimori Danica , Ott Melanie
Published: November 2021

Inhibitors of Bromodomain and Extra-terminal domain (BET) proteins are possible anti-SARS-CoV-2 prophylactics as they downregulate angiotensin-converting enzyme 2 (ACE2). Here, we show that BET proteins should not be inactivated therapeutically as they are critical antiviral factors at the post-entry level. Knockouts of BRD3 or BRD4 in cells overexpressing ACE2 exacerbate SARS-CoV-2 infection; the same is observed when cells with endogenous ACE2 expression are treated with BET inhibitors during infection, and not before. Viral replication and mortality are also enhanced in BET inhibitor-treated mice overexpressing ACE2. BET inactivation suppresses interferon production induced by SARS-CoV-2, a process phenocopied by the envelope (E) protein previously identified as a possible “histone mimetic.” E protein, in an acetylated form, directly binds the second bromodomain of BRD4. Our data support a model where SARS-CoV-2 E protein evolved to antagonize interferon responses via BET protein inhibition; this neutralization should not be further enhanced with BET inhibitor treatment.
Presence of SARS-CoV-2 in food surfaces and public space surfaces in 3 districts of Lima, Peru
Authors: Alvis-Chirinos Katherine , Angulo-Bazán Yolanda , Escalante-Maldonado Oscar , Fuentes Duilio , Rodriguez Miryam Guillermina Palomino , Gonzales-Achuy Elena , Mormontoy Henry , Hinojosa Paul , Huamán-Espino Lucio , Aparco Juan Pablo
Published: November 2021

Resume

Objective

The goal of this study is to determine the presence of SARS-CoV-2 in food surfaces and public space surfaces in 3 districts of Lima, Peru.

Material and methods

Cross-sectional descriptive study, carried out in the districts of San Juan de Lurigancho, San Martin de Porres and Villa el Salvador. Surfaces that were exposed to the greatest user manipulation were selected, samples were swabbed for 4 weeks and transported to the laboratory to determine the presence of the virus.

Results

1095 inert surface samples and 960 food surface samples were evaluated for the identification of SARS-CoV-2 by the RT-PCR molecular test, whereby only one sample from an ATM (Automated Teller Machine) was positive.

Conclusions

Most of the inert and food surfaces evaluated did not show the presence of SARS-CoV-2 during the time of sample collection. Despite the negative results, the frequency of disinfection measures should be maintained and increased, especially on inert high-contact surfaces, and hygiene measures on food should be continue.
Fecal genomic DNA extraction method impacts outcome of MinION based metagenome profile of tuberculosis patients
Authors: Sahu Sukanya , Kaushik Sandeep Rai , Goswami Bidhan , Dasgupta Arunabha , Guha Hritusree , Das Ranjit , Saha Sourav , Das Anjan , Nanda Ranjan Kumar
Published: November 2021

In the present era, emergence of next generation sequencing approaches has revolutionized the field of gut microbiome study. However, the adopted DNA extraction step used in metagenomics experiments and its efficiency may play a critical role in their reproducibility and outcome. In this study, fecal samples from active and non-tuberculosis subjects (ATB/NTB, n=7) were used. Fecal samples of a subgroup of these subjects were subjected to Mechanical enzymatic lysis (MEL) and Phenol: Chloroform: Isoamyl Alcohol (PCIA) methods of DNA extraction and a third-generation sequencing platform i.e. MinION was employed for microbiome profiling. Findings of this study demonstrated that DNA extraction method significantly impacts the DNA yield and microbial diversity. Irrespective of the adopted method of DNA extraction, ATB patients showed altered microbial diversity compared to NTB controls. Also, the fecal microbial diversity details are better captured in samples processed by MEL method and may be suitable to be adopted for high-throughput gut microbiome studies.
Positive end expiratory pressure in invasive and non-invasive ventilation of COVID-19 acute respiratory distress syndrome: computational modeling illuminates the data
Authors: Weaver Liam , Bates Declan G. , Camporota Luigi
Published: November 2021

