bluuebunny/crossref_metadata_2025 huggingface dataset:
National Surgical Quality Improvement Program Adverse Events Combined With Clavien-Dindo Scores Can Direct Quality Improvement Processes in Surgical Patients
Authors: Ghannam Alexander D. , Crandall Marie L. , Woodruff Grant , Ra Jin , Kerwin Andrew J. , Awad Ziad T. , Tepas Joseph
Published: February 2022

Objective

The burden of postoperative adverse events (AE) weighs immediately on the patient as unanticipated stress and on the healthcare system as unreimbursed cost. Applying the Clavien-Dindo (C-D) system of AE gradation as a surrogate of cost, we analyzed 4 years’ data from a single-state National Surgical Quality Improvement Program (NSQIP) collaboration, hypothesizing that trends of AE were consistent over time and that more frequently performed cases would be associated with less and more minor AE.

Methods

The NSQIP defined AEs, consisting of 21 listed postoperative occurrences, which were analyzed using deidentified 30-day postoperative data for 2015 to 2018. Each AE was graded using (C-D) severity (1, lowest; 4, highest with survival). The C-D severity weight, as defined in previous multi-institutional studies, was used as a surrogate for cost and unplanned patient burden. Adverse event incidence was calculated as sum AE/case volume, and population burden as total AE burden/case volume.

Results

There were 12,567 surgical cases recorded by members of the state collaborative. The overall data demonstrated no significant difference in AE incidence; however, the burden of AE increased by 18.8%. The 8 most common Current Procedural Terminology codes had approximately 50% lower AE incidence compared with overall cases; however, the incidence increased by 56.0% and the AE burden/case increased by 48.0%.

Conclusions

Although the 8 most common Current Procedural Terminology codes showed a 50% lower AE incidence compared with overall cases, the incidence increased over the study period. Surgical quality initiatives should be patient centered and focus on high burden AE.
Virtual Noncontrast Imaging of the Liver Using Photon-Counting Detector Computed Tomography
Authors: Sartoretti Thomas , Mergen Victor , Higashigaito Kai , Eberhard Matthias , Alkadhi Hatem , Euler André
Published: February 2022

Objectives

The aim of this study was to assess the accuracy of virtual noncontrast (VNC) images of the liver in a phantom and patients using dual-source photon-counting detector computed tomography (PCD-CT).

Materials and Methods

An anthropomorphic abdominal phantom with a liver insert containing liver parenchyma (1.4 mgI/mL) and 19 liver lesions (iodine content 0–5 mgI/mL) was imaged on a clinical dual-source PCD-CT (tube voltage 120 kV) and in the dual-energy mode on a dual-source energy-integrating detector (EID) CT (tube voltage combinations, 80/Sn150 kV, 90/Sn150 kV, and 100/Sn150 kV). Rings of fat-equivalent material were added to the phantom to emulate 3 sizes (small, medium, large). Each setup was imaged at 3 different radiation doses (volume CT dose index: 5, 10, and 15 mGy). Virtual noncontrast images were reconstructed and CT attenuation was measured in each lesion and liver parenchyma. The absolute error of CT attenuation (VNCerror) was calculated using the phantom specifications as reference. In addition, 15 patients with hypodense liver lesions who were clinically scanned on PCD-CT were retrospectively included. Attenuation values in lesions and liver parenchyma in VNC images reconstructed from portal venous phase CT were compared with true noncontrast images. Statistical analysis included analysis of variance with post hoc t tests and generalized linear models to assess the impact of various variables (dose, patient size, base material, iodine content, and scanner/scan mode) on quantification accuracy.

Results

In the phantom, the overall mean VNCerror for PCD-CT was 4.1 ± 3.9 HU. The overall mean VNCerror for EID-CT was 7.5 ± 5, 6.3 ± 4.7, and 6.7 ± 4.8 HU for 80/Sn150 kV, 90/Sn150 kV, and 100/Sn150 kV, respectively, with the VNCerror of EID-CT being significantly higher at all tube voltage settings (P < 0.001), even after adjusting for dose, size, iodine content of the lesion, and attenuation of base material. For PCD-CT, a smaller phantom size was associated with higher quantification accuracy (P = 0.007–0.046), whereas radiation dose did not impact accuracy (P > 0.126). For EID-CT, but not for PCD-CT, VNCerror increased with lesion iodine content (P < 0.001). In patients, there was no difference in attenuation measured on true noncontrast and VNC images (P = 0.093), with a mean VNCerror of 3.7 ± 2.2 HU.

Conclusions

Photon-counting detector CT allows for the reconstruction of VNC images of the liver both in a phantom and in patients with accurate attenuation values, being independent of dose, attenuation of base material, and liver iodine content.
The Combined Roles of Race/Ethnicity and Substance Use in Predicting Likelihood of Kidney Transplantation
Authors: DeBlasio Richelle N. , Myaskovsky Larissa , DiMartini Andrea F. , Croswell Emilee , Posluszny Donna M. , Puttarajappa Chethan , Switzer Galen E. , Shapiro Ron , DeVito Dabbs Annette J. , Tevar Amit D. , Hariharan Sundaram , Dew Mary Amanda
Published: February 2022

Background.

Racial/ethnic minorities face known disparities in likelihood of kidney transplantation. These disparities may be exacerbated when coupled with ongoing substance use, a factor also reducing likelihood of transplantation. We examined whether race/ethnicity in combination with ongoing substance use predicted incidence of transplantation.

