bluuebunny/crossref_metadata_2025 huggingface dataset:
Breast density in dedicated breast computed tomography
Authors: Wieler Jann , Berger Nicole , Frauenfelder Thomas , Marcon Magda , Boss Andreas
Published: May 2021

The aim of this study was to develop a new breast density classification system for dedicated breast computed tomography (BCT) based on lesion detectability analogous to the ACR BI-RADS breast density scale for mammography, and to evaluate its interrater reliability.

In this retrospective study, 1454 BCT examinations without contrast media were screened for suitability. Excluding datasets without additional ultrasound and exams without any detected lesions resulted in 114 BCT examinations. Based on lesion detectability, an atlas-based BCT density (BCTD) classification system of breast parenchyma was defined using 4 categories. Interrater reliability was examined in 40 BCT datasets between 3 experienced radiologists.

Among the included lesions were 63 cysts (55%), 18 fibroadenomas (16%), 7 lesions of fatty necrosis (6%), and 6 breast cancers (5%) with a median diameter of 11 mm. X-ray absorption was identical between lesions and breast tissue; therefore, the lack of fatty septae was identified as the most important criteria for the presence of lesions in glandular tissue. Applying a lesion diameter of 10 mm as desired cut-off for the recommendation of an additional ultrasound, an atlas of 4 BCTD categories was defined resulting in a distribution of 17.5% for density A, 39.5% (B), 31.6% (C), and 11.4% (D) with an intraclass correlation coefficient (ICC) among 3 readers of 0.85 to 0.87.

We propose a dedicated atlas-based BCTD classification system, which is calibrated to lesion detectability. The new classification system exhibits a high interrater reliability and may be used for the decision whether additional ultrasound is recommended.
Acute myeloid leukaemia presenting with ecthyma gangrenosum as the first manifestation
Authors: Hadano Yoshiro , Yoshida-Sakai Nao , Imamura Yutaka , Inoue Tomohiro , Koga Hitoshi
Published: May 2021

Rationale

Ecthyma gangrenosum (EG) is an uncommon cutaneous infection usually associated with Pseudomonas aeruginosa bacteremia in immunocompromised patients, particularly those with underlying malignant diseases. Despite its rarity, especially in immunocompetent or nondiagnosed immunodeficiency patients, EG can present as the first manifestation of an underlying immunosuppression.

Patient concerns

A 42-year-old Japanese man was admitted to our hospital with a 3-day history of a painless red macule on his right forearm and fever.

Diagnoses

Blood culture on admission revealed the presence of Pseudomonas aeruginosa, whereas pus culture of the skin lesion showed Pseudomonas aeruginosa and methicillin-susceptible Staphylococcus aureus positivity.

Interventions

Additional bone marrow aspirate examination and immunophenotyping were performed to confirm the diagnosis of acute promyelocytic leukaemia with PML-retinoic acid alpha receptor.

Outcomes

The patient was successfully treated with a 14-day course of antibiotics, and no evidence of relapse was noted. The patient achieved complete remission after treatment for acute promyelocytic leukaemia.

Lessons

It should be kept in mind that EG is an important cutaneous infection that is typically associated with P aeruginosa bacteremia and the presence of underlying immunodeficiency, such as acute leukaemia.
Continued Dangers From Bed Pole Mobility Devices
Authors: Byard Roger W. , Ritchey Donald
Published: May 2021

Bed poles are held in place by a frame that is inserted underneath a bed mattress and are designed to assist in moving an incumbent from a lying to an upright sitting position, or to help with turning, repositioning, or transferring. Two cases demonstrate, however, that lethal entrapment may be caused by such devices—a 76-year-old man and an 84-year-old woman were both found beside their beds hanging by their necks from bed poles. Gaps between bed poles and mattress/bed sides may provide potentially lethal confined spaces. Individuals at particular risk of such an event are elderly with limited strength and/or obesity with an incomplete awareness of environmental dangers and have a history of mobility issues and/or falls. Any railing used to assist with movement to and from, or within, a bed must sit flush with the bed/mattress side to minimize any chances of entrapment.
Self-Poisoning With Safer Insecticide
Authors: Naveen A. , Sahu Manas Ranjan , Padhi Kimi Soumya , Maharik Sasank Shekhar
Published: May 2021

