bluuebunny/crossref_metadata_2025 huggingface dataset:
Factors associated with severity of COVID-19 disease in a multicenter cohort of people with HIV in the United States, March-December 2020
Authors: Shapiro Adrienne E. , Bender Ignacio Rachel A. , Whitney Bridget M. , Delaney Joseph A. , Nance Robin M. , Bamford Laura , Wooten Darcy , Keruly Jeanne C. , Burkholder Greer , Napravnik Sonia , Mayer Kenneth H. , Webel Allison R. , Kim H. Nina , Van Rompaey Stephen E. , Christopoulos Katerina , Jacobson Jeffrey , Karris Maile , Smith Davey , Johnson Mallory O. , Willig Amanda , Eron Joseph J. , Hunt Peter , Moore Richard D. , Saag Michael S. , Mathews W. Christopher , Crane Heidi M. , Cachay Edward R. , Kitahata Mari M. ,   for the CFAR Network of Integrated Clinical Systems
Published: October 2021

Background

Understanding the spectrum of SARS-CoV-2 infection and COVID-19 disease in people with HIV (PWH) is critical to provide clinical guidance and implement risk-reduction strategies.

Objective

To characterize COVID-19 in PWH in the United States and identify predictors of disease severity.

Design

Observational cohort study.

Setting

Geographically diverse clinical sites in the CFAR Network of Integrated Clinical Systems (CNICS)

Participants

Adults receiving HIV care through December 31, 2020.

Measurements

COVID-19 cases and severity (hospitalization, intensive care, death).

Results

Of 16,056 PWH in care, 649 were diagnosed with COVID-19 between March-December 2020. Case fatality was 2%; 106 (16.3%) were hospitalized and 12 died. PWH with current CD4 count <350 cells/mm3(aRR 2.68; 95%CI 1.93-3.71; P<.001) or lowest recorded CD4 count <200 (aRR 1.67; 95%CI 1.18-2.36; P<.005) had greater risk of hospitalization. HIV viral load suppression and antiretroviral therapy (ART) status were not associated with hospitalization, although the majority of PWH were suppressed (86%). Black PWH were 51% more likely to be hospitalized with COVID-19 compared to other racial/ethnic groups (aRR 1.51; 95%CI 1.04-2.19, P=.03). Chronic kidney disease (CKD), chronic obstructive pulmonary disease, diabetes, hypertension, obesity, and increased cardiovascular and hepatic fibrosis risk scores were associated with higher risk of hospitalization. PWH who were older, not on ART, with current CD4 <350, diabetes, and CKD were overrepresented amongst PWH who required intubation or died.

Limitations

Unable to compare directly to persons without HIV; underestimate of total COVID-19 cases.

Conclusions

PWH with CD4 <350 cells/mm3, low CD4/CD8 ratio, and history of CD4 <200, have a clear excess risk of severe COVID-19, after accounting for comorbidities also associated with severe outcomes. PWH with these risk factors should be prioritized for COVID-19 vaccination, early treatment, and monitored closely for worsening illness.
SVRare: discovering disease-causing structural variants in the 100K Genomes Project
Authors: Yu Jing , Szabo Anita , Pagnamenta Alistair T , Shalaby Ahmed , Giacopuzzi Edoardo , Taylor Jenny , Shears Deborah , Pontikos Nikolas , Wright Genevieve , Michaelides Michel , Halford Stephanie , Downes Susan ,   Genomics England Research Consortium
Published: October 2021

Discovery of disease-causing structural variants (dcSV) from whole genome sequencing data is difficult due to high number of false positives and a lack of efficient way to estimate allele frequency. Here we introduce SVRare, an application that aggregates structural variants (SV) called by other tools, and efficiently annotates rare SVs to aid dcSVs discovery.

Applied in the Genomics England (GEL) research environment to data from the 100K Genomes Project, SVRare aggregated 554,060,126 SVs called by Manta and Canvas in all the 71,408 participants in the rare-disease arm. From a pilot study of 4313 families, SVRare identified 36 novel protein-coding disrupting SVs on diagnostic grade genes that may explain proband’s phenotype. It is estimated that SVRare can increase SV-based diagnosis yield by at least 4-fold. We also performed a genome-wide association study, and uncovered clusters of dcSVs in genes with known pathogenicity, such as PKD1/2 - cystic kidney diseases and LDLR - familial hypercholesterolaemia.
The usefulness of antigen testing in predicting contagiousness in COVID-19
Authors: Lopera Tulio J. , Alzate-Ángel Juan Carlos , Díaz Francisco J , Rugeles María T. , Aguilar-Jiménez Wbeimar
Published: October 2021

Increasing the diagnostic capacity of COVID-19 (SARS-CoV-2 infection) is required to improve case detection, reduce COVID-19 expansion, and boost the world economy. Rapid antigen detection tests are cheaper and easier to implement, but their diagnostic performance has been questioned compared to RT-PCR. Here, we evaluate the performance of the Standard Q COVID-19 antigen test for diagnosing SARS-CoV-2 infection and predicting contagiousness compared to RT-PCR and viral culture, respectively. The antigen test was 100.0% specific but only 40.9% sensitive for diagnosing infection compared to RT-PCR. Interestingly, SARS-CoV-2 contagiousness is highly unlikely with a negative antigen test since it exhibited a negative predictive value of 99.9% than viral culture. Furthermore, a cycle threshold (Ct) value of 18.1 in RT-PCR was shown to be the one that best predicts contagiousness (AUC 97.6%). Thus, screening people with antigen testing is a good approach to prevent SARS-CoV-2 contagion and allow returning to daily activities.
BugSplit: highly accurate taxonomic binning of metagenomic assemblies enables genome-resolved metagenomics
Authors: Chandrakumar Induja , Gauthier Nick P.G. , Nelson Cassidy , Bonsall Michael B. , Locher Kerstin , Charles Marthe , MacDonald Clayton , Krajden Mel , Manges Amee R. , Chorlton Samuel D.
Published: October 2021