Methods.

Patients were enrolled between March 2010 and October 2012 at the time of transplant evaluation. Substance use data were retrieved from transplant evaluations. Following descriptive analyses, the primary multivariable analyses evaluated whether, relative to the referent group (White patients with no substance use), racial/ethnic minority patients using any substances at the time of evaluation were less likely to receive transplants by the end of study follow-up (August 2020).

Results.

Among 1152 patients, 69% were non-Hispanic White, 23% non-Hispanic Black, and 8% Other racial/ethnic minorities. White, Black, and Other patients differed in percentages of current tobacco smoking (15%, 26%, and 18%, respectively;P= 0.002) and illicit substance use (3%, 8%, and 9%;P< 0.001) but not heavy alcohol consumption (2%, 4%, and 1%;P= 0.346). Black and Other minority patients using substances were each less likely to receive transplants than the referent group (hazard ratios ≤0.45,P≤ 0.021). Neither White patients using substances nor racial/ethnic minority nonusers differed from the referent group in transplant rates. Additional analyses indicated that these effects reflected differences in waitlisting rates; once waitlisted, study groups did not differ in transplant rates.

Conclusions.

The combination of minority race/ethnicity and substance use may lead to unique disparities in likelihood of transplantation. To facilitate equity, strategies should be considered to remove any barriers to referral for and receipt of substance use care in racial/ethnic minorities.
Trade-offs between cost of ingestion and rate of intake drive defensive toxin use
Authors: Douglas Tyler E. , Beskid Sofia G. , Gernand Callie E. , Nirtaut Brianna E. , Tamsil Kristen E. , Fitch Richard W. , Tarvin Rebecca D.
Published: February 2022

Animals that ingest toxins can become unpalatable and even toxic to predators and parasites through toxin sequestration. Because most animals rapidly eliminate toxins to survive their ingestion, it is unclear how populations transition from susceptibility and toxin elimination to tolerance and accumulation as chemical defence emerges. Studies of chemical defence have generally focused on species with active toxin sequestration and target-site insensitivity mutations or toxin-binding proteins that permit survival without necessitating toxin elimination. Here, we investigate whether animals that presumably rely on toxin elimination for survival can use ingested toxins for defence. We use the A4 and A3
Drosophila melanogaster
fly strains from the Drosophila Synthetic Population Resource (DSPR), which respectively possess high and low metabolic nicotine resistance among DSPR fly lines. We find that ingesting nicotine increased A4 but not A3 fly survival against
Leptopilina heterotoma
wasp parasitism. Further, we find that despite possessing genetic variants that enhance toxin elimination, A4 flies accrued more nicotine than A3 individuals, likely by consuming more medium. Our results suggest that enhanced toxin metabolism can allow greater toxin intake by offsetting the cost of toxin ingestion. Passive toxin accumulation that accompanies increased toxin intake may underlie the early origins of chemical defence.
The impact of molecular data on the phylogenetic position of the putative oldest crown crocodilian and the age of the clade
Authors: Darlim Gustavo , Lee Michael S. Y. , Walter Jules , Rabi Márton
Published: February 2022

The use of molecular data for living groups is vital for interpreting fossils, especially when morphology-only analyses retrieve problematic phylogenies for living forms. These topological discrepancies impact on the inferred phylogenetic position of many fossil taxa. In Crocodylia, morphology-based phylogenetic inferences differ fundamentally in placing
Gavialis
basal to all other living forms, whereas molecular data consistently unite it with crocodylids. The Cenomanian
Portugalosuchus azenhae
was recently described as the oldest crown crocodilian, with affinities to
Gavialis
, based on morphology-only analyses, thus representing a potentially important new molecular clock calibration
.
Here, we performed analyses incorporating DNA data into these morphological datasets, using scaffold and supermatrix (total evidence) approaches, in order to evaluate the position of basal crocodylians, including
Portugalosuchus
. Our analyses incorporating DNA data robustly recovered
Portugalosuchus
outside Crocodylia (as well as thoracosaurs, planocraniids and
Borealosuchus
spp.), questioning the status of
Portugalosuchus
as crown crocodilian and any future use as a node calibration in molecular clock studies. Finally, we discuss the impact of ambiguous fossil calibration and how, with the increasing size of phylogenomic datasets, the molecular scaffold might be an efficient (though imperfect) approximation of more rigorous but demanding supermatrix analyses.
Peptides before and during the nucleotide world: an origins story emphasizing cooperation between proteins and nucleic acids
Authors: Fried Stephen D. , Fujishima Kosuke , Makarov Mikhail , Cherepashuk Ivan , Hlouchova Klara
Published: February 2022