Imidacloprid (IMI) is a systemic insecticide that belongs to the neonicotinoid group of insecticides. It is highly effective against sucking, boring, and root-feeding insects. Besides, it has a favorable toxicological profile on humans. Currently, IMI is the largest selling insecticide in the world by replacing organophosphates and carbamates. It acts as nicotinic acetylcholine receptor agonist in the central nervous system of insects. To date, there is no specific antidote available for IMI poisoning. Despite a better safety profile on humans, severe toxicity from IMI poisoning is not uncommon. Here, we report a series of 4 cases who were admitted to our tertiary care center with a history of IMI poisoning.
Multisite Veno-Venous Cannulation for Neonates and Nonambulatory Children*
Authors: Lillie Jon , Pienaar Alison , Budd Jenny , Speggiorin Simone , Gordon Anne , James Paul , Perkins Jo , Griffiths Benedict , Fine-Goulden Miriam , Austin Conal , Salih Caner , Agnew Nicola , Nyman Andrew G.
Published: May 2021

OBJECTIVES:

Neonates with respiratory failure are ideally supported with veno-venous rather than veno-arterial extracorporeal membrane oxygenation due to the reduced rate of neurologic complications. However, the proportion of neonates supported with veno-venous extracorporeal membrane oxygenation is declining. We report multisite veno-venous extracorporeal membrane oxygenation, accessing the neck, returning to the inferior vena cava via the common femoral vein in neonates and children less than 10 kg.

DESIGN:

Retrospective case series with 1 year minimum follow-up.

PATIENTS:

Patients less than 10 kg supported with veno-venous extracorporeal membrane oxygenation accessing the jugular and returning to the femoral vein

SETTING:

A 30-bed pediatric intensive care delivering extracorporeal membrane oxygenation to approximately 20 children annually.

INTERVENTIONS:

Veno-venous extracorporeal membrane oxygenation accessing the jugular and returning to the femoral vein was delivered using two single lumen cannulae.

MEASUREMENTS AND MAIN RESULTS:

January 2015 to August 2019, 11 patients underwent veno-venous extracorporeal membrane oxygenation accessing the jugular and returning to the femoral vein with median weight of 3.6 kg (interquartile range 2.8–6.1 kg), and median corrected gestational age of 13 days (interquartile range, 2–175 d). The smallest patient weighed 2.1 kg. Seven patients had comorbidities. Extracorporeal membrane oxygenation was technically successful in all patients with median flows of 126 mL/kg/min (interquartile range, 120–138 mL/kg/min) and median arterial oxygenation saturation of 94% (interquartile range, 91–98%) at 24 hours. Nine survived to home discharge, and two were palliated. Common femoral vein occlusion was observed in all patients on ultrasound post decannulation. There was no clinical or functional deficit in the cannulated limb at follow-up, a minimum of 1 year post extracorporeal membrane oxygenation.

CONCLUSIONS:

Veno-venous extracorporeal membrane oxygenation accessing the jugular and returning to the femoral vein was performed safely in patients under 10 kg with the smallest patient weighing 2.1 kg. Although occlusion of the common femoral vein was observed in patients post decannulation, subsequent follow-up demonstrated no clinical implications. We challenge current practice that veno-venous extracorporeal membrane oxygenation accessing the jugular and returning to the femoral vein cannot be performed in nonambulatory patients and suggest that this strategy is preferred over veno-arterial extracorporeal membrane oxygenation in infants requiring extracorporeal membrane oxygenation for respiratory failure.
Thromboembolic Complications of Vascular Catheters Used for Pediatric Continuous Renal Replacement Therapy: Prevalence in a Single-Center, Retrospective Cohort*
Authors: Szeps Isabelle , Östlund Åsa , Norberg Åke , Fläring Urban , Andersson Andreas
Published: May 2021

OBJECTIVES:

Pediatric venous thromboembolic events are commonly associated with in situ central venous catheters. The risk for severe venous thromboembolism increases if a larger portion of the vessel lumen is occupied by the central venous catheter. A functioning vascular catheter is required when the continuous renal replacement therapy is used in critically ill children. Due to the high blood flow required for continuous renal replacement therapy, the external diameter of the catheter needs to be larger than a conventional central venous catheter used for venous access, potentially increasing the risk of venous thromboembolism. However, children on continuous renal replacement therapy often receive systemic anticoagulation to prevent filter clotting, possibly also preventing venous thromboembolism. The frequency of catheter-related venous thromboembolic events in this setting has not been described. Our main objective was to determine the prevalence of catheter-related venous thromboembolism in pediatric continuous renal replacement therapy.