A large gap remains between sequencing a microbial community and characterizing all of the organisms inside of it. Here we develop a novel method to taxonomically bin metagenomic assemblies through alignment of contigs against a reference database. We show that this workflow, BugSplit, bins metagenome-assembled contigs to species with a 33% absolute improvement in F1-score when compared to alternative tools. We perform nanopore mNGS on patients with COVID-19, and using a reference database predating COVID-19, demonstrate that BugSplit’s taxonomic binning enables sensitive and specific detection of a novel coronavirus not possible with other approaches. When applied to nanopore mNGS data from cases ofKlebsiella pneumoniaeandNeisseria gonorrhoeaeinfection, BugSplit’s taxonomic binning accurately separates pathogen sequences from those of the host and microbiota, and unlocks the possibility of sequence typing,in silicoserotyping, and antimicrobial resistance prediction of each organism within a sample. BugSplit is available athttps://bugseq.com/academic.
The power of peer networking for improving STEM faculty job applications: a successful pilot program
Authors: Guardia Carlos M. , Kane Erin , Tebo Alison G. , Sanders Anna A.W.M. , Kaya Devrim , Grogan Kathleen E.
Published: October 2021

In order to successfully obtain a faculty position, postdoctoral fellows or ‘postdocs’, must submit an application which requires considerable time and effort to produce. These job applications are often reviewed by mentors and colleagues, but rarely are postdocs offered the opportunity to solicit feedback multiple times from reviewers with the same breadth of expertise often found on an academic search committee. To address this gap, this manuscript describes an international peer reviewing program for small groups of postdocs with a broad range of expertise to reciprocally and iteratively provide feedback to each other on their application materials. Over 145 postdocs have participated, often multiple times, over three years. A survey of participants in this program revealed that nearly all participants would recommend participation in such a program to other faculty applicants. Furthermore, this program was more likely to attract participants who struggled to find mentoring and support elsewhere, either because they changed fields or because of their identity as a woman or member of an underrepresented population in STEM. Participation in programs like this one could provide early career academics like postdocs with a diverse and supportive community of peer mentors during the difficult search for a faculty position. Such psychosocial support and encouragement has been shown to prevent attrition of individuals from these populations and programs like this one target the largest ‘leak’ in the pipeline, that of postdoc to faculty. Implementation of similar peer reviewing programs by universities or professional scientific societies could provide a valuable mechanism of support and increased chances of success for early-career academics in their search for independence.
Safety and efficacy of a prehospital initiated protocol of nitrates plus non-invasive ventilation on prehospital and Emergency Department outcomes for acute cardiogenic pulmonary oedema
Authors: Howard Ian , Castle Nicholas , Al Shaikh Loua , Owen Robert
Published: October 2021

Background

Acute heart failure is a common presentation to Emergency Departments (ED) the world over. Amongst the most common presenting signs and symptoms is dyspnoea due to acute pulmonary oedema, a life-threatening emergency that if left untreated or poorly managed. There is increasing evidence demonstrating improved outcomes following the use of vasodilators or non-invasive ventilation for these patients in the emergency setting. Consequently, the potential exists that initiating these therapies in the prehospital setting will similarly improve outcomes.

Methods

A historical cohort study was conducted to assess the effect of a prehospital initiated treatment protocol of nitrates plus non-invasive ventilation (NIV) versus regular therapy for severe cardiogenic APO on all-cause in-hospital mortality at 7 days, 30 days, and in total. Secondary outcomes included changes in EMS respiratory and haemodynamic parameters; admission status; length of stay; and emergency endotracheal intubation.

Results

The intervention led to an approximate 85% reduction in adjusted odds of mortality at 7 days compared to the regular therapy (AOR 0.15, 95% CI: 0.05 – 0.46, p = 0.001); approximate 80% reduction in odds of mortality at 30 days (AOR 0.19, 95% CI: 0.07 – 48, p < 0.0001); and Approximate 60% reduction in odds of total mortality (AOR 0.25, 95% CI: 0.12 – 0.56, p = 0.001).

Conclusion

The results of this analysis provide strong evidence of the potential synergistic benefits that can be achieved with the early implementation of a simple treatment protocol of prehospital administered nitrates and initiation of NIV for cardiogenic APO.
Time-Varying Effectiveness of Three Covid-19 Vaccines in Puerto Rico
Authors: Robles Fontán Mónica M. , Nieves Elvis G. , Gerena Iris Cardona , Irizarry Rafael A.
Published: October 2021

Background

As of October 1, 2021 2,217,547 individuals were fully vaccinated against COVID-19 in Puerto Rico. Since the vaccination process commenced on December 15, 2020 111,052 laboratory-confirmed SARS-CoV-2 infections have been reported. These data permitted us to quantify the benefits of the immunization campaign and to compare effectiveness of the mRNA-1273 (Moderna), BNT162b2 (Pfizer), and Ad26.COV2.S (J&J) vaccines.