Recent developments in Origins of Life research have focused on substantiating the narrative of an abiotic emergence of nucleic acids from organic molecules of low molecular weight, a paradigm that typically sidelines the roles of peptides. Nevertheless, the simple synthesis of amino acids, the facile nature of their activation and condensation, their ability to recognize metals and cofactors and their remarkable capacity to self-assemble make peptides (and their analogues) favourable candidates for one of the earliest functional polymers. In this mini-review, we explore the ramifications of this hypothesis. Diverse lines of research in molecular biology, bioinformatics, geochemistry, biophysics and astrobiology provide clues about the progression and early evolution of proteins, and lend credence to the idea that early peptides served many central prebiotic roles before they were encodable by a polynucleotide template, in a putative ‘peptide-polynucleotide stage’. For example, early peptides and mini-proteins could have served as catalysts, compartments and structural hubs. In sum, we shed light on the role of early peptides and small proteins
before
and
during
the nucleotide world, in which nascent life fully grasped the potential of primordial proteins, and which has left an imprint on the idiosyncratic properties of extant proteins.
Defining An Expanded RAS Conformational Landscape Based on Over 700 Experimentally Determined Structures of KRAS, NRAS, and HRAS
Authors: Parker Mitchell I. , Meyer Joshua E. , Golemis Erica A. , Dunbrack Roland L.
Published: February 2022

For many human cancers and tumor-associated diseases, mutations in the RAS isoforms (KRAS, NRAS, and HRAS) are the most common oncogenic alterations, making these proteins high-priority therapeutic targets. Effectively targeting the RAS isoforms requires an exact understanding of their active, inactive, and druggable conformations. However, there is no structure-guided catalogue of RAS conformations to guide therapeutic targeting or examining the structural impact of RAS mutations. We present an expanded classification of RAS conformations based on analyzing their catalytic switch 1 (SW1) and switch 2 (SW2) loops. From all 721 available human KRAS, NRAS, and HRAS structures in the Protein Data Bank (PDB) (206 RAS-protein complexes, 190 inhibitor-bound, and 325 unbound, including 204 WT and 517 mutated structures), we created a broad conformational classification based on the spatial positions of residue Y32 in SW1 and residue Y71 in SW2. Subsequently, we defined additional conformational subsets (some previously undescribed) by clustering all well modeled SW1 and SW2 loops using a density-based machine learning algorithm with a backbone dihedral-based distance metric. In all, we identified three SW1 conformations and nine SW2 conformations, each which are associated with different nucleotide states (GTP-bound, nucleotide-free, and GDP-bound) and specific bound proteins or inhibitor sites. The GTP-bound SW1 conformation can be further subdivided based on the hydrogen (H)-bond type made between residue Y32 and the GTP γ-phosphate: water-mediated, direct, or no H-bond. Further analyzing these structures clarified the catalytic impact of the G12D and G12V RAS mutations, and the inhibitor chemistries that bind to each druggable RAS conformation. To facilitate future RAS structural analyses, we have created a web database, called Rascore, presenting an updated and searchable dataset of human KRAS, NRAS, and HRAS structures in the PDB, and which includes a page for analyzing user uploaded RAS structures by our algorithm (http://dunbrack.fccc.edu/rascore/).

Significance

Analyzing >700 experimentally determined RAS structures helped define an expanded landscape of active, inactive and druggable RAS conformations, the structural impact of common RAS mutations, and previously uncharacterized RAS-inhibitor binding modes.
Plasma proteomic biomarkers identify non-responders and reveal biological insights about the tumor microenvironment in melanoma patients after PD1 blockade
Authors: Mehta Arnav , Rucevic Marijana , Sprecher Emmett , Parikh Milan , Chen Jiajia , Frederick Dennie T. , Woods Elliot , Bi Lynn , Lieb David , Hultin-Rosenberg Lina , Guess Jamey , Park Ryan J. , Schneider Alexis , Michaud William , Miao Benchun , Kasumova Gyulnara , Kim Michelle S. , Bai Xue , Jenkins Russell W. , Klempner Samuel J. , Gonye Anna L. K. , Yizhak Keren , Sade-Feldman Moshe , Liu David , Sullivan Ryan J. , Flaherty Keith T. , Hacohen Nir , Boland Genevieve M.
Published: February 2022

Most patients treated with immune checkpoint blockade (ICB) do not have durable treatment responses. Therefore, there is a critical need to identify early non-invasive biomarkers of response. We performed plasma proteomic analysis (>700 proteins) at three timepoints on 174 metastatic melanoma patients treated with ICB. We leverage independent training and testing cohorts to build a predictor of immunotherapy response that outperforms several tissue-based approaches. We found 217 differentially expressed proteins between ICB responders (R) and non-responders (NR), including a co-regulated module of proteins enriched in certain NR patients. By analyzing single-cell RNA-sequencing data of tumor biopsies from 32 patients, we dissected the relative contribution of cells in the tumor to proteins in circulation. The majority of proteins in the co-regulated NR module derived from tumor and myeloid cells. Amongst myeloid cells, we identified a subset of tumor-associated macrophages (TAMs) with a suppressive phenotype that expressed high levels of the co-regulated NR module, thus suggesting they are key drivers of non-response signatures. Together, our data demonstrates the utility of plasma proteomics in biomarker discovery and in understanding the biology of host response to tumors.
Quantifying the Local Adaptive Landscape of a Nascent Bacterial Community
Authors: Ascensao Joao A , Wetmore Kelly M , Good Benjamin H , Arkin Adam P , Hallatschek Oskar
Published: February 2022