Positive end expiratory pressure (PEEP) is routinely used as part of lung protective ventilation strategies in the treatment of acute respiratory distress syndrome (ARDS). In the case of ARDS arising due to COVID-19 (CARDS), there is some debate as to whether the atypical pathophysiological characteristics of the disease which lead to hypoxaemia could warrant a modified approach to ventilator management, particularly with regards to PEEP settings. Here we review the available evidence for the existence of a unique underlying lung pathophysiology in CARDS, and for the suitability of standard approaches to setting PEEP, in both the invasive and non-invasive ventilation settings. We show how detailed computational models informed by this evidence can shed light on the available data, and help to interpret recent results in the literature.
Mental and social wellbeing and the UK Coronavirus Job Retention Scheme: evidence from nine longitudinal studies
Authors: Wels Jacques , Booth Charlotte , Wielgoszewska Bożena , Green Michael , Di Gessa Giorgio , Huggins Charlotte F. , Griffith Gareth J. , Kwong Alex S. F. , Bowyer Ruth C. E. , Maddock Jane , Patalay Praveetha , Silverwood Richard J. , Fitzsimons Emla , Shaw Richard , Thompson Ellen J. , Steptoe Andrew , Hughes Alun , Chaturvedi Nishi , Steves Claire J. , Katikireddi Srinivasa Vittal , Ploubidis George B.
Published: November 2021

Background

The COVID-19 pandemic has led to major economic disruptions. In March 2020, the UK implemented the Coronavirus Job Retention Scheme – known as furlough – to minimize the impact of job losses. We investigate associations between change in employment status and mental and social wellbeing during the early stages of the pandemic.

Methods

Data were from 25,670 respondents, aged 17 to 66, across nine UK longitudinal studies. Furlough and other employment changes were defined using employment status pre-pandemic and during the first lockdown (April-June 2020). Mental and social wellbeing outcomes included psychological distress, life satisfaction, self-rated health, social contact, and loneliness. Study-specific modified Poisson regression estimates, adjusting for socio-demographic characteristics and pre-pandemic mental and social wellbeing measures, were pooled using meta-analysis.

Results

Compared to those who remained working, furloughed workers were at greater risk of psychological distress (adjusted risk ratio, ARR=1.12; 95% CI: 0.97, 1.29), low life satisfaction (ARR=1.14; 95% CI: 1.07, 1.22), loneliness (ARR=1.12; 95% CI: 1.01, 1.23), and poor self-rated health (ARR=1.26; 95% CI: 1.05, 1.50), but excess risk was less pronounced than that of those no longer employed (e.g., ARR for psychological distress=1.39; 95% CI: 1.21, 1.59) or in stable unemployment (ARR=1.33; 95% CI: 1.09, 1.62).

Conclusions

During the early stages of the pandemic, those furloughed had increased risk for poor mental and social wellbeing. However, their excess risk was lower in magnitude than that of those who became or remained unemployed, suggesting that furlough may have partly mitigated poorer outcomes.
Inhaled Prostacyclin Improves Oxygenation in Patients with COVID-19-induced Acute Respiratory Distress Syndrome
Authors: Haeberle Helene A. , Calov Stefanie , Martus Peter , Higuita Lina Maria Serna , Koeppen Michael , Goll Almuth , Zarbock Alexander , Meersch Melanie , Weiss Raphael , Mehrländer Martin , Marx Gernot , Putensen Christian , Nieswandt Bernhard , Mirakaj Valbona , Rosenberger Peter
Published: November 2021

Background

Acute Respiratory Distress Syndrome (ARDS) results in significant hypoxia, and ARDS is the central pathology of COVID-19. Inhaled prostacyclin has been proposed as a therapy for ARDS, but data regarding its role in this syndrome are unavailable. Therefore, we investigated whether inhaled prostacyclin would affect the oxygenation and survival of patients suffering from ARDS.