Methods

Department of Health databases holding vaccination status, SARS-CoV-2 test results, and COVID-19 hospitalizations and deaths were integrated. We fit a statistical model that adjusted for time-varying incidence rates and age to estimate vaccine effectiveness and hospitalization and death relative risks. Code and data are provided here: https://github.com/rafalab/vax-eff-pr.

Results

At the peak of their protection, mRNA-1273, BNT162b2, and Ad26.COV2.S had an effectiveness of 90% (88%-91%), 87% (85%-89%), and 58% (51%-65%), respectively. After four months, effectiveness waned to about 70%, 60%, and 30%. We found no evidence that effectiveness was different after the Delta variant became dominant. For those infected, the vaccines provided further protection against hospitalization and deaths across all age groups. All vaccines had a lower effectiveness for those over 85 years, with a larger decrease for the Ad26.COV2.S vaccine. Overall, thousands of hospitalizations and deaths were avoided thanks to the vaccines.

Conclusions

The mRNA-1273 and BNT162b2 vaccines were highly effective across all age groups. They were still effective after four months although the protection waned. The Ad26.COV2.S vaccine was effective but to a lesser degree, especially for older age groups.
Radical versus partial nephrectomy and survival from stage T1 renal cell carcinoma in three prospective cohorts
Authors: Sauer Christopher M. , Markt Sarah C. , Mucci Lorelei A. , Sanchez Alejandro , Chang Steven L. , Graff Rebecca E. , Preston Mark A.
Published: October 2021

Background

Whether or not a survival difference exists between radical and partial nephrectomy for stage T1 renal cell carcinoma (RCC) is controversial. We therefore aimed to evaluate cancer-specific, other cause, and overall survival among patients undergoing radical or partial nephrectomy for stage pT1 RCC.

Materials and methods

We identified 330 participants with pT1a-b RCC diagnosed between 2000-2015 in three prospective cohort studies and compared treatment with radical nephrectomy (N=196) versus partial nephrectomy (N=134). The primary outcome was overall survival. Secondary outcomes were other-cause and cancer-specific mortality. Kaplan-Meier plots were used to visualize overall survival for the two treatment groups. Cox proportional hazards regression was utilized to compare outcomes between groups, and Fine and Gray competing risks regression was used to compare cancer-specific and other cause mortality between groups. Multivariable models adjusted for age, tumor size, sex, year of diagnosis, body mass index, history of smoking, history of hypertension, surgical technique, and pathological differentiation.

Results

During a median follow-up of eight years, overall survival was 84%. We did not detect a statistically significant difference in overall survival between partial and radical nephrectomy (Hazard Ratio (HR) = 0.84, 95% Confidence Interval: 0.40-1.78). There was no significant difference in cause-specific or other cause mortality between groups. This study had 80% power to detect an HR ≥2.20.

Conclusions

These results did not suggest a difference in long-term survival outcomes between radical and partial nephrectomy.
Meta-analysis of coagulation disbalances in COVID-19: 41 studies and 17601 patients
Authors: Len Polina , Iskakova Gaukhar , Sautbayeva Zarina , Kussanova Aigul , Tauekelova Ainur T. , Sugralimova Madina M. , Dautbaeva Anar S. , Abdieva Meruert M. , Ponomarev Eugene D. , Tikhonov Alexander , Bekbossynova Makhabbat S. , Barteneva Natasha S.
Published: October 2021

Introduction

Coagulation parameters are important determinants for COVID-19 infection. We conducted meta-analysis to assess the early hemostatic parameters in retrospective studies in association with severity of infection.

Methods

Ovid, PubMed, Web of Sciences, and Google Scholar were searched for research articles that addressed clinical characteristics of COVID-19 patients and disease severity. Results were filtered using exclusion and inclusion criteria and then pooled into a meta-analysis to estimate the standardized mean difference with 95% CI for each of five coagulation parameters (D-dimers, fibrinogen, prothrombin time, platelets count, activated partial thromboplastin time). Two authors independently extracted data and assessed study quality. To explore the heterogeneity and robustness of our fundings, sensitivity and subgroup analyses were conducted. Publication bias was assessed with contour-enhanced funnel plots and Egger test by linear regression.

Results

Overall, 41 original studies (17601 patients) on SARS-CoV2 were included. For the two groups of patients, stratified by severity, we identified that D-dimers, fibrinogen, activated partial thromboplastin time, and prothrombin time were significantly higher in the severe group (SMD 0.6985 with 95%CI [0.5155; 0.8815]); SMD 0.661with 95%CI [0.3387; 0.9833]; SMD 0.2683 with 95%CI [0.1357; 0.4009]; SMD 0.284 with 95%CI [0.1472; 0.4208]). In contrast, PLT was significantly lower in patients with more severe cases of COVID-19 (SMD −0.1684 with 95%CI [-0.2826; −0.0542]). Neither the analysis by the leave-one-out method nor the influence diagnostic have identified studies that solely cause significant change in the effect size estimates. Subgroup analysis showed no significant difference between articles originated from different countries but revealed that severity assessment criteria might have influence over estimated effect sizes for platelets and D-dimers. Contour-enhanced funnel plots and the Egger test for D-dimers and fibrinogen revealed significant asymmetry that might be a sign of publication bias.

