bluuebunny/crossref_metadata_2025 huggingface dataset:
Changes in practice patterns of nephrolithiasis in the era of the coronavirus disease 2019 pandemic: a review
Authors: Hout Mohammad , Marcovich Robert , Shah Hemendra
Published: December 2021

Purpose of review

The coronavirus disease 2019 (COVID-19) pandemic led to a drastic change in healthcare priorities, availability of resources and accommodation of different needs and scenarios. We sought to review the effect of the pandemic on different aspects of nephrolithiasis.

Recent findings

The pandemic resulted in a significant impact on management of patients with nephrolithiasis around the world. A significant decrease in patient presentation and differences in strategies of management to truncate exposure and surgery time and expedite patient discharge deferring definitive management has been noted. Moreover, new safety measures such as COVID-19 PCR testing prior to surgery and limiting any intervention for COVID-19 positive patients to only life-saving scenarios has been implemented. Different emergency triaging proposals are being used, mainly including high risk patients with septic shock or complete obstruction/renal injury. Moreover, the emergence of telehealth has changed outpatient practice dramatically with a significant adoption to minimize exposure. Lastly, the effect of COVID-19 on renal physiology has been described with significant potential to cause morbidity from immediate or delayed acute kidney. No physiological effect on stone formation has yet been described, and transmission through urine is rare.

The COVID-19 pandemic has markedly shifted the treatment of nephrolithiasis in many ways, including emergency triage, outpatient care, and definitive management. Although various approaches and algorithms proposed are meant to optimize management in the time of the pandemic, further studies are required for validation.
Well-developed Cerebellum in an Ovarian Mature Teratoma From a Pregnant Female
Authors: Sauer Madeline A. , Coy Shannon , Quade Bradley J. , Nucci Marisa R.
Published: December 2021

Teratomas are the most common neoplasm of the ovary, comprising over half of all diagnosed tumors in patients under 50. Most lesions are classified as benign mature teratomas and are histologically defined by the presence of mature tissues from one or more of the embryological germ layers: ectoderm, mesoderm, and endoderm. Neuroectodermal derivatives, including glia, neurons, ependymal cells, and meninges are present in a third to half of mature teratomas. Although teratomatous tissue elements are typically arranged in a haphazard fashion, well-developed and organized embryonic organ structures have been rarely reported and often with limited histologic, clinical, or gross characterization. In this report, we describe the case of an ovarian mature cystic teratoma identified in a pregnant female which exhibited remarkably well-developed posterior fossa structures including lobated and foliated cerebellum with appropriate anatomic organization and associated brainstem, ventricular, and meningeal structures.
Virtual Objective Structured Clinical Examination Experiences and Performance in Physical Medicine and Rehabilitation Residency
Authors: Kelly Ryan , Leung Gentson , Lindstrom Heather , Wunder Shane , Yu Jaime C.
Published: December 2021

Background

Virtual education has been described before and during the COVID-19 pandemic. Studies evaluating virtual objective structured clinical examinations with postgraduate learners are lacking. This study (1) evaluated the experiences of all participants in a virtual objective structured clinical examination and (2) assessed the validity and reliability of selected virtual objective structured clinical examination stations for skills in physical medicine and rehabilitation.

Methods

Convergent mixed-methods design was used. Participants included three physical medicine and rehabilitation residency programs holding a joint virtual objective structured clinical examination. Analysis included descriptive statistics and thematic analysis. Performance of virtual to previous in-person objective structured clinical examination was compared using independent t tests.

Results

Survey response rate was 85%. No participants had previous experience with virtual objective structured clinical examination. Participants found the virtual objective structured clinical examination to be acceptable (79.4%), believable (84.4%), and valuable for learning (93.9%). No significant differences between in-person and virtual objective structured clinical examination scores was found for three-fourth stations and improved scores in one fourth. Four themes were identified: (1) virtual objective structured clinical examinations are better for communication stations; (2) significant organization is required to run a virtual objective structured clinical examination; (3) adaptations are required compared with in-person objective structured clinical examinations; and (4) virtual objective structured clinical examinations provide improved accessibility and useful practice for virtual clinical encounters.

Conclusions

Utility of virtual objective structured clinical examinations as a component of a program of assessment should be carefully considered and may provide valuable learning opportunities going forward.
Biomarkers in the Degenerative Human Intervertebral Disc Tissue and Blood
Authors: Zhang Yejia , Yao Lutian , Robinson Keith M. , Dillingham Timothy R.
Published: December 2021

Patients with back pain comprise a large proportion of the outpatient practice among physiatrists. Diagnostic tools are limited to clinical history, physical examinations, and imaging. Nonsurgical treatments are largely empirical, encompassing medications, physical therapy, manual treatments, and interventional spinal procedures. A body of literature is emerging confirming elevated levels of biomarkers including inflammatory cytokines in patients with back pain and/or radiculopathy, largely because the protein assay sensitivity has increased. These biomarkers may serve as tools to assist diagnosis and assess outcomes.