Methods

We performed a prospective randomized controlled single-blind multicenter trial across Germany. The trial was conducted from March 2019 with final follow-up on 12th of August 2021. Patients with moderate to severe ARDS were included and randomized to receive either inhaled prostacyclin (3 times/day for 5 days) or sodium chloride. The primary outcome was the oxygenation index in the intervention and control groups on Day 5 of therapy. Secondary outcomes were mortality, secondary organ failure, disease severity and adverse events.

Findings

Of 707 patients approached 150 patients were randomized to receive inhaled prostacyclin (n=73) or sodium chloride (n=77). Data from 144 patients were analyzed. The baseline oxygenation index did not differ between groups. The primary analysis of the study was negative, and prostacyclin improved oxygenation by 20 mmHg more than NaCl (p=0·17). Oxygenation was significantly improved in patients with ARDS who were COVID-19-positive (34 mmHg, p=0·04). Mortality did not differ between groups. Secondary organ failure and adverse events were similar in the intervention and control groups.

Interpretation

Although the primary result of our study was negative, our data suggest that inhaled prostacyclin might be a more beneficial treatment than standard care for patients with ARDS.
Dengue Fever Distribution, Climate and Visitors: A Study from Badung District of Bali, Indonesia
Authors: Maulana Mochamad Rizal , Yudhastuti Ririh , Lusno Muhammad Farid Dimjati , Mirasa Yudied Agung , Haksama Setya , Husnina Zida
Published: November 2021

As a national and international tourism destination, Badung district has recorded the highest dengue fever (DF) in Bali Province with multiple suspected influencing factors. This research presents the distribution of dengue fever (DF) incidence in Badung district and analyses its association with climate and visitors. The monthly data of DF surveillance, climate and reported number of visitors during January 2013 – December 2017 was analysed using Poisson Regression. 10689 new DF cases were notified from January 2013 to December 2017 while 2016 was recorded as the heaviest DF incidence. Monthly DF cases have positive association with average temperature, precipitation, humidity and local visitors. While negative association was shown between DF cases with foreign visitors. This study underlines the urgency to integrate climate and tourism for dengue fever control. Further study is recommended to take both factors together with population mobility at finer spatial and time unit of analysis.
Seasonal variation in blood pressure recorded in routine primary care
Authors: Shahsanai Armindokht , Kalia Sumeet , Aliarzadeh Babak , Moineddin Rahim , Bhatt Aashka , Greiver Michelle
Published: November 2021

Objective

Seasonal variations in blood pressure (BP) exist. There is limited information about important clinical factors associated with increased BP and the strength and amplitude of seasonal variation in primary care.

Methods

This was a repeated cross-sectional observational study of routinely measured BPs in primary care using data from electronic medical records in the greater Toronto region, from January 2009 to June 2019. We used time-series models and mean monthly systolic BPs (SBPs) and diastolic BPs (DBPs) to estimate the strength and amplitude of seasonal oscillations, as well as their associations with patient characteristics.

Results

314,518 patients were included. Mean SBPs and DBPs were higher in winter than summer. There was strong or perfect seasonality for all characteristics studied, except for BMI less than 18.5 (underweight). Overall, the mean maximal amplitude of the oscillation was 1.51mmHg for SPB (95% CI 1.30mmHg to 1.72mmHg) and 0.59mmHg for DBP (95% CI 0.44mmHg to 0.74mmHg). Patients aged 81 years or older had larger SBP oscillations than younger patients aged 18 to 30 years; the difference was 1.20mmHg (95% CI 1.15mmHg to 1.66mmHg). Hypertension was also associated with greater oscillations, difference 0.53mmHg (95% CI 0.18mmHg to 0.88mmHg). There were no significant differences in SBP oscillations by other patient characteristics, and none for DBP.