Conclusions

The standard coagulation laboratory parameters with exception of platelets counts are significantly elevated in patients with severe COVID-19. However, fibrinolysis shutdown requires evaluation outside conventional coagulation tests and analysis of additional specific markers related to clotting formation and PLT characteristics. We hypothesize that a proportion and parameters of immature reticulated platelets may serve as additional biomarkers for prediction of adverse events.
Self-reported safety of the BBIBP-CorV (Sinopharm) COVID-19 vaccine among Iranian people with multiple sclerosis
Authors: Etemadifar Masoud , Abhari Amir Parsa , Nouri Hosein , Sigari Amirhosein Akhavan , Piran Daliyeh Seyed Mohammad , Maracy Mohammad Reza , Salari Mehri , Maleki Shiva , Sedaghat Nahad
Published: October 2021

To affirm the short-term safety of the BBIBP-CorV (Sinopharm) COVID-19 vaccine among people with multiple sclerosis (pwMS), 517 vaccinated and 174 unvaccinated pwMS were interviewed. 16.2% of the vaccinated pwMS reported at least one neurological symptom in their respective at-risk periods (ARP) – a period from the first until two weeks after the second vaccine dose. In a multivariable logistic regression model, presence of comorbidities (P = 0.01), being on natalizumab (P = 0.03), and experiencing post-vaccination myalgia (P < 0.01) predicted the development of post-vaccination neurological symptoms. One MS relapse, one COVID-19 contraction, and one ulcerative colitis flare after the first, and four MS relapses after the second dose, were the only reported serious adverse events during the ARPs. A multivariable Poisson regression model accounting for possible confounders failed to show any statistically-significant increase in relapse rates during the ARPs of vaccinated, compared to the prior year of unvaccinated pwMS (P = 0.78). Hence, the BBIBP-CorV vaccine does not seem to affect short-term MS activity. Furthermore, as 83.33% of the unvaccinated pwMS reported fear of possible adverse events to be the reason of their vaccination hesitancy, provision of misinformed pwMS with evidence-based consultations in this regard is encouraged.
Reductions in US life expectancy during the COVID-19 pandemic by race and ethnicity: Is 2021 a repetition of 2020?
Authors: Andrasfay Theresa , Goldman Noreen
Published: October 2021

COVID-19 had a huge mortality impact in the US in 2020 and accounted for most of the overall reduction in 2020 life expectancy at birth. There were also extensive racial/ethnic disparities in the mortality impact of COVID-19 in 2020, with the Black and Latino populations experiencing reductions in life expectancy at birth over twice as large as that of the White population. Despite continued vulnerability of these populations, the hope was that widespread distribution of effective vaccines would mitigate the overall impact and reduce racial/ethnic disparities in 2021. In this study, we quantify the mortality impact of the COVID-19 pandemic on 2021 US period life expectancy by race and ethnicity and compare these impacts to those estimated for 2020. Our estimates indicate that racial/ethnic disparities have persisted, and that the US population experienced a decline in life expectancy at birth in 2021 of 2.2 years from 2019, 0.6 years more than estimated for 2020. The corresponding reductions estimated for the Black and Latino populations are slightly below twice that for Whites, suggesting smaller disparities than those in 2020. However, all groups experienced additional reductions in life expectancy relative to 2020, and this apparent narrowing of disparities is primarily the result of Whites experiencing proportionately greater increases in mortality in 2021 compared with the corresponding increases in mortality for the Black and Latino populations in 2021. Estimated declines in life expectancy at age 65 increased slightly for Whites between 2020 and 2021 but decreased for both the Black and Latino populations, resulting in the same overall reduction (0.8 years) estimated for 2020 and 2021.
The premature mortality to incidence ratio (PREMIER): a person-centred measure of cancer burden
Authors: Banham David , Karnon Jonathan , Brown Alex , Roder David , Lynch John
Published: October 2021

Background

Cancer control initiatives are informed by quantifying the capacity to reduce cancer burden through effective interventions. Burden measures using health administrative data are a sustainable way to support monitoring and evaluating of outcomes among patients and populations. The PREmature Mortality to IncidencE Ratio (PREMIER) is one such burden measure. We use data on Aboriginal and non-Aboriginal South Australians from 1990 to 2010 to show how PREMIER quantifies disparities in cancer burden: between populations; between sub-population cohorts where stage at diagnosis is available; and when follow-up is constrained to 24-months after diagnosis.

Method

PREMIERcancer is the ratio of years of life expectancy lost due to cancer (YLLcancer) to life expectancy years at risk at time of cancer diagnosis (LYAR) for each person. The Global Burden of Disease standard life table provides referent life expectancies. PREMIERcancer was estimated for the population of cancer cases diagnosed in South Australia from 1990 to 2010. Cancer stage at diagnosis was also available for cancers diagnosed in Aboriginal people and a cohort of non-Aboriginal people matched by sex, year of birth, primary cancer site and year of diagnosis.

Results

Cancers diagnoses (N=144,891) included 777 among Aboriginal people. Cancer burden described by PREMIERcancer was higher among Aboriginal than non-Aboriginal (0.55, 95%CIs 0.52-0.59 versus 0.39, 95%CIs 0.39-0.40). Diagnoses at younger ages among Aboriginal people, 7 year higher LYAR (31.0, 95%CIs 30.0-32.0 versus 24.1, 95%CIs 24.1-24.2) and higher premature cancer mortality (YLLcancer=16.3, 95%CIs 15.1-17.5 versus YLLcancer=8.2, 95%CIs 8.2-8.3) influenced this. Disparities in cancer burden between the matched Aboriginal and non-Aboriginal cohorts manifested 24-months after diagnosis with PREMIERcancer 0.44, 95%CIs 0.40-0.47 and 0.28, 95%CIs 0.25-0.31 respectively.