The fitness effects of all possible mutations available to an organism largely shapes the dynamics of evolutionary adaptation. Tremendous progress has been made in quantifying the strength and abundance of selected mutations available to single microbial species in simple environments, lacking strong ecological interactions. However, the adaptive potential of strains that are part of multi-strain communities remains largely unclear. We sought to fill this gap by analyzing a stable community of two closely related ecotypes (“L” and “S”) shortly after they emerged within theE. coliLong-Term Evolution Experiment (LTEE). We engineered genome-wide barcoded transposon libraries to measure the fitness effects of all possible gene knockouts in the coexisting strains as well as their ancestor, for many different, ecologically relevant conditions. We found that the fitness effects of many gene knockouts sensitively depends on the genetic background and the ecological conditions, as set by the abiotic environment and relative frequency of both ecotypes. Despite the idiosyncratic behavior of individual knockouts, we still see consistent statistical patterns of fitness effect variation across both genetic background and community composition. Genes that are in the same operon, or that strongly interact with each other, are more likely to be correlated with each other across backgrounds compared to random pairs of genes. Additionally, fitness effects are correlated with evolutionary outcomes for a number of conditions, possibly revealing shifting patterns of adaptation. Together, our results reveal how ecological and epistatic effects combine to drive adaptive potential in a nascent ecological community.
High-performance Flexible Microelectrode Array with PEDOT:PSS Coated 3D Micro-cones for Electromyographic Recording
Authors: Lu Jiaao , Zia Muneeb , Williams Matthew J. , Jacob Amanda L. , Chung Bryce , Sober Samuel J. , Bakir Muhannad S.
Published: February 2022

High signal-to-noise ratio (SNR) electromyography (EMG) recordings are essential for identifying and analyzing single motor unit activity. While high-density electrodes allow for greater spatial resolution, the smaller electrode area translates to a higher impedance and lower SNR. In this study, we developed an implantable and flexible 3D microelectrode array (MEA) with low impedance that enables high-quality EMG recording. With polyimide micro-cones realized by standard photolithography process and PEDOT:PSS coating, this design can increase effective surface area by up to 250% and significantly improve electrical performance for electrode sites with various geometric surface areas, where the electrode impedance is at most improved by 99.3%. Acute EMG activity from mice was recorded by implanting the electrodes in vivo, and we were able to detect multiple individual motor units simultaneously and with high resolution (SNR ≫ 100). The charge storage capacity was measured to be 34.2 mC/cm2, indicating suitability of the electrodes for stimulation applications as well.
A heterogeneous drug tolerant persister state in BRAF-mutant melanoma is characterized by ion channel dysregulation and susceptibility to ferroptosis
Authors: Hayford Corey E. , Stauffer Philip E. , Baleami Blake , Paudel B. Bishal , Tyson Darren R. , Al’Khafaji Aziz , Johnson Kaitlyn E. , Harris Leonard A. , Brock Amy , Quaranta Vito
Published: February 2022

There is increasing interest in cancer cell subpopulations that can withstanding treatment via non-genetic mechanisms, such as tumor cell plasticity and adaptation. These cell populations may be comprised of cells with diverse phenotypes, e.g., quiescent or slow cycling. Such populations have been broadly termed “drug-tolerant persisters” (DTPs) and may be responsible for minimal residual disease following anticancer treatment and acquired resistance. Understanding molecular mechanisms that drive emergence of DTPs could lead to new strategies to improve therapeutic outcomes. Recently, we reported that BRAF-mutant melanoma cells under prolonged BRAF inhibition enter a DTP state with balanced cell death and division, which we termed “idling.” Here, we apply single cell barcoding to show that idling DTP populations emerge via cell state transitions, rather than selection of a few pre-existing drug-tolerant clones. Within the time frame of our experiments, DTPs exhibit varying proportions of fast- and slow-cycling cells within each lineage, suggesting that entry into the DTP state is a stochastic process. Furthermore, single-cell transcriptomics and bulk epigenomics reveal common gene expression and ontology signatures in DTP lineages that are consistent with rebalancing of ion channels. Calcium flux experiments uncover a reduction of divalent cation reserves in intracellular organelles, likely leading to endoplasmic reticulum stress. Accordingly, idling DTPs are more prone to ferroptotic cell death, as indicated by increased sensitivity to inhibition of glutathione peroxidase 4 (GPX4), which prevents removal of toxic lipid peroxides. In summary, we propose that ion channel homeostasis is a central process underlying idling DTP emergence in BRAF-mutated melanoma. Future studies will investigate translational aspects of this insight.
Laboratory and field trials reveal the potential of a gel formulation of entomopathogenic nematodes as biocontrol against the fall armyworm (Spodoptera frugiperda)
Authors: Fallet Patrick , Bazagwira Didace , Guenat Julie , Bustos-Segura Carlos , Karangwa Patrick , Mukundwa Ishimwe Primitive , Kajuga Joelle , Degen Thomas , Toepfer Stefan , Turlings Ted C.J.
Published: February 2022

1.

The fall armyworm (FAW), Spodoptera frugiperda (Lepidoptera: Noctuidae) can cause tremendous yield losses in maize. Its invasion into Africa and Asia has led to an enormous influx of insecticides into maize agro-ecosystems. Safe, effective and readily available alternatives are desperately needed. Entomopathogenic nematodes (EPN) are commonly used against soil insect pests, but can also control some above-ground pests. We explored the possibility to control FAW by incorporating EPN into a formulation that can be easily applied into the whorl of maize plants, where the caterpillars mostly feed. We tested this approach in laboratory cage experiments as well as in field trials. In the laboratory, treating maize plants with a low dose of EPN in a carboxymethyl cellulose (CMC) gel formulation (about 3000 infective juveniles per plant), caused 100% mortality of FAW caterpillars and prevented plant damage considerably, whereas EPN applied in water or a surfactant-polymer-formulation (SPF) caused 72% and 94% mortality, respectively. Under field conditions, one-time treatments with EPN applied in water, SPF or CMC gel were all able to prevent significant plant damage, but only the EPN-gel formulation significantly reduced FAW infestation. Notably, the gel formulation was as effective as a standard dose of cypermethrin, an insecticide commonly used against FAW. Repeated applications may be needed to reduce re-infestations by FAW across a whole cropping season depending on the local maize phenology and pest dynamics. These findings demonstrate that EPN are excellent candidates for the biological control of FAW and are a safe and sustainable alternative to chemical insecticides.