The presence of inflammatory mediators in the intervertebral disc tissues and blood helped to confirm the inflammatory underpinnings of back pain related to intervertebral disc degeneration. Literature reviewed here suggests that biomarkers could assist clinical diagnosis and monitor physiological outcomes during and after treatments for spine-related pain. Biomarkers must be measured in a large and diverse asymptomatic population, in the context of age and comorbidities to prevent false-positive tests. These levels can then be rationally compared with those in patients with back disorders including discogenic back pain, radiculopathy, and spinal stenosis. While studies reviewed here used “candidate marker” approaches, future nonbiased approaches in clearly defined patient populations could uncover novel biomarkers in clinical management of patients.
Ability Realization Improves During Inpatient Rehabilitation for Guillain-Barré Syndrome
Authors: Shniper Miriam , Elkayam Keren , Bluvshtein Vadim , Gelernter Ilana , Rozenblum Rotem , Catz Amiram , Eidinoff Elena
Published: December 2021

Objective

The aim of the study was to investigate improvement in ability realization and additional long-term outcomes, during and after inpatient rehabilitation for Guillain-Barré syndrome.

Design

This is a retrospective, longitudinal cohort study, in which outcomes were examined using validated scales, for 47 inpatients with Guillain-Barré syndrome.

Results

Scores improved from 65 on the American Spinal Injury Association Motor Score and 50 on the Spinal Cord Independence Measure, at admission to inpatient rehabilitation, to 81 and 80 at discharge, and to 92 and 95 at the end of 7.5 yrs, on average, at the follow-up (P = 0.001). The mean Spinal Cord Independence Measure/American Spinal Injury Association Motor Score ratio, which reflects the ability realization, increased during rehabilitation from 50/65 to 80/81 (P = 0.001), and tended to increase further at follow-up to 95/92 (P = 0.228). At follow-up, pain did not correlate, and fatigue showed a weak correlation with the American Spinal Injury Association Motor Score, Spinal Cord Independence Measure, and the Adult Subjective Assessment of Participation (r = −0.363, P = 0.012; r = −0.362, P = 0.012; r = −0.392, P = 0.006).

Conclusions

Ability realization improved during inpatient rehabilitation for Guillain-Barré syndrome and remained high after discharge, suggesting a likely contribution of rehabilitation to the functional outcome, beyond the contribution of neurological recovery. Despite residual fatigue and pain, there was only minor or no effect on daily function or participation.
How to use new antibiotics in the therapy of ventilator-associated pneumonia
Authors: Miwa Toshiki , Lizza Bryan , Burnham Jason , Honda Hitoshi , Kollef Marin
Published: December 2021

Purpose of review

Ventilator-associated pneumonia (VAP) is a common nosocomial infection in critically ill patients requiring endotracheal intubation and mechanical ventilation. Recently, the emergence of multidrug-resistant Gram-negative bacteria, including carbapenem-resistant Enterobacterales, multidrug-resistant Pseudomonas aeruginosa and Acinetobacter species, has complicated the selection of appropriate antimicrobials and contributed to treatment failure. Although novel antimicrobials are crucial to treating VAP caused by these multidrug-resistant organisms, knowledge of how to optimize their efficacy while minimizing the development of resistance should be a requirement for their use.

Recent findings

Several studies have assessed the efficacy of novel antimicrobials against multidrug-resistant organisms, but high-quality studies focusing on optimal dosing, infusion time and duration of therapy in patients with VAP are still lacking. Antimicrobial and diagnostic stewardship should be combined to optimize the use of these novel agents.

Improvements in diagnostic tests, stewardship practices and a better understanding of dosing, infusion time, duration of treatment and the effects of combining various antimicrobials should help optimize the use of novel antimicrobials for VAP and maximize clinical outcomes while minimizing the development of resistance.
Geriatric assessment-informed treatment decision making and downstream outcomes: what are the research priorities?
Authors: Hsu Tina , Leung Bonnie , Mariano Caroline
Published: December 2021

Purpose of review

Geriatric assessment (GA) can predict outcomes relevant to patients and clinicians but is not widely used. The objective of this review is to summarize the evidence supporting use of GA to facilitate decision making and improve outcomes and identify gaps that need to be addressed to further bolster the rationale for the use of GA.

Recent findings

Recently several randomized controlled studies exploring the impact of GA-directed care have been reported. Although GA-directed care has not been shown to improve survival, it can decrease moderate to severe toxicity from chemotherapy, increase the likelihood of completing planned chemotherapy and improve quality of life without adversely affecting survival. In the surgical setting, GA-directed care may decrease duration of hospitalization, but does not affect rates of re-hospitalization.

GA-directed care can improve patient-important outcomes compared to usual care. However, more research on whether these findings apply to other contexts and whether GA-directed care can improve other outcomes important to patients, such as function and cognition, is needed. Also more clarity about how oncologic treatments should be modified based on results of a GA are needed if oncologists are to utilize this information effectively to obtain the reported results.
Correlation Between Microvascular Inflammation in Endomyocardial Biopsies and Rejection Transcripts, Donor-specific Antibodies, and Graft Dysfunction in Antibody-mediated Rejection
Authors: Coutance Guillaume , Zouhry Ilyass , Racapé Maud , Drieux Fanny , Viailly Pierre-Julien , Rouvier Philippe , François Arnaud , Chenard Marie-Pierre , Toquet Claire , Rabant Marion , Berry Gerald J. , Angelini Annalisa , Bruneval Patrick , Duong Van Huyen Jean-Paul
Published: December 2021

Background.