Conclusion

PREMIER described disproportionately higher cancer burden among Aboriginal people in comparisons involving: all people diagnosed with cancer; the matched cohorts; and, within groups diagnosed with same staged disease. The extent of disparities were evident 24-months after diagnosis. This is evidence of Aboriginal peoples’ substantial capacity to benefit from cancer control initiatives, particularly those leading to earlier detection and treatment of cancers. PREMIER’s use of readily available, person-level administrative records can help evaluate health care initiatives addressing this need.
Active reconfiguration of cytoplasmic lipid droplets governs migration of nutrient-limited phytoplankton
Authors: Sengupta Anupam , Dhar Jayabrata , Danza Francesco , Ghoshal Arkajyoti , Müller Sarah , Kakavand Narges
Published: October 2021

As open oceans continue to warm, modified currents and enhanced stratification exacerbate nitrogen and phosphorus limitation, constraining primary production. The ability to migrate vertically bestows motile phytoplankton a crucial–albeit energetically expensive–advantage toward vertically redistributing for optimal growth, uptake and resource storage in nutrient-limited water columns. However, this traditional view discounts the possibility that the phytoplankton migration strategy may be actively selected by the storage dynamics when nutrients turn limiting. Here we report that storage and migration in phytoplankton are coupled traits, whereby motile species harness energy storing lipid droplets (LDs) to biomechanically regulate migration in nutrient limited settings. LDs grow and translocate–directionally–within the cytoplasm to accumulate below the cell nucleus, tuning the speed, trajectory and stability of swimming cells. Nutrient reincorporation reverses the LD translocation, restoring the homeostatic migratory traits measured in population-scale millifluidic experiments. Combining intracellular LD tracking and quantitative morphological analysis of red-tide forming alga, Heterosigma akashiwo, along with a model of cell mechanics, we discover that the size and spatial localization of growing LDs govern the ballisticity and orientational stability of migration. The strain-specific shifts in migration which we identify here are amenable to a selective emergence of mixotrophy in nutrient-limited phytoplankton. We rationalize these distinct behavioral acclimatization in an ecological context, relying on concomitant tracking of the photophysiology and reactive oxygen species (ROS) levels, and propose a dissipative energy budget for motile phytoplankton alleviating nutrient limitation. The emergent resource acquisition strategies, enabled by distinct strain-specific migratory acclimatizing mechanisms, highlight the active role of the reconfigurable cytoplasmic LDs in guiding vertical movement. By uncovering the mechanistic coupling between dynamics of intracellular changes to physiologically-governed migration strategies, this work offers a tractable framework to delineate diverse strategies which phytoplankton may harness to maximize fitness and resource pool in nutrient-limited open oceans of the future.

One sentence summary

Phytoplankton harness reconfigurable lipid droplets to biomechanically tune migratory strategies in dynamic nutrient landscapes.
VISTA as a ligand downregulates LPS-mediated inflammation in macrophages and neutrophils
Authors: Ma Yu-Heng Vivian , Sparkes Amanda , Gariépy Jean
Published: October 2021

V-domain immunoglobulin suppressor of T-cell activation (VISTA) has emerged as a unique immunoregulatory receptor on cells of the myeloid lineage. Agonizing VISTA on myeloid cells has recently been demonstrated to have a profound effect on dampening inflammatory responses. VISTA has been proposed to function both as a ligand and as a receptor. In this context, the role of VISTA as a ligand has been largely ignored. Using a high-avidity agonist of the VISTA receptor (VISTA-COMP), we investigated the effect of exogenous VISTA, as a ligand, on macrophages and neutrophil cellular pathways in an acute inflammatory setting. RNA sequencing analysis demonstrated that VISTA-COMP downregulates pro-inflammatory cytokines and chemokines and upregulates immunoregulatory genes in both LPS-stimulated macrophages and neutrophils ex vivo. Interestingly, unlike VISTA itself, the receptor is only expressed following LPS stimulation of these cell populations. Furthermore, the administration of VISTA-COMP attenuated the rise in circulating TNFα levels in LPS-treated mice in vivo. These results suggest that VISTA serves a redundant role on macrophages and neutrophils acting as both a ligand and a receptor in the context of an acute inflammatory event.
Nanoscopic resolution within a single imaging frame
Authors: García Esley Torres , Cámara Raúl Pinto , Linares Alejandro , Martínez Damián , Abonza Víctor , Brito-Alarcón Eduardo , Calcines-Cruz Carlos , Galindo Gustavo Valdés , Torres David , Jabloñski Martina , Torres-Martínez Héctor H. , Martínez José L. , Hernández Haydee O. , Ocelotl-Oviedo José P. , Garcés Yasel , Barchi Marco , D’Antuono Rocco , Boskovic Ana , Dubrovsky Joseph G. , Darszon Alberto , Buffone Mariano G. , Morales Roberto Rodríguez , Rendon-Mancha Juan Manuel , Wood Christopher D. , Hernández-García Armando , Krapf Diego , Crevenna Álvaro H. , Guerrero Adán
Published: October 2021

Mean-Shift Super Resolution (MSSR) is a principle based on the Mean Shift theory that extends spatial resolution in fluorescence images, beyond the diffraction limit. MSSR works on low- and high-density fluorophore images, is not limited by the architecture of the detector (EM-CCD, sCMOS, or photomultiplier-based laser scanning systems) and is applicable to single images as well as temporal series. The theoretical limit of spatial resolution, based on optimized real-world imaging conditions and analysis of temporal image series, has been measured to be 40 nm. Furthermore, MSSR has denoising capabilities that outperform other analytical super resolution image approaches. Altogether, MSSR is a powerful, flexible, and generic tool for multidimensional and live cell imaging applications.
Structural and functional properties of a magnesium transporter of the SLC11/NRAMP family
Authors: Ramanadane Karthik , Straub Monique S. , Dutzler Raimund , Manatschal Cristina
Published: October 2021