Conclusion

Strong seasonality was detected for almost all patient subgroups studied and was greatest for older patients and for those with hypertension. The variation in BP between summer and winter should be considered by clinicians when making BP treatment decisions.
The hospital burden of intergenerational contact with the welfare system:A whole-of-population liked data study
Authors: Procter Alexandra M , Chittleborough Catherine R , Pilkington Rhiannon M , Pearson Odette , Montgomerie Alicia , Lynch John W
Published: November 2021

Background

Intergenerational welfare contact (IWC) is a policy issue because of the personal and social costs of intergenerational disadvantage. We estimated the hospital burden of IWC for children aged 11-20 years.

Methods

This linked data study of children born in South Australia, 1991-1995 (n=94,358), and their parent/s (n=143,814) used de-identified data from the Better Evidence Better Outcomes Linked Data platform. Using Australian Government Centrelink data, welfare contact (WC) was defined as parent/s receiving a means-tested welfare payment (low-income, unemployment, disability or caring) when children were aged 11-15, or children receiving payment at ages 16-20. IWC was WC occurring in both parent and child generations. Children were classified as: No WC, parent only WC, child only WC, or IWC. Hospitalisation rates and cumulative incidence were estimated by age and WC group.

Findings

IWC affected 34.9% of children, who had the highest hospitalisation rate (133.5 per 1,000 person-years) compared to no WC (46.1 per 1,000 person-years), parent only WC (75.0 per 1,000 person-years), and child only WC (87.6 per 1,000 person-years). Of all IWC children, 43.0% experienced at least one hospitalisation between 11-20, frequently related to injury, mental health, and pregnancy.

Interpretation

Children experiencing IWC represent a third of the population aged 11-20. Compared to children with parent-only WC, IWC children had 78% higher hospitalisation rates from age 11 to 20, accounting for over half of all hospitalisations in this age group. Frequent IWC hospitalisation causes were injuries, mental health, and pregnancy.

Funding

Medical Research Future Fund, National Health and Medical Research Council, Westpac Scholars Trust.
Cortex-independent open-loop control of a voluntary orofacial motor action
Authors: Elbaz Michaël , Demers Maxime , Kleinfeld David , Ethier Christian , Deschênes Martin
Published: November 2021

Whether using our eyes or our hands, we interact with our environment through mobile sensors. The efficient use of these sensory organs implies the ability to track their position; otherwise, perceptual stability and prehension would be profoundly impeded1,2. The nervous system may be informed about the position of a sensory organ via two complementary feedback mechanisms: peripheral reafference (external, sensory feedback) and efference copy (internal feedback)3-6. Yet, the potential contributions of these mechanisms remain largely unexplored. By training rats to place their vibrissae within a predetermined angular range without contact, a task that depends on knowledge of vibrissa position relative to their face, we found that peripheral reafference is not required. The presence of motor cortex is not required either, even in the absence of peripheral reafference. On the other hand, the red nucleus, which receives descending inputs from motor cortex and the cerebellum and projects to facial motoneurons7-10, is critical for the execution of the vibrissa task. All told, our results demonstrate the existence of an open-loop control by an internal model that is sufficient to drive voluntary motion. The internal model is independent of motor cortex and likely contains the cerebellum and associated nuclei.
An atypical NLR protein modulates the NRC immune receptor network
Authors: Adachi Hiroaki , Sakai Toshiyuki , Harant Adeline , Duggan Cian , Bozkurt Tolga O , Wu Chih-hang , Kamoun Sophien
Published: November 2021