The pathology-based diagnosis of cardiac antibody-mediated rejection (AMR) relies on the 2013 International Society for Heart and Lung Transplantation Working Formulation, in which microvascular inflammation (MVI) is considered as present or absent regardless of its extent. This work assessed the biological and clinical value of a semiquantitative evaluation of the extent of MVI in endomyocardial biopsies (EMBs).

Methods.

We retrospectively graded the extent of MVI in 291 EMB from 291 patients according to a 4-point scale in which MVI scores of 0, 1, 2, and 3 represented 0%, 1%–10%, 11%–50%, and >50% of the myocardial area, respectively. We analyzed the association between the MVI score and tissue rejection molecular activity assessed by microarrays or reverse transcriptase multiplex ligation-dependent probe amplification, current pathology classification (pathologic AMR [pAMR]), anti-HLA donor-specific antibodies, and graft dysfunction.

Results.

Overall, 172 (59.1%), 33 (11.4%), 42 (14.4%), and 44 (15.1%) EMB were given MVI scores of 0, 1, 2, and 3, respectively. pAMR1(H+) and pAMR2/3 categories were found to be heterogeneous in terms of MVI score. Acute cellular rejection grades did not influence the MVI score. In both molecular approaches, we observed a stepwise increase in the expression of AMR-related transcripts with increasing MVI scores, independent of the C4d or CD68 status (P < 0.001). Both the frequency and mean fluorescence intensity of donor-specific antibodies gradually increased with the MVI score (P < 0.001). Acute graft dysfunction was more frequent in MVI score 3 (P < 0.001).

Conclusions.

The intensity of MVI in EMB, based on a semiquantitative evaluation of its extent, has biological and clinical importance.
DAMPs Released From Injured Renal Tubular Epithelial Cells Activate Innate Immune Signals in Healthy Renal Tubular Epithelial Cells
Authors: DeWolf Sean E. , Kasimsetty Sashi G. , Hawkes Alana A. , Stocks Lisa M. , Kurian Sunil M. , McKay Dianne B.
Published: December 2021

Background.

Renal ischemia-reperfusion injury (IRI) predictably causes acute kidney injury after shock and major cardiovascular procedures in all kidneys procured for transplantation. The earliest events of IRI are triggered by molecules released from injured cells, damage-associated molecular patterns (DAMPs), that bind pattern recognition receptors (PRRs) constitutively expressed on many cells within the kidney. Activation of PRR signaling leads to production of proinflammatory molecules, which incite a cascade of inflammatory events leading to acute kidney injury. Renal tubular epithelial cells (RTECs) are particularly susceptible to ischemic injury, and proximal RTEC injury is pathognomonic of renal IRI. To better understand how injured RTECs contribute to the cycle of deleterious inflammation in the setting of renal IRI, this study asked whether DAMPs released from injured RTECs induced PRR signals in healthy RTECs.

Methods.

Human RTECs were necrosed ex vivo to release intracellular DAMPs and resulting necrotic supernatant used to stimulate healthy RTECs, T lymphocytes, and monocytes.

Results.

DAMPs released from necrosed RTECs upregulated PRRs known to be associated with renal IRI and activated mitogen-activated protein kinase signaling pathways. Proinflammatory cytokines were upregulated in response to necrotic supernatant, and this upregulation was abrogated by MEK-1 inhibition. The RTEC-derived DAMPs were also potent inducers of T-cell activation/proliferation and monocyte migration.

Conclusions.

This is the first study to our knowledge to show that endogenous DAMPs released from injured RTECs directly activate PRR signaling in healthy RTECs. These findings provide new insights directed to therapeutics for renal IRI.
The mental health of children and young people living in big cities in a revolving postpandemic world
Authors: Marchionatti Laura Estivalete , Caye Arthur , Kieling Christian
Published: December 2021

Purpose of review

The world's population is increasingly urban, with most children and young people growing up and living in cities. Evidence suggests that urbanicity is linked to an increased risk for the development of mental health disorders. Rather than an accumulation of risk factors, urbanization is a complex process that profoundly structures living conditions. In this sense, it is timely to discuss what are the social and structural determinants of mental health of children and young people in such settings.

Recent findings

Three domains of determinants of mental health were selected for discussion: economics and living conditions, crime and violence, and urban layouts. For each, we debated realities faced by urban children and young people, providing an overview of recent evidence on implications for mental disorders and well being. We also discuss the potential impacts of the covid-19 pandemic on each domain, as well as recommendations for future action.

Structural factors are of major relevance for the mental health of children and young people living in cities. The agenda of mental health promotion and prevention must include whole-of-society interventions aimed at improving living conditions, including economic and social capital, violence prevention and urbanistic planning.
Air pollution and mental health: associations, mechanisms and methods
Authors: King Jacob D. , Zhang Shuo , Cohen Alex
Published: December 2021

Purpose of review

There is increasing interest in the links between exposure to air pollution and a range of health outcomes. The association with mental health however is much less established. This article reviews developments in the field over the past 12 months, highlighting the evidence for causation, associations between multiple air pollutants and mental health outcomes, and assesses the challenges of researching this topic.