Highlights

Entomopathogenic nematodes are highly lethal to fall armyworm caterpillars.

Appropriate formulation of the nematodes is crucial for above-ground application.

A gel formulation of entomopathogenic nematodes was as effective as chemical insecticides.

Entomopathogenic nematodes can be used for the control of fall armyworm in maize.
The GLasses Against transmission of SARS-CoV-2 in the communitY (GLASSY) trial: A pragmatic randomized trial (study protocol)
Authors: Fretheim Atle , Hemkens Lars G. , Helleve Arnfinn , Elgersma Ingeborg Hess , Elstrøm Petter , Kacelnik Oliver
Published: February 2022

Background

A systematic review of observational studies indicated that eye protection may be an effective measure to prevent SARS-CoV-2 infections. Randomized trials are needed to assess whether the observed associations are caused by protection of the eye or confounding factors such as other systematic differences between users and non-users of eye protection, co-interventions, or changes in COVID-19 incidence when comparisons were done over time.

Methods

Pragmatic, virtual, parallel group, 1:1 randomized, superiority trial. We will recruit and randomize participants via an online portal. The trial will be fully remote and virtual without any personal interaction between investigators and participants. All members of the public are eligible who confirm that they are at least 18 years of age, do not regularly wear glasses, have not contracted COVID-19 since December 15th 2021, and are willing to be randomized to wear, or not wear glasses in public when close to other people, for a 2-week period. Persons who are dependent on visual aids but typically use contact lenses are eligible. The participants will be randomized (1:1) to wear glasses (sunglasses or other types of glasses) in public spaces when close to others (public transport, shopping centers etc.), or to the control group. The control group will be asked not to wear glasses in public spaces when close to others. The primary outcome is positive test for COVID-19. We aim to include about 25,000 participants to have a statistical power of 80% to detect a relative risk reduction of 25% for the primary outcome.

Discussion

Many have easy access to sunglasses or other glasses. Wearing glasses may provide eye protection and repurposing sunglasses for infection control could be a simple, readily available, environmentally friendly, safe, and sustainable infection prevention measure.

Trial registration

NCT05217797 (Clinicaltrials.gov)
Estimating the incidence and key risk factors of cardiovascular disease in patients at high risk of imminent fracture using routinely collected real-world data from the UK
Authors: Pineda-Moncusí Marta , El-Hussein Leena , Delmestri Antonella , Cooper Cyrus , Alireza Moayyeri , Libanati Cesar , Toth Emese , Prieto-Alhambra Daniel , Khalid Sara
Published: February 2022

The objective of this work was to estimate the incidence rate of cardiovascular disease (CVD) events (myocardial infarction, stroke or CVD-death) at 1 year among 3 cohorts of patients at high risk of fracture (osteoporosis; previous fracture; and anti-osteoporosis medication), and to identify the key risk factors of CVD events in these three cohorts. To do so, this prospective cohort study used data from the Clinical Practice Research Datalink, a primary care database from United Kingdom. MACE events (a composite outcome for the occurrence of either myocardial infarction (MI), stroke or CVD death) were identified in patients aged fifty or over at high or imminent fracture risk identified in three different cohorts (not mutually exclusive): recently diagnosed with osteoporosis (OST, n=65,295), incident fragility fracture (IFX, n=80,587), and starting oral bisphosphonates (OBP, n=145,959). MACE incidence rates (cases/1000 person-years) were: 19.63 (18.54;20.73) in OST, 51.09 (49.39;52.80) in IFX, and 26.26 (25.41;27.12) in OBP cohorts. Candidate risk factors from QRISK tool, and candidates from literature selected by lasso regression, were fitted into prediction models to estimate 1-year risk of MACE for each cohort. OST and OBP models had a discrimination of ≥ 70% and IFX cohort ≥ 60%. Calibration plots showed good internal validity of the models. Generally, models from lasso regression were better than QRISK. Main risk factors common in all MACE models were sex, alcohol, atrial fibrillation, anti-hypertensive medication, age, prior MI/stroke, established CVD, glomerular filtration rate, systolic blood pressure, and number of GP visits and concomitant medicines. Incidence of MACE in the studied populations was 4.35% or lower, with IFX as the cohort with the higher risk. Identified key risk factors highlight the differences of patients at high risk of fracture versus general population. Proposed models could improve prediction of CVD events in patients with osteoporosis in primary care settings.
Effects of socio-economic factors on elementary school student COVID-19 infections in Ontario, Canada
Authors: Srivastava Prachi , Lau Tsz Tan , Ansari Daniel , Thampi Nisha
Published: February 2022

Background

The prevalence of SARS-CoV-2 infections in Ontario is disproportionately concentrated in areas with lower-income and racialized groups. We examined whether school-level and area-level socio-economic factors were associated with elementary school student infections in Ontario.