The NRC immune receptor network has evolved in asterid plants from a pair of linked genes into a genetically dispersed and phylogenetically structured network of sensor and helper NLR (nucleotide-binding domain and leucine-rich repeat-containing) proteins. In some species, such as the model plant Nicotiana benthamiana and other Solanaceae, the NRC network forms up to half of the NLRome, and NRCs are scattered throughout the genome in gene clusters of varying complexities. Here, we describe NRCX, an atypical, but essential member of the NRC family that lacks canonical features of these NLR helper proteins, such as a functional N-terminal MADA motif and the capacity to trigger autoimmunity. In contrast to other NRCs, systemic gene silencing of NRCX markedly impairs plant growth resulting in a dwarf phenotype. Remarkably, dwarfism of NRCX silenced plants is partially dependent on NRCX paralogs NRC2 and NRC3, but not NRC4. Despite its negative impact on plant growth when silenced systemically, transient RNA interference of NRCX in mature N. benthamiana leaves doesn’t result in visible cell death phenotypes. However, alteration of NRCX expression modulates the hypersensitive response mediated by NRC2 and NRC3 in a manner consistent with a negative role for NRCX in the NRC network. We conclude that NRCX is an atypical member of the NRC network that has evolved to contribute to the homeostasis of this genetically unlinked NLR network.
The effect of sequencing and assembly on the inference of horizontal gene transfer on chromosomal and plasmid phylogenies
Authors: Huisman Jana S. , Vaughan Timothy G. , Egli Adrian , Tschudin-Sutter Sarah , Stadler Tanja , Bonhoeffer Sebastian
Published: November 2021

The spread of antibiotic resistance genes on plasmids is a threat to human and animal health. Phylogenies of bacteria and their plasmids contain clues regarding the frequency of plasmid transfer events, as well as the co-evolution of plasmids and their hosts. However, whole genome sequencing data from diverse ecological or clinical bacterial samples is rarely used to study plasmid phylogenies and resistance gene transfer. This is partially due to the difficulty to extract plasmids from short-read sequencing data. Here, we use both short- and long-read sequencing data of 24 clinical extended-spectrum β-lactamase producing Escherichia coli to estimate chromosomal and plasmid phylogenies. We compare the impact of different sequencing and assembly methodologies on these phylogenies and on the inference of horizontal gene transfer. We find chromosomal phylogenies can be estimated robustly with all methods, whereas plasmid phylogenies have more variable topology and branch lengths across the methods used. Specifically, hybrid methods that use long reads to resolve short-read assemblies (HybridSPAdes and Unicycler) perform better than those that started from long-reads during assembly graph generation (Canu). In contrast, the inference of plasmid and antibiotic resistance gene transfer using a parsimony-based criterion is mostly robust to the choice of sequencing and assembly method.
The assessment of similarity vectors of fingerprint and UMLS in adverse drug reaction prediction
Authors: Beshartifard Milad , Ghorbanali Zahra , Zare-Mirakabad Fatemeh
Published: November 2021

Identifying and controlling adverse drug reactions is a complex problem in the pharmacological field. Despite the studies done in different laboratory stages, some adverse drug reactions are recognized after being released, such as Rosiglitazone. Due to such experiences, pharmacists are now more interested in using computational methods to predict adverse drug reactions. In computational methods, finding and representing appropriate drug and adverse reaction features are one of the most critical challenges. Here, we assess fingerprint and target as drug features; and phenotype and unified medical language system as adverse reaction features to predict adverse drug reaction. Meanwhile, we show that drug and adverse reaction features represented by similarity vectors can improve adverse drug prediction. In this regard, we propose four frameworks. Two frameworks are based on random forest classification and neural networks as machine learning methods called F_RF and F_NN, respectively. The rest of them improve two state-of-art matrix factorization models, CS and TMF, by considering target as a drug feature and phenotype as an adverse reaction feature. However, machine learning frameworks with fewer drug and adverse reaction features are more accurate than matrix factorization frameworks. In addition, the F_RF framework performs significantly better than F_NN with ACC = %89.15, AUC = %96.14 and AUPRC = %92.9. Next, we contrast F_RF with some well-known models designed based on similarity vectors of drug and adverse reaction features. Unlike other methods, we do not remove rare reactions from the data set in our frameworks. The data and implementation of proposed frameworks are available at http://bioinformatics.aut.ac.ir/ADRP-ML-NMF/.
Neural decoding dissociates perceptual grouping between proximity and similarity in visual perception
Authors: Hua Lin , Gao Fei , Leong Chantat , Yuan Zhen
Published: November 2021