Recent findings

Increasingly rigorous methods are being applied to the investigation of a broader range of mental health outcomes. These methods include basic science, neuroimaging, and observational studies representing diverse geographical locations. Cohort studies with linked high-resolution air pollutant exposure data are common, facilitating advanced analytic methods. To date, meta-analyses have demonstrated small and significant positive associations between long-term exposure to fine particulate matter and depressive symptoms and cognitive decline. Methodological complexities in measuring exposure and outcome pose ongoing difficulties for the field.

Literature on this topic has recently seen an appreciable expansion. Work that better estimates daily exposure, controls for complex confounders, and is driven by hypotheses founded in candidate causal mechanisms would help clarify associations, and inform targeted interventions and policymakers.
Neuropsychological and neuropsychiatric recovery from mild traumatic brain injury
Authors: Ritchie Kathryn A. , Slomine Beth S.
Published: December 2021

Purpose of review

Mild traumatic brain injury (mTBI) is a significant public health concern for children. This review summarizes recent literature on early symptoms and neuropsychiatric and neuropsychological outcomes following pediatric mTBI and highlights factors that predict prolonged recovery. Evidence-based recommendations for assessment and treatment are also discussed.

Recent findings

Whereas most children recover within 1 month after mTBI, 10–30% of children experience lingering neuropsychiatric or neuropsychological symptoms 3 months or more after injury. For the subset who experience prolonged recovery, new or worsening emotional and behavioral symptoms are the most frequent concerns. Recent research has suggested that specific factors, including preinjury mental health concerns, female sex, and family characteristics, are associated with increased risk of experiencing prolonged recovery. Early management includes reassurance, brief rest (1–3 days), and gradual return to typical activities. When symptoms linger for more than 4 weeks, evaluation in a specialty clinic is recommended and multimodal therapies are considered. Active recovery models, which include gradual return to aerobic exercise and cognitive behavioral approaches, are promising for the management of prolonged symptoms.

A minority of children with mTBI experience prolonged neuropsychiatric or neuropsychological concerns. While our understanding of pediatric mTBI is growing, and recommendations for assessment and management have been developed, many gaps remain.
Social health, social reserve and dementia
Authors: Sachdev Perminder S.
Published: December 2021

Purpose of review

There is increasing recognition of social health being protective against disease, including age-related cognitive decline and dementia. Many concepts around social health, reserve and connectedness are imprecise and without agreed definitions. The mechanisms by which social health is protective are not well understood.

Recent findings

Several observational studies suggest that social participation and connectedness are protective against cognitive decline whereas loneliness is a risk factor for dementia. The possible mechanisms include effects on inflammatory process and immune function, reduced vascular disease risk, improved health behaviours, lower risk of depression, and increased cognitive reserve through cognitive stimulation and physical activity. Social networks have been shown to modify the relationship between Alzheimer's disease and cognitive impairment. The relationship of social networks is, however, reciprocal, with dementia leading to social loss, which in turn worsens cognitive decline. Social reserve is conceptualized as both brain processes underlying the ability and predisposition to form meaningful social ties, and their instantiation as an environmental resource in high-quality social networks.

Consistent definitions of social health-related terms will lead to better understanding of their determinants so that tailored interventions can be developed to increase social reserve and improve social health of an individual.
Dying From COVID-19 or With COVID-19: A Definitive Answer Through a Retrospective Analysis of Mortality in Italy
Authors: Rovetta Alessandro , Bhagavathula Akshaya Srikanth
Published: December 2021

Background

COVID-19 mortality was associated with several reasons, including conspiracy theories and infodemic phenomena. However, little is known about the potential endogenous reasons for the increase in COVID-19 associated mortality in Italy.

Objective

This study aimed to search the potential endogenous reasons for the increase in COVID-19 mortality recorded in Italy during the year 2020 and evaluate the statistical significance of the latter.

Methods

We analyzed all the trends in the timelapse 2011-2019 related to deaths by age, sex, region, and cause of death in Italy and compared them with those of 2020. Ordinary least squares (OLS) linear regressions and ARIMA (p, d, q) models were applied to investigate the predictions of death in 2020 as compared to death reported in the same year. Grubbs and Iglewicz-Hoaglin tests were used to identify the statistical differences between the predicted and observed deaths. The relationship between mortality and predictive variables was assessed using OLS multiple regression models.

Results

Both ARIMA and OLS linear regression models predicted the number of deaths in Italy during 2020 to be between 640,000 and 660,000 (95% confidence intervals range: 620,000 – 695,000) and these values were far from the observed deaths reported (above 750,000). Significant difference in deaths at national level (P = 0.003), and higher male mortality than women (+18% versus +14%, P < 0.001 versus P = 0.01) was observed. Finally, higher mortality was strongly and positively correlated with latitude (R = 0.82, P < 0.001).