Members of the ubiquitous SLC11/NRAMP family catalyze the uptake of divalent transition metal ions into cells. They have evolved to efficiently select these trace elements from a large pool of Ca2+and Mg2+, which are both orders of magnitude more abundant, and to concentrate them in the cytoplasm aided by the cotransport of H+serving as energy source. In the present study, we have characterized a member of a distant clade of the family found in prokaryotes, termed NRMTs, that were proposed to function as transporters of Mg2+. The protein transports Mg2+and Mn2+but not Ca2+by a mechanism that is not coupled to H+. Structures determined by cryo-EM and X-ray crystallography revealed a generally similar protein architecture compared to classical NRAMPs, with a restructured ion binding site whose increased volume provides suitable interactions with ions that likely have retained much of their hydration shell.
Calling the Amino Acid Sequence of a Protein/Peptide from the Nanospectrum Produced by a Sub-nanometer Diameter Pore
Authors: Liu Xiaowen , Dong Zhuxin , Timp Gregory
Published: October 2021

The blockade current that develops when a protein translocates across a thin membrane through a sub-nanometer diameter pore (i.e., a nanospectrum) informs with extreme sensitivity on the sequence of amino acids that constitute the protein. Whereas mass spectrometry (MS) is still the dominant technology for protein identification, it suffers limitations. In proteome-wide studies, MS fails to sequence proteins de novo, but merely classifies a protein and it is not very sensitive requiring about a femtomole to do that. Compared with MS, a sub-nanometer diameter pore (i.e. a sub-nanopore) directly reads the amino acids constituting a single protein molecule, but efficient computational tools are still required for processing and interpreting the blockade current. Here, we delineate computational methods for processing sub-nanopore nanospectra and predicting electrical blockade currents from protein sequences, which are essential for protein identification.
Brain hubs defined in the group do not overlap with regions of high inter-individual variability
Authors: Smith D.M. , Kraus B. T. , Dworetsky A. , Gordon E. M. , Gratton C.
Published: October 2021

Connector ‘hubs’ are brain regions with links to multiple networks. These regions are hypothesized to play a critical role in brain function. While hubs are often identified based on group-average functional magnetic resonance imaging (fMRI) data, there is considerable inter-subject variation in the functional connectivity profiles of the brain, especially in association regions where hubs tend to be located. Here we investigated how group hubs are related to locations of inter-individual variability, to better understand if hubs are (a) relatively conserved across people, (b) locations with malleable connectivity, leading individuals to show variable hub profiles, or (c) artifacts arising from cross-person variation. To answer this question, we compared the locations of hubs and regions of strong idiosyncratic functional connectivity (“variants”) in both the Midnight Scan Club and Human Connectome Project datasets. Group hubs defined based on the participation coefficient did not overlap strongly with variants. These hubs have relatively strong similarity across participants and consistent cross-network profiles. Consistency across participants was further improved when participation coefficient hubs were allowed to shift slightly in local position. Thus, our results demonstrate that group hubs defined with the participation coefficient are generally consistent across people, suggesting they may represent conserved cross-network bridges. More caution is warranted with alternative hub measures, such as community density, which are based on spatial proximity and show higher correspondence to locations of individual variability.
Physarum polycephalum: Establishing an Assay for Testing Decision-making Under Shifting Somatic Boundaries
Authors: Levin Samuel P. , Levin Michael
Published: October 2021

Prior studies of decision-making generally assume a fixed agent which maximizes utility among its various options. Physarum polycephalum is a popular model for basal cognition that can be cut into pieces that may or may not re-join. We exploited this capacity to develop a novel assay in which radical changes to the agent itself are among the options of the decision-making process. Specifically, we transected a Physarum culture in the presence of a food reward that was located closer to the new smaller piece. In this scenario, the newly created branch must choose between exploiting the reward itself, or first re-connecting with the original mass (and sharing the nutrient reward across a large body). We report a pilot study establishing a protocol in which the number of agents is part of the decision-making process. We observed that despite the presence of food, new branches strongly prefer to merge back to the syncytium before exploiting the reward. Many improvements to the protocol are possible, to extend this effort to understand the interplay between behavioral options and the structure and boundary of the individual making choices in its environment.
Nuclear PHGDH promotes neutrophil recruitment to drive liver cancer progression
Authors: Zhu Hongwen , Yu Hua , Zhou Hu , Zhu Wencheng , Wang Xiongjun
Published: October 2021