Previous research on perceptual grouping primarily focused on the dynamics of single grouping principle in light of the Gestalt psychology. Yet, there has been comparatively little emphasis on the dissociation across two or more grouping principles. To tackle this issue, the current study aims at investigating how, when, and where the processing of two grouping principles (proximity and similarity) are established in the human brain by using a dimotif lattice paradigm and adjusting the strength of one grouping principle. Specifically, we measured the modulated strength of the other grouping principle, thus forming six visual stimuli. The current psychophysical results showed that similarity grouping effect was enhanced with reduced proximity effect when the grouping cues of proximity and similarity were presented simultaneously. Meanwhile, electrophysiological (EEG) response patterns were able to decode the specific pattern out of the six visual stimuli involving both principles in each trail by using time-resolved multivariate pattern analysis (MVPA). The onsets of the dissociation between the two grouping principles coincided within three time windows: the earliest proximity-defined local visual element arrangement in the middle occipital cortex, the middle-stage processing for feature selection modulating low-level visual cortex in the inferior occipital cortex and fusiform cortex, and the higher-level cognitive integration to make decisions for specific grouping preference in the parietal areas. In addition, brain responses were highly correlated with behavioral grouping. The results therefore provide direct evidence for a link between human perceptual space of grouping decision-making and neural space of these brain response patterns.

Significance statement

How does our brain aggregate meaningless local elements to meaningful global patterns? Here, we used visual stimuli that can be perceived as a whole orientation from one of the two grouping cues (proximity and similarity) when they were presented simultaneously. Behavioral responses showed a trade-off between proximity and similarity. Further, time-resolved MVPA and source estimation results showed three stages for the processing of two grouping cues, involving an early stage in the low-level visual cortex, then the middle stage in the lateral visual cortex, and finally the late stage in the parietal areas. This was among the first attempt employing multivariate analysis to decode the dissociative processing of both proximity and similarity principles within one single study.
Ly6Chi monocytes are metabolically reprogrammed in the blood during inflammatory stimulation allowing for macrophage lineage commitment
Authors: Purvis Gareth S.D. , McNeill Eileen , Wright Benjamin , Revale Santiago , Lockstone Helen , Channon Keith M. , Greaves David R.
Published: November 2021

Acute inflammation is a rapid and dynamic process involving the recruitment and activation of multiple cell types in a co-ordinated and precise manner. Using cell tracking, linage tracing and single cell transcriptomics we investigated the origin and transcriptional reprogramming of monocytes and macrophages in acute inflammation.

Monocyte trafficking and adoptive transfer experiments revealed that monocytes undergo rapid phenotypic change as they exit the blood and give rise to monocyte-derived macrophages that persist during the resolution of inflammation. Single cell transcriptomics revealed significant heterogeneity within the surface marker defined CD11b+Ly6G-Ly6Chi monocyte population within the blood and at the site of inflammation. Lineage trajectory analysis revealed that Ly6Chi monocytes in the blood are re-programmed into a defined differentiation pathway following inflammatory stimulus. We show that two major transcriptional reprogramming events occur during the initial 6 h of Ly6Chi monocyte mobilisation, one in the blood priming monocytes for migration and a second at the site of inflammation. Pathway analysis revealed an important role for oxidative phosphorylation (OxPhos) during both these reprogramming events in a subset of M2-like cells. Experimentally we also demonstrate that OxPhos is essential for murine and human monocyte chemotaxis. These new findings opening up the possibility that altering monocyte metabolic capacity towards OxPhos could facilitate enhanced macrophage M2-like polarisation to aid inflammation resolution and tissue repair.