Conclusions

Our findings support the absence of historical endogenous reasons capable of justifying the increase in deaths and mortality observed in Italy in 2020. Together with the current knowledge on the novel coronavirus 2019, these findings provide decisive evidence on the devastating impact of COVID-19 in Italy. We suggest that this research be leveraged by government, health, and information authorities to furnish proof against conspiracy hypotheses. Moreover, given the marked concordance between the predictions of the ARIMA and OLS regression models, we suggest that these models be exploited to predict mortality trends.
IL4I1 binds to TMPRSS13 and competes with SARS-Cov2 Spike
Authors: Gatineau Jérôme , Nidercorne Charlotte , Dupont Aurélie , Puiffe Marie-Line , Cohen José L , Molinier-Frenkel Valérie , Niedergang Florence , Castellano Flavia
Published: December 2021

The secreted enzyme interleukin four-induced gene 1 (IL4I1) is involved in the negative control of the adaptive immune response. IL4I1 expression in human cancer is frequent and correlates with poor survival and resistance to immunotherapy. Nevertheless, its mechanism of action remains partially unknown. Here, we identified transmembrane serine protease 13 (TMPRSS13) as an immune cell-expressed surface protein that binds IL4I1. TMPRSS13 is a paralog of TMPRSS2, whose protease activity participates in the cleavage of SARS-Cov2 Spike protein and facilitates virus induced-membrane fusion. We show that TMPRSS13 is expressed by human lymphocytes, monocytes and monocyte-derived macrophages, can cleave the Spike protein and allow Sars-Cov2 Spike pseudotyped virus entry into cells. We identify regions of homology between IL4I1 and Spike and demonstrate competition between the two proteins for TMPRSS13 binding. These findings may be relevant for both interfering with SARS-Cov2 infection and limiting IL4I1-dependent immunosuppressive activity in cancer.

One-Sentence Summary

Through binding to its newly identified receptor TMPRSS13, the enzyme IL4I1 interferes with SARS-Cov2 Spike cleavage thereby blocking viral entry into host cells.
Scholar Metrics Scraper (SMS): automated retrieval of citation and author data
Authors: Cheung Nicole A. , Giustini Dean , LeDue Jeffrey , Murphy Tim H.
Published: December 2021

Academic departments, research clusters and evaluators analyze author and citation data to measure research impact and to support strategic planning. We created a tool, Scholar Metrics Scraper (SMS), to automate the retrieval of this bibliometric data for our research team. The project contains Jupyter notebooks (publicly-shared here) that take a list of researchers as an input to export a CSV file of citation metrics from Google Scholar and figures to visualize the group’s impact. SMS is a scalable, open and publicly-accessible solution for automating the retrieval of citation data over time for a group of researchers.
Human KIR+CD8+ T cells target pathogenic T cells in Celiac disease and are active in autoimmune diseases and COVID-19
Authors: Li Jing , Zaslavsky Maxim , Su Yapeng , Sikora Michael J. , van Unen Vincent , Christophersen Asbjørn , Chiou Shin-Heng , Chen Liang , Li Jiefu , Ji Xuhuai , Wilhelmy Julie , McSween Alana M. , Palanski Brad A. , Aditya Mallajosyula Venkata Vamsee , Dhondalay Gopal Krishna R. , Bhamidipati Kartik , Pai Joy , Kipp Lucas B. , Dunn Jeffrey E. , Hauser Stephen L. , Oksenberg Jorge R. , Satpathy Ansuman T. , Robinson William H. , Steinmetz Lars M. , Khosla Chaitan , Utz Paul J. , Sollid Ludvig M. , Heath James R. , Fernandez-Becker Nielsen Q. , Nadeau Kari C. , Saligrama Naresha , Davis Mark M.
Published: December 2021

Previous reports show that Ly49+CD8+ T cells can suppress autoimmunity in mouse models of autoimmune diseases. Here we find a markedly increased frequency of CD8+ T cells expressing inhibitory Killer cell Immunoglobulin like Receptors (KIR), the human equivalent of the Ly49 family, in the blood and inflamed tissues of various autoimmune diseases. Moreover, KIR+CD8+ T cells can efficiently eliminate pathogenic gliadin-specific CD4+ T cells from Celiac disease (CeD) patients’ leukocytes in vitro. Furthermore, we observe elevated levels of KIR+CD8+ T cells, but not CD4+ regulatory T cells, in COVID-19 and influenza-infected patients, and this correlates with disease severity and vasculitis in COVID-19. Expanded KIR+CD8+ T cells from these different diseases display shared phenotypes and similar T cell receptor sequences. These results characterize a regulatory CD8+ T cell subset in humans, broadly active in both autoimmune and infectious diseases, which we hypothesize functions to control self-reactive or otherwise pathogenic T cells.

One-Sentence Summary

Here we identified KIR+CD8+ T cells as a regulatory CD8+ T cell subset in humans that suppresses self-reactive or otherwise pathogenic CD4+ T cells.
Reward priming differentially modulates enhancement and inhibition in auditory decision-making
Authors: Nagamura Hidekazu , Onishi Hiroshi , Hishitani Momoko , Murai Shota , Osako Yuma , Kobayasi Kohta I.
Published: December 2021

In cognitive sciences, rewards, such as money and food, play a fundamental role in individuals’ daily lives and well-being. Moreover, rewards that are irrelevant to the task alter individuals’ behavior. However, it is unclear whether explicit knowledge of reward irrelevancy has an impact on reward priming enhancements and inhibition. In this study, an auditory change-detection task with task-irrelevant rewards was introduced. The participants were informed explicitly in advance that the rewards would be given randomly. The results revealed that while inhibition related to reward priming only occurred when the participants were explicitly informed about rewards, implicit instruction thereof resulted in enhancement and inhibition associated with reward priming. These findings highlight the contribution of explicit information about rewards associated with auditory decisions.
Designing multi-epitope based peptide vaccine targeting spike protein SARS-CoV-2 B1.1.529 (Omicron) variant using computational approaches
Authors: Parmar Meet , Thumar Ritik , Sheth Jigar , Patel Dhaval
Published: December 2021