Metabolic dysregulation and the communications between cancer and immune cells are emerging as two essential features of malignant tumors. In this study, we observed that nuclear localization of phosphoglycerate dehydrogenase (PHGDH) associates with poor prognosis of liver cancer patients, and Phgdh is required for liver cancer progression in a mouse model. Unexpectedly, the impairment of Phgdh enzyme activity exerts a slight effect on liver cancer model, indicating PHGDH contributes to liver cancer progression mainly depending on its non-metabolic roles with nuclear location. PHGDH uses its ACT domain to bind cMyc in nuclear and forms a transactivation axis “PHGDH/p300/cMyc/AF9” which drives CXCL1/8 gene expression. Chemokines CXCL1/8 promotes neutrophils recruitment and then supports tumor associated macrophages (TAMs) filtration in liver, thereby urging liver cancer into advanced stages. Forced cytosolic location of PHGDH or destruction of the PHGDH/cMyc interaction abolishes the oncogenic function of nuclear PHGDH. Collectively, this study reveals a non-metabolic role of PHGDH with altered cellular location in liver cancer, and suggests a promising drug target for liver cancer therapy by targeting the interaction between PHGDH and “undruggable” cMyc.
RTX-KG2: a system for building a semantically standardized knowledge graph for translational biomedicine
Authors: Wood E. C. , Glen Amy K. , Kvarfordt Lindsey G. , Womack Finn , Acevedo Liliana , Yoon Timothy S. , Ma Chunyu , Flores Veronica , Sinha Meghamala , Chodpathumwan Yodsawalai , Termehchy Arash , Roach Jared C. , Mendoza Luis , Hoffman Andrew S. , Deutsch Eric W. , Koslicki David , Ramsey Stephen A.
Published: October 2021

Background

Biomedical translational science is increasingly using computational reasoning on repositories of structured knowledge (such as UMLS, SemMedDB, ChEMBL, Reactome, DrugBank, and SMPDB in order to facilitate discovery of new therapeutic targets and modalities. The NCATS Biomedical Data Translator project is working to federate autonomous reasoning agents and knowledge providers within a distributed system for answering translational questions. Within that project and the broader field, there is a need for a framework that can efficiently and reproducibly build an integrated, standards-compliant, and comprehensive biomedical knowledge graph that can be downloaded in standard serialized form or queried via a public application programming interface (API).

Results

To create aknowledge providersystem within the Translator project, we have developed RTX-KG2, an open-source software system for building—and hosting a web API for querying—a biomedical knowledge graph that uses an Extract-Transform-Load (ETL) approach to integrate 70 knowledge sources (including the aforementioned core six sources) into a knowledge graph with provenance information including (where available) citations. The semantic layer and schema for RTX-KG2 follow the standard Biolink model to maximize interoperability. RTX-KG2 is currently being used by multiple Translator reasoning agents, both in its downloadable form and via its SmartAPI-registered interface. Serializations of RTX-KG2 are available for download in both the pre-canonicalized form and in canonicalized form (in which synonyms are merged). The current canonicalized version (KG2.7.3) of RTX-KG2 contains 6.4M nodes and 39.3M edges with a hierarchy of 77 relationship types from Biolink.

Conclusion

RTX-KG2 is the first knowledge graph that integrates UMLS, SemMedDB, ChEMBL, DrugBank, Reactome, SMPDB, and 64 additional knowledge sources within a knowledge graph that conforms to the Biolink standard for its semantic layer and schema. RTX-KG2 is publicly available for querying via its API atarax.rtx.ai/api/rtxkg2/v1.2/openapi.json. The code to build RTX-KG2 is publicly available atgithub:RTXteam/RTX-KG2.
Adaptation of peristaltic pumps for laminar flow experiments
Authors: Abello Javier , Yien Yvette Y. , Stratman Amber N.
Published: October 2021

Endothelial cells (ECs) are the primary cellular constituent of blood vessels that are in direct contact with hemodynamic forces over the course of a lifetime. Throughout the body, vessels experience different types of blood flow patterns and rates that alter vascular architecture and cellular behavior. Because of the complexities of studying blood flow in an intact organism, particularly during development, modeling of blood flow in vitro has become a powerful technique for studying hemodynamic dependent signaling mechanisms in ECs. While commercial flow systems that recirculate fluids exist, many commercially available pumps are peristaltic and best model pulsatile flow conditions. However, there are many important in vivo situations in which ECs experience laminar flow conditions, such as along long, straight stretches of the vasculature. To understand EC function under these situations, it is important to be able to consistently model laminar flow conditions in vitro. Here, we outline a method to reliably adapt commercially available peristaltic pumps to reproducibly study laminar flow conditions. Our proof of concept study focuses on 2-dimensional (2D) models but could be further adapted to 3-dimensional (3D) environments to better model in vivo scenarios such as organ development. Our studies make significant inroads into solving technical challenges associated with flow modeling, and allow us to conduct functional studies towards understanding the mechanistic role of flow forces on vascular architecture, cellular behavior, and remodeling during a variety of physiological contexts.
Comparative assessment of methods for short-term forecasts of COVID-19 hospital admissions in England at the local level
Authors: Meakin Sophie , Abbott Sam , Bosse Nikos , Munday James , Gruson Hugo , Hellewell Joel , Sherratt Katherine ,   CMMID COVID-19 Working Group, Funk Sebastian
Published: October 2021

Background

Forecasting healthcare demand is essential in epidemic settings, both to inform situational awareness and facilitate resource planning. Ideally, forecasts should be robust across time and locations. During the COVID-19 pandemic in England, it is an ongoing concern that demand for hospital care for COVID-19 patients in England will exceed available resources.

Methods

We made weekly forecasts of daily COVID-19 hospital admissions for National Health Service (NHS) Trusts in England between August 2020 and April 2021 using three disease-agnostic forecasting models: a mean ensemble of autoregressive time series models, a linear regression model with 7-day-lagged local cases as a predictor, and a scaled convolution of local cases and a delay distribution. We compared their point and probabilistic accuracy to a mean-ensemble of them all, and to a simple baseline model of no change from the last day of admissions. We measured predictive performance using the Weighted Interval Score (WIS) and considered how this changed in different scenarios (the length of the predictive horizon, the date on which the forecast was made, and by location), as well as how much admissions forecasts improved when future cases were known.