Methods

We performed multi-level modeling analyses using data from the Ministry of Education on school-based infections in Ontario in the 2020-21 school year and on school-level demographics, the Ontario Marginalization Index, and census data to estimate the variability of the cumulative incidence of SARS-CoV-2 infections amongst elementary school students attributable to individual schools (school level, Level 1) and forward sortation areas (FSAs) of schools (area level, Level 2). We explored whether socio-economic factors within individual schools and/or factors common to schools within FSAs predicted the incidence of elementary school student infections.

Results

At the school level, the proportion of students from low-income households within a school was positively related with the cumulative incidence of SARS-CoV-2 elementary school student infections (β = .083, p < 0.001). At the area level, the dimensions of FSA marginalization were significantly related with cumulative incidence. Ethnic concentration (β = .454, p < 0.001), residential instability (β = .356, p < 0.001), and material deprivation (β = .212, p < 0.001) were positively related. Area-related variables were more likely to explain variance in cumulative incidence than school-related variables (58% versus 1%, respectively).

Interpretation

Socio-economic characteristics of the geographic location of schools were more important in determining the cumulative incidence of SARS-CoV-2 elementary school student infections than individual school characteristics. Given inequitable effects of protracted education disruption, schools in marginalized areas should be prioritized for infection prevention measures and education continuity and recovery plans.
Nociception-dependent CCL21 induce dorsal root ganglia axonal growth via CCR7-ERK activation
Authors: Mesquida-Veny Francina , Martinez-Torres Sara , Del Rio Jose Antonio , Hervera Arnau
Published: February 2022

While chemokines were originally described for their ability to induce cell migration, many studies show how chemokines also take part in a variety of other cell functions, acting as adaptable messengers in the communication between a diversity of cell types. In the nervous system, chemokines participate both in physiological and pathological processes, and while their expression is often described on glial and immune cells, growing evidence describe the expression of chemokines and their receptors in neurons, highlighting, their potential in auto- and paracrine signalling. In this study we analysed the role of nociception in the neuronal chemokinome, and their role in axonal growth. We found that stimulating TRPV1+ nociceptors induces a transient increase in CCL21. Interestingly we found that, this CCL21 increases neurite growth of large diameter proprioceptors in vitro. Consistent with this, we show that proprioceptors express the CCL21 receptor CCR7, and a CCR7 neutralizing antibody dose-dependently attenuates CCL21-induced neurite outgrowth. Mechanistically, we found that CCL21 binds locally to its receptor CCR7 at the growth cone, activating the downstream MEK-ERK pathway, that in turn activates N-WASP, triggering actin filament ramification in the growth cone, resulting in increased axonal growth.
Single-value scores of memory-related brain activity reflect dissociable neuropsychological and anatomical signatures of neurocognitive aging
Authors: Richter Anni , Soch Joram , Kizilirmak Jasmin M. , Fischer Larissa , Schütze Hartmut , Assmann Anne , Behnisch Gusalija , Feldhoff Hannah , Knopf Lea , Raschick Matthias , Schult Annika , Seidenbecher Constanze I. , Yakupov Renat , Düzel Emrah , Schott Björn H.
Published: February 2022

Memory-related functional magnetic resonance imaging (fMRI) activations show age-related differences across multiple brain regions that can be captured in summary statistics like single-value scores. Recently, we described two single-value scores reflecting deviations from prototypical whole-brain fMRI activity of young adults during novelty processing and successful encoding. Here, we investigate the brain-behavior associations of these scores with age-related neurocognitive changes in 153 healthy older adults. All scores were associated with episodic recall performance. The memory network scores, but not the novelty network scores, additionally correlated with medial temporal gray matter and a composite measure comprising pro-active inhibition, episodic memory, tonic alertness, flexibility, and working memory. Our results thus suggest that novelty-network-based fMRI scores show high brain-behavior associations with episodic memory and that encoding-network-based fMRI scores additionally capture individual differences in global cognitive function. More generally, our results suggest that single-value scores of memory-related fMRI provide a comprehensive measure of individual differences in network dysfunction that may contribute to age-related cognitive decline.
Selective influence of dopamine on electrocortical signatures of error monitoring: a combined EEG and immersive virtual reality study in Parkinson’s disease
Authors: Pezzetta R. , Ozkan D.G. , Era V. , Tieri G. , Zabberoni S. , Taglieri S. , Costa A. , Peppe A. , Caltagirone C. , Aglioti S.M.
Published: February 2022

Detecting errors in one’s own and other’s actions is likely linked to the discrepancy between intended or expected and produced or observed output. To detect and process the occurrence of salient events seems associated to the release of dopamine, the balance of which is profoundly altered in Parkinson’s disease (PD). EEG studies in healthy participants indicate that the occurrence of errors in observed actions triggers a variety of electrocortical indices (like mid-frontal theta activity, error-related delta and the Error Positivity, oPe), that seem to map different aspects of error detection and performance monitoring. Whether these indices are differently modulated by dopamine in the same individual has never been investigated. To explore this issue, we recorded EEG markers of error detection by asking healthy controls (HCs) and PD patients to observe ecological reach-to-grasp a glass actions performed by a virtual arm seen in first person perspective. PD patients were tested under their dopaminergic medication (‘on-condition’), and after dopaminergic withdrawal (‘off-condition’). HCs showed a clear oPe and an increase of delta and theta power during the observation of erroneous vs. correct actions. In PD patients, oPe and delta responses were always preserved. Crucially, however, an error-related increase of theta power was found in ‘on’ but not in ‘off’ state PD patients. Thus, different EEG error signatures may index the activity of independent systems and error related theta power is selectively modulated by dopamine depletion. Our findings may pave the way to the discovery of dopamine-related biomarkers of higher-order motor cognition dysfunctions that may have crucial theoretical and clinical implications.