Since the SARS-CoV-2 outbreak in 2019, millions of people have been infected with the virus, and due to its high human-to-human transmission rate, there is a need for a vaccine to protect people. Although some vaccines are in use, due to the high mutation rate in the SARS-CoV-2 multiple variants, the current vaccines may not be sufficient to immunize people against new variant threats. One of the emerging variants of concern is B1.1.529 (Omicron), which carries∼30 mutations in the Spike protein of SARS-CoV-2 is predicted to evade antibodies recognition even from vaccinated people. We used a structure-based approach along with an epitope prediction server to develop a Multi-Epitope based Subunit Vaccine (MESV) involving SARS-CoV-2 B1.1.529 variant spike glycoprotein. The predicted epitope with better antigenicity and non-toxicity were used for designing and predicting vaccine construct features and structure models. The MESV construct In-silico cloning in pET28a expression vector predicted the construct to be highly translational. The proposed MESV vaccine construct was also subjected to immune simulation prediction and was found to be highly antigenic and elicit a cell-mediated immune response. The proposed MESV in the present study has the potential to be evaluated further for vaccine production against the newly identified B1.1.529 (Omicron) variant of concern.
Analyzing the interaction of human ACE2 and RBD of spike protein of SARS-CoV-2 in perspective of Omicron variant
Authors: Samanta Arijit , Mahafujul Alam Syed Sahajada , Ali Safdar , Hoque Mehboob
Published: December 2021

The newly identified Omicron (B.1.1.529) variant of Severe Acute Respiratory Syndrome Voronavirus 2 (SARS-CoV-2) has steered concerns across the world due to the possession of large number of mutations leading to high infectivity and vaccine escape potential. The Omicron variant houses 32 mutations in S protein alone. The viral infectivity is determined mainly by the ability of spike (S) protein receptor binding domain (RBD) to bind to the human Angiotensin I Converting Enzyme 2 (hACE2) receptor. In this paper, the interaction of the RBDs of SARS-CoV-2 variants with hACE2 was analyzed by using protein-protein docking and compared with the novel Omicron variant. Our findings reveal that the Omicron RBD interacts strongly with hACE2 receptor via unique amino acid residues as compared to the Wuhan and many other variants. However, the interacting residues of RBD are found to be the same in Lamda (C.37) variant. These unique binding of Omicron RBD with hACE2 suggests an increased potential of infectivity and vaccine evasion potential of the new variant. The evolutionary drive of the SARS-CoV-2 may not be exclusively driven by RBD variants but surely provides for the platform for emergence of new variants.
Human 14-3-3 proteins site-selectively bind the mutational hotspot region of SARS-CoV-2 nucleoprotein modulating its phosphoregulation
Authors: Tugaeva Kristina V. , Sysoev Andrey A. , Kapitonova Anna A. , Smith Jake L. R. , Zhu Phillip , Cooley Richard B. , Antson Alfred A. , Sluchanko Nikolai N.
Published: December 2021

Phosphorylated within its Ser/Arg-rich region, the SARS-CoV-2 nucleoprotein (N) recruits the phosphopeptide-binding human 14-3-3 proteins that play a well-recognized role in replication of many viruses. Here we use genetic code expansion to demonstrate that phosphorylation of SARS-CoV-2 N at either of two pseudo-repeats centered at Ser197 and Thr205 is sufficient for 14-3-3 binding. According to fluorescence anisotropy, the pT205-motif, present in SARS-CoV-2 but not in SARS-CoV, is preferred over the pS197-motif by all seven human 14-3-3 isoforms, which display unforeseen pT205/pS197 binding selectivity hierarchy. Crystal structures demonstrate that pS197 and pT205 are mutually exclusive 14-3-3-binding sites, whereas SAXS and biochemical data indicate 14-3-3 binding occludes the Ser/Arg-rich region, inhibiting its dephosphorylation. This Ser/Arg-rich region of N is highly prone to mutations, as exemplified by the Omicron and Delta variants, with our data suggesting how the strength of its 14-3-3 binding can be linked with the replicative fitness of the virus.
Convergent evolution of multiple mutations improves the viral fitness of SARS-CoV-2 variants by balancing positive and negative selection
Authors: Upadhyay Vaibhav , Patrick Casey , Lucas Alexandra , Mallela Krishna M.G.
Published: December 2021