Results

All models outperformed the baseline in the majority of scenarios. Forecasting accuracy varied by forecast date and location, depending on the trajectory of the outbreak, and all individual models had instances where they were the top- or bottom-ranked model. Forecasts produced by the mean-ensemble were both the most accurate and most consistently accurate forecasts amongst all the models considered. Forecasting accuracy was improved when using future observed, rather than forecast, cases, especially at longer forecast horizons.

Conclusions

Assuming no change in current admissions is rarely better than including at least a trend. Using confirmed COVID-19 cases as a predictor can improve admissions forecasts in some scenarios, but this is variable and depends on the ability to make consistently good case forecasts. However, ensemble forecasts can make forecasts that make consistently more accurate forecasts across time and locations. Given minimal requirements on data and computation, our admissions forecasting ensemble could be used to anticipate healthcare needs in future epidemic or pandemic settings.
Diagnostic Value of Genetic Mutation Analysis and Mutation Profiling of cfDNA in Intraocular Fluid for Vitreoretinal Lymphoma
Authors: Chen Xiaoqing , Hu Yunwei , Su Wenru , Yang Shizhao , Wang Xiaoxiao , Zhang Ping , Hong Xiaoyu , Liang Chuqiao , Qian Zhuyun , Li Ziqiang , Tao Yong , Huang Huiqiang , Liang Dan
Published: October 2021

Objective

Vitreoretinal lymphoma (VRL) is a rare but aggressive masquerade syndrome, with challenging diagnosis. Since the tumor-related genetic mutation analysis based on cell-free DNA (cfDNA) are underutilized in ocular oncology, we aimed to test the VRL diagnostic value of cfDNA genetic mutation analysis using intraocular fluid (IOF) samples and to identify its mutation profile.

Subjects

Seventeen VRL and 6 uveitis patients from Zhongshan Ophthalmic Centre were selected as training group, and 5 VRL and 5 uveitis patients from Beijing Chaoyang Hospital were selected as validation group.

Methods

The medical records and genetic mutation analysis using a panel containing 446 tumor-related genes of included patients were retrospectively reviewed. We analyzed the mutation profile, and identified the molecular subtypes and subdivisions of B-cell differentiation pathways of our VRL patients.

Main outcomes

The cfDNA genetic mutations detected in IOF.

Results

The VRL patients from the training group exhibited abundant cfDNA mutations in IOF (sensitivity 100%), while only 2 out of 6 uveitis patients were positive (specificity 67%). However, the number of cfDNA mutations observed in VRL patients was higher than that of uveitis patients. The mutation-positive patients from the validation group were diagnosed with VRL while the mutation-negative patients were diagnosed with uveitis (sensitivity and specificity 100%). VRL patients were characterized by the high mutation frequencies of PIM1, MYD88, CD79B, ETV6, and IRF4.

Conclusions

The genetic mutation analysis of IOF samples represents a feasible diagnosis method for VRL with 100% sensitivity; it could track genetic profiles; thus, revealing genetic heterogeneity of VRL.

Statement of translational relevance

The anterior chamber paracentesis and diagnostic vitrectomy have been widely used in ophthalmic clinics, as they are less invasive sampling techniques for liquid biopsies. Genetic mutation analysis of cell-free DNA (cfDNA) of intraocular fluid using a panel containing 446 targeted genes represents a feasible method with 100% sensitivity for vitreoretinal lymphoma (VRL) diagnosis. Furthermore, it can address cytological diagnostic issues including limited cellular yield, cell lysis associated with the fragile nature of lymphoma cells, and high risks associated with retinal tissue biopsies. Furthermore, it allows for genetic profile tracking, having the potential to reveal genetic heterogeneity and molecular characteristics of VRL in the future
Circulatory neutrophils exhibit enhanced neutrophil extracellular trap formation in early puerperium: NETs at the nexus of thrombosis and immunity?
Authors: Giaglis Stavros , Chowdhury Chanchal Sur , van Breda Shane Vontelin , Stoikou Maria , Schaefer Guenther , Buser Andreas , Walker Ulrich A. , Lapaire Olav , Hoesli Irene , Hasler Paul , Hahn Sinuhe
Published: October 2021

Pregnancy is associated with elevated maternal levels of cell-free DNA of neutrophil extracellular trap (NET) origin, as circulatory neutrophils exhibit increased spontaneous NET formation, mainly driven by G-CSF and finely modulated by sex hormones. The postpartum period, on the other hand, involves physiological alterations consistent with the need for protection against infections and fatal haemorrhage. Our findings indicate that all relevant serum markers of neutrophil degranulation and NET release are substantially augmented postpartum. Neutrophil pro-NETotic activity in vitro is also upregulated particularly in post-delivery neutrophils. Moreover, maternal puerperal neutrophils exhibit a strong pro-NETotic phenotype, associated with increased levels of all key players in the generation of NETs – citH3, MPO, NE and ROS, compared to non-pregnant and pregnant controls. Intriguingly, post-delivery NET formation is independent of G-CSF in contrast to late gestation and complemented by the presence of TF on the NETs, alterations in the platelet activity status, and activation of the coagulation cascade, triggered by circulating microparticles. Taken together, our results reveal the highly pro-NETotic and potentially procoagulant nature of postpartum neutrophils, bridging an overt immune activation with possible harmful thrombotic incidence.