Significance Statement

Dopaminergic neurons respond to salient events during performance monitoring. Yet, the impact of dopamine depletion on the human reactivity to observed errors is still unclear. We recorded EEG in patients with Parkinson’s Disease (PD) under dopaminergic treatment (‘on-condition’) and medication withdrawal (‘off-condition’) while they observed correct and erroneous goal-related actions performed by a virtual limb. Analysis of Error Positivity (oPe) and theta and delta power increase, markers of physiological error-monitoring, indicates that while the formers were intact, the latter was preserved in the ‘on’ and altered in the ‘off’ condition. Thus, different EEG markers of error monitoring likely rely on independent circuits. Moreover, mid-frontal theta activity alterations may represent a marker of dopamine-related neurophysiological impairments of higher-order cognition.
Genesis of bursting activity: Role of inhibitory constraints on persistent Na+ currents
Authors: Neveu Curtis L. , Baxter Douglas A. , Byrne John H.
Published: February 2022

Some neurons express a plateau of spike activity greatly outlasting a stimulus, whereas others do not. This difference could be due to differential expression of ion channels (e.g., persistent Na+, and Ca2+) or similar expression of channels that differ in their properties. We compared three Aplysia neurons with varying capacity to generate plateau potentials: B51 with self-terminating plateaus, B64 with plateau potentials that do not self-terminate, and the regular spiking neuron B8. Our results indicate the three neurons expressed outward currents IA and ID, voltage-gated Ca2+ currents ICaL and ICaR, and persistent inward INaP. The most notable difference observed was a larger IA, ID, and IKCa currents in B8, and the plateau generating B64 did not express IKCa. Computational models suggest outward currents suppress and temporally constrain the plateau potential and that inward Ca2+ currents suppress plateau potentials when coupled with IKCa.
Chlamydomonas RABL4/IFT27 Mediates Phototaxis via Promoting BBSome-dependent Ciliary Export of Phospholipase D
Authors: Liu Yan-Xia , Xue Bin , Fan Zhen-Chuan
Published: February 2022

Phospholipase D (PLD) interacts with the BBSome for loading onto retrograde intraflagellar transport (IFT) trains to exit cilia in Chlamydomonas reinhardtii. PLD ciliary retention and depletion of Rab-like 4 (RABL4) GTPase IFT27 cause the same non-phototactic phenotype but not impair IFT and ciliation. Here, we show that the IFT-B1 subunit IFT27 binds its partner IFT25 to form the heterodimeric IFT25/27 in an IFT27 nucleotide state-independent manner. IFT25/27, IFT-A, and IFT-B are irrelevant for maintaining the stability of one another. GTP-loading onto IFT27 enhances the IFT25/27 affinity for IFT-B1 in cytoplasm, while GDP-loaded IFT27 does not prevent IFT25/27 from entering and cycling through cilia by integrating into IFT-B1. Upon at the ciliary tip, IFT25/27 cycles on and off IFT-B1 and this process is irrelevant with the nucleotide state of IFT27. During BBSome remodeling at the ciliary tip, IFT25/27 promotes BBSome reassembly independent of IFT27 nucleotide state, making post-remodeled BBSomes available for PLD to interact with. Therefore, IFT25/27 facilitates BBSome-dependent PLD export from cilia via controlling availability of intact BBSomes at the ciliary tip, providing a regulatory mechanism for IFT27 to mediate phototaxis in C. reinhardtii.
Perception of RNA Nanotechnology among students and recommendations towards improved educational outreach
Authors: Kozlov Seraphim
Published: February 2022

Translating new technologies to industrial and biomedical applications requires a highly skilled workforce. In the past, colleges and graduate schools played a primary role in preparing students for various areas of industry and medicine. The learning process and introduction of new concepts have recently extended beyond college education. High schools saw the rise of specialized career programs, while both high and middle school curricula got infused with challenging concepts. Nucleic acids, such as DNA and RNA, are broadly known for their role in the foundation of life. However, nucleic acid nanotechnology, an area of material science manipulating DNA and RNA to create complex structures with controlled properties, is less known. Herein, I report the results of a study investigating the perception of RNA nanotechnology among school students and suggest educational resources to improve understanding of RNA nanotechnology.
Improving breast cancer diagnostics with artificial intelligence for MRI
Authors: Witowski Jan , Heacock Laura , Reig Beatriu , Kang Stella K. , Lewin Alana , Pyrasenko Kristine , Patel Shalin , Samreen Naziya , Rudnicki Wojciech , Łuczyńska Elżbieta , Popiela Tadeusz , Moy Linda , Geras Krzysztof J.
Published: February 2022

Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) has a very high sensitivity in detecting breast cancer, but it often leads to unnecessary biopsies and patient workup. In this paper, we used an artificial intelligence (AI) system to improve the overall accuracy of breast cancer diagnosis and personalize management of patients undergoing DCE-MRI. On the internal test set (N=3,936 exams), our system achieved an area under the receiver operating characteristic curve (AUROC) of 0.92 (95% CI: 0.92-0.93). In a retrospective reader study, there was no statistically significant difference between 5 board-certified breast radiologists and the AI system (mean ΔAUROC +0.04 in favor of the AI system). Radiologists’ performance improved when their predictions were averaged with AI’s predictions (mean ΔAUPRC [area under the precision-recall curve] +0.07). Those hybrid predictions also increase interreader agreement (Fleiss’ kappa Δ +0.21 (0.16-0.26)). We demonstrated the generalizability of the AI system using multiple data sets from Poland and the US. In subgroup analysis, we observed consistent results across different cancer subtypes and patient demographics. Using the decision curve analysis, we showed that the AI system can reduce unnecessary biopsies in the range of clinically relevant risk thresholds. This would lead to avoiding benign biopsies in up to 20% of all BI-RADS category 4 patients. Finally, we performed an error analysis, investigating situations where AI predictions were mostly incorrect. This exploratory work creates a foundation for deployment and prospective analysis of AI-based models for breast MRI.

One Sentence Summary

We developed and evaluated an AI system for predicting breast cancer in MRI that matches the performance of board-certified radiologists and has the potential to prevent unnecessary biopsies.
Post-acute sequelae of COVID-19 and adverse psychiatric outcomes: an etiology and risk systematic review protocol
Authors: Effiong Andem
Published: February 2022

Introduction

The post-acute sequelae of COVID-19 (PASC) is a syndrome characterized by persistent COVID-19 symptoms or the onset of new symptoms following recovery from the initial or acute phase of the illness. Such symptoms often occur four or more weeks after being diagnosed with COVID-19. Although a lot of work has gone into understanding the long-term mental health effects of PASC, many questions related to the etiology and risk of this condition remain. Thus, this protocol is for a systematic review assessing the association between PASC and adverse psychiatric outcomes and whether people with PASC are at greater risk of developing an adverse psychiatric outcome than those without PASC.

Methods and analysis

Various medical databases (e.g., PubMed and EMBASE) will be searched for eligible articles using predefined search criteria. Gray literature will also be explored. Epidemiological observational studies and secondary analyses of randomized controlled trials that report a quantitative relationship between PASC and at least one adverse psychiatric outcome will be included. The Population, Exposure of interest, Comparator, and Outcome (PECO) framework will be used as a standardized framework for the inclusion criteria. The Joanna Briggs Institute (JBI) critical appraisal tools will be used to assess methodological quality and critically appraise the risk of bias in included studies. A random-effects meta-analysis will be conducted if possible. A formal narrative synthesis will be performed if a meta-analysis is impossible due to substantial heterogeneity across studies. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach will be used to rate the cumulative certainty of the evidence for all outcomes.

Ethics and Dissemination

Ethical approval is not required for this study. The study results will be published in a peer-reviewed journal.

Prospero registration number

CRD42022308737

Strengths and limitations of this study

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This study documents and addresses etiology, risk factors, and long-term symptoms of COVID-19 among people with post-acute sequelae of COVID-19 (PASC).

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It focuses on a key priority area for new evidence syntheses on the clinical management of COVID-19 and pandemic-related conditions.

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It will include evidence on non-hospitalized and hospitalized patients with a history of PASC.

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Substantial heterogeneity across studies may limit the ability to perform a meta-analysis.

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Findings will inform disease prevention, decision-making, healthcare policy, and clinical research.
A novel pathway phenotype of temporal lobe epilepsy and comorbid psychiatric disorders: results of precision nomothetic medicine
Authors: Maes Michael , Barbosa Décio Sabbatini , Kanchanatawan Buranee
Published: February 2022

No precision medicine models of temporal lobe epilepsy (TLE) and associated mental comorbidities were developed to date. This observational 11study aimed to develop a precision nomothetic, data driven comorbid TLE model with endophenotype classes and pathways phenotypes that may have prognostic and therapeutical implications. We recruited forty healthy controls and 108 TLE patients for this research and assessed TLE and psychopathology (PP) features as well as oxidative stress (OSTOX, e.g., malondialdehyde or MDA, lipid hydroperoxides, and advanced oxidation protein products) and antioxidant (paraoxonase 1 or PON1 status, -SH groups, and total radical trapping potential or TRAP) biomarkers. A large part (57.2%) of the variance in a latent vector (LV) extracted from the above TLE and PP features was explained by these OSTOX and antioxidant biomarkers. The PON1 Q192R genetic variant showed indirect effects on this LV which were completely mediated by PON1 activity and MDA. Factor analysis showed that a common core could be extracted from TLE, PP, OSTOX and antioxidant scores, indicating that these features are manifestations of a common underlying construct, i.e., a novel pathway phenotype of TLE. Based on the latter we constructed a new phenotype class that is characterized by increased severity of TLE, PP and OSTOX features and lowered antioxidant defenses. A large part of the variance in episode frequency was explained by increased MDA, lowered antioxidant, and nitric oxide metabolite levels. In conclusion a) PP symptoms belong to the TLE phenome and signal increased severity; and b) cumulative effects of aldehyde formation and lowered antioxidants determine epileptogenic kindling.