Multiple mutations have been seen to undergo convergent evolution in SARS-CoV-2 variants of concern. One such evolution occurs in Beta, Gamma, and Omicron variants at three amino acid positions K417, E484, and N501 in the receptor binding domain of the spike protein. We examined the physical mechanisms underlying the convergent evolution of three mutations K417T/E484K/N501Y by delineating the individual and collective effects of mutations on binding to angiotensin converting enzyme 2 receptor, immune escape from neutralizing antibodies, protein stability and expression. Our results show that each mutation serves a distinct function that improves virus fitness supporting its positive selection, even though individual mutations have deleterious effects that make them prone to negative selection. Compared to the wild-type, K417T escapes Class 1 antibodies, has increased stability and expression; however, it has decreased receptor binding. E484K escapes Class 2 antibodies; however, it has decreased receptor binding, stability and expression. N501Y increases receptor binding; however, has decreased stability and expression. When these mutations come together, the deleterious effects are mitigated due to the presence of compensatory effects. Triple mutant K417T/E484K/N501Y has increased receptor binding, escapes both Class 1 and Class 2 antibodies, and has similar stability and expression as that of the wild-type. These results show the implications of presence of multiple mutations on virus evolution that enhance viral fitness on different fronts by balancing both positive and negative selection and improves the chances of selection of mutations together.
Establishment of a stable SARS-CoV-2 replicon system for application in high-throughput screening
Authors: Tanaka Tomohisa , Saito Akatsuki , Suzuki Tatsuya , Miyamoto Yoichi , Takayama Kazuo , Okamoto Toru , Moriishi Kohji
Published: December 2021

Experiments with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are limited by the need for biosafety level 3 (BSL3) conditions. A SARS-CoV-2 replicon system rather than anin vitroinfection system is suitable for antiviral screening since it can be handled under BSL2 conditions and does not produce infectious particles. However, the reported replicon systems are cumbersome because of the need for transient transfection in each assay. In this study, we constructed a bacterial artificial chromosome vector (the replicon-BAC vector) including the SARS-CoV-2 replicon and a fusion gene encodingRenillaluciferase and neomycin phosphotransferase II, examined the antiviral effects of several known compounds, and then established a cell line stably harboring the replicon-BAC vector. Several cell lines transiently transfected with the replicon-BAC vector produced subgenomic replicon RNAs (sgRNAs) and viral proteins, and exhibited luciferase activity. In the transient replicon system, treatment with remdesivir or interferon-β but not with camostat or favipiravir suppressed the production of viral agents and luciferase, indicating that luciferase activity corresponds to viral replication. VeroE6/Rep3, a stable replicon cell line based on VeroE6 cells, was successfully established and continuously produced viral proteins, sgRNAs and luciferase, and their production was suppressed by treatment with remdesivir or interferon-β. Molnupiravir, a novel coronavirus RdRp inhibitor, inhibited viral replication more potently in VeroE6/Rep3 cells than in VeroE6-based transient replicon cells. In summary, our stable replicon system will be a powerful tool for the identification of SARS-CoV-2 antivirals through high-throughput screening.
Estimating the impact of implementation and timing of the COVID-19 vaccination programme in Brazil: a counterfactual analysis
Authors: Ferreira Leonardo Souto , Darcie Marquitti Flavia Maria , da Silva Rafael Lopes Paixão , Borges Marcelo Eduardo , da Costa Gomes Marcelo Ferreira , Cruz Oswaldo Gonçalves , Kraenkel Roberto André , Coutinho Renato Mendes , Prado Paulo Inácio , Bastos Leonardo Soares
Published: December 2021

Background

Vaccines developed between 2020 - 2021 against the SARS-CoV-2 virus were designed to diminish the severity and prevent deaths due to COVID-19. However, estimates of the effectiveness of vaccination campaigns in achieving these goals remain a methodological challenge. In this work, we developed a Bayesian statistical model to estimate the number of deaths and hospitalisations averted by vaccination of older adults (above 60 years old) in Brazil.

Methods

We fit a linear model to predict the number of deaths and hospitalisations of older adults as a function of vaccination coverage in this group and casualties in younger adults. We used this model in a counterfactual analysis, simulating alternative scenarios without vaccination or with faster vaccination roll-out. We estimated the direct effects of COVID-19 vaccination by computing the difference between hypothetical and realised scenarios.

Findings

We estimated that more than 165,000 individuals above 60 years of age were not hospitalised due to COVID-19 in the first seven months of the vaccination campaign. An additional contingent of 104,000 hospitalisations could have been averted if vaccination had started earlier. We also estimated that more than 58 thousand lives were saved by vaccinations in the period analysed for the same age group and that an additional 47 thousand lives could have been saved had the Brazilian government started the vaccination programme earlier.

Interpretation

Our estimates provided a lower bound for vaccination impacts in Brazil, demonstrating the importance of preventing the suffering and loss of older Brazilian adults. Once vaccines were approved, an early vaccination roll-out could have saved many more lives, especially when facing a pandemic.

Funding

The Coordenação de Aperfeiçoamento de Pessoal de Nível Superior – Brazil (Finance Code 001 to FMDM and LSF), Conselho Nacional de Desenvolvimento Científico e Tecnológico – Brazil (grant number: 315854/2020-0 to MEB, 141698/2018-7 to RLPS, 313055/2020-3 to PIP, 311832/2017-2 to RAK), Fundação de Amparo à Pesquisa do Estado de São Paulo – Brazil (contract number: 2016/01343-7 to RAK), Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro – Brazil (grant number: E-26/201.277/2021 to LSB) and Inova Fiocruz/Fundação Oswaldo Cruz – Brazil (grant number: 48401485034116) to LSB, OGC and MGFC. The funding agencies had no role in the conceptualization of the study.
Mature Neurons’ sensitivity to oxidative stress is epigenetically programmed by alternative splicing and mRNA stability
Authors: Zhou Yuan , Rashad Sherif , Tominaga Teiji , Niizuma Kuniyasu
Published: December 2021

Neuronal differentiation is a complex process that entails extensive morphological, transcriptional, metabolic, and functional changes that dictate neuronal lineage commitment. Much less understood is the role that epigenetic and epi-transcriptional reprogramming plays in the process of neuronal differentiation and maturation. To depict the whole landscape of transcriptomics and epigenetic changes during neuronal differentiation and maturation, we differentiated SH-SY5Y cells and performed RNA sequencing on differentiated and undifferentiated cells. 728 differentially expressed genes (DEGs) enriched in synaptic signaling and cell morphogenesis pathways were observed. Moreover, transcriptome-wide mRNA stability profiling revealed that genes with altered stability were exceptionally enriched for redox homeostasis pathways. Mature neurons are known to be highly sensitive to oxidative stress, which is crucial in the pathophysiology of neurodegenerative disease. Our results suggest that this heightened sensitivity is regulated at the mRNA stability level (i.e., epigenetic) rather than at the transcriptional level. Alternative splicing analysis revealed the exon skipping and alternative mRNA isoforms enriched for morphogenesis related pathway. Alternatively, alternative 5 and 3 prime splicing site, intron retention and mutually exclusive exon events exclusively clustered in the translation and translation initiation pathways, suggesting the potential effect of alternative splicing on translation following neuronal maturation. Splice motif analysis revealed enriched motifs for RBPs that regulate various splice types and can be further correlated to distinct phenotypical changes during neuronal differentiation and maturation. Here we present an extensive exploration of the transcriptional and epigenetic changes and their potential association with the process of neuronal differentiation, providing a new insight into understanding the molecular mechanism of neuronal function and behavior.
An ultrapotent RBD-targeted biparatopic nanobody neutralizes broad SARS-CoV-2 variants
Authors: Chi Xiaojing , Zhang Xinhui , Pan Shengnan , Yu Yanying , Lin Tianli , Duan Huarui , Liu Xiuying , Chen Wenfang , Yang Xuehua , Ding Qiang , Wang Jianwei , Yang Wei
Published: December 2021

The wide transmission and host adaptation of SARS-CoV-2 have led to the rapid accumulation of mutations, posing significant challenges to the effectiveness of vaccines and therapeutic antibodies. Although several neutralizing antibodies were authorized for emergency clinical use, convalescent patients derived natural antibodies are vulnerable to SARS-CoV-2 Spike mutation. Here, we describe the screen of a panel of SARS-CoV-2 receptor-binding domain (RBD) targeted nanobodies (Nbs) from a synthetic library and the design of a biparatopic Nb, named Nb1-Nb2, with tight affinity and super wide neutralization breadth against multiple SARS-CoV-2 variants of concern. Deep-mutational scanning experiments identify the potential binding epitopes of the Nbs on the RBD and demonstrate that biparatopic Nb1-Nb2 has a strong escape resistant feature against more than 60 tested RBD amino acid substitutions. Using pseudovirion-based and trans-complementation SARS-CoV-2 tools, we determine that the Nb1-Nb2 broadly neutralizes multiple SARS-CoV-2 variants, including Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), Delta (B.1.617.2), Lambda (C.37), Kappa (B.1.617.1) and Mu (B.1.621). Furthermore, a heavy chain antibody is constructed by fusing the human IgG1 Fc to Nb1-Nb2 (designated as Nb1-Nb2-Fc) to improve its neutralization potency, yield, stability and potential half-life extension. For the new Omicron variant (B.1.1.529) that harbors unprecedented multiple RBD mutations, Nb1-Nb2-Fc keeps a firm affinity (KD < 1.0×10−12 M) and strong neutralizing activity (IC50 = 0.0017 nM). Together, we developed a tetravalent biparatopic human heavy chain antibody with ultrapotent and broad-spectrum SARS-CoV-2 neutralization activity which highlights the potential clinical applications.
Force Recruitment of Neuromuscular Magnetic Stimulation Predicted Through High-Resolution Anatomical 3D Models
Authors: Goetz S.M. , Weyh T. , Kammermann J. , Helling F. , Li Z.
Published: December 2021

Neuromuscular magnetic stimulation is a promising tool in neurorehabilitation due to its deeper penetration, notably lower distress, and respectable force levels compared to electrical stimulation. However, this method faces great challenges from a technological perspective. The systematic design of better equipment and the incorporation into modern training setups requires better understanding of the mechanisms and predictive quantitative models of the recruited forces. This article proposes a model for simulating the force recruitment in isometric muscle stimulation of the thigh extensors based on previous theoretical and experimental findings. The model couples a 3D field model for the physics with a parametric recruitment model, which is identified with a mixed-effects design to learn the most likely model based on available experimental data with a wide range of field conditions. This approach intentionally keeps the model as mathematically simple and statistically parsimonious as possible in order to avoid over-fitting. The coupled model is able to accurately predict key phenomena observed so far, such as a threshold shift for different distances between coil and body, the different recruiting performance of various coils with available measurement data in the literature, and the saturation behaviour with its onset amplitude. The presented recruitment model could also be readily incorporated into dynamic models for biomechanics as soon as sufficient experimental data are available for calibration.