DESIGN:

Retrospective cohort study.

SETTING:

Tertiary multidisciplinary academic pediatric hospital.

PATIENTS:

Patients 0–18 years old with a vascular catheter used for continuous renal replacement therapy.

INTERVENTIONS:

None.

MEASUREMENTS AND MAIN RESULTS:

In our series of 80 patients, we used 105 vascular catheters. The median age of the patients was 10 months and PICU mortality rate was 21%. Venous thromboembolic events were considered to be catheter related if located in the same vein as the vascular catheter and radiologically verified. Six (5.7%) catheter-related venous thromboembolic events were found. The clinically relevant complications of venous thromboembolism included superior vena cava syndrome and catheter dysfunction. In one patient, severe and life-threatening pulmonary embolism occurred. In comparison with patients without venous thromboembolism, venous thromboembolic events were associated with lower body weight (p = 0.03) and longer durations of continuous renal replacement therapy (p < 0.01), mechanical ventilation (p = 0.03), and PICU stay (p < 0.01). Five out of six venous thromboembolisms appeared in neonates.

CONCLUSIONS:

Catheter-related venous thromboembolism is a clinically relevant complication of pediatric continuous renal replacement therapy, with a prevalence of 5.7% in our cohort. Clinicians involved in pediatric continuous renal replacement therapy need to be vigilant for symptoms of venous thromboembolisms and initiate appropriate treatment as soon as possible.
Increasing hemoglobin concentration with an artificial oxygen carrier improves severe anemia-induced degraded cognitive function
Authors: Weiskopf Richard B. , Davenport Robertson , Cap Andrew P. , Reddy Vineet , Waters Jonathan H. , Cserti-Gazdewich Christine
Published: May 2021

Before death, patients commonly experience impaired consciousness for a significant period, frequently preventing family and others from final interactions with the patient. Some of these episodes of cognitive impairment may be treatable, with treatment not offered owing to the perception of ultimate futility or expense, or both. One of the causes of terminal loss of consciousness or decreased lucidity can be inadequate cerebral oxygen delivery. We report five cases from four institutions where an infusion of a hemoglobin-based oxygen carrier to patients who were unconscious or not lucid owing to acute severe anemia (hemoglobin range, 2.1–5.2 g/dL) resulted in awakening or lucidity. We review briefly human cognitive function and anemia and remark about the use of a hemoglobin-based oxygen carrier for acute severe anemia when red cell transfusion is not an option.
Increased mortality with resuscitative endovascular balloon occlusion of the aorta only mitigated by strong unmeasured confounding: An expanded analysis using the National Trauma Data Bank
Authors: Linderman George C. , Lin Winston , Becher Robert D. , Maung Adrian A. , Bhattacharya Bishwajit , Davis Kimberly A. , Schuster Kevin M.
Published: May 2021

BACKGROUND

Resuscitative endovascular balloon occlusion of the aorta (REBOA) is being increasingly adopted to manage noncompressible torso hemorrhage, but a recent analysis of the 2015 to 2016 Trauma Quality Improvement Project (TQIP) data set showed that placement of REBOA was associated with higher rates of death, lower extremity amputation, and acute kidney injury (AKI). We expand this analysis by including the 2017 data set, quantifying the potential role of residual confounding, and distinguishing between traumatic and ischemic lower extremity amputation.

METHODS

This retrospective study used the 2015 to 2017 TQIP database and included patients older than 18 years, with signs of life on arrival, who had no aortic injury and were not transferred. Resuscitative endovascular balloon occlusions of the aorta placed after 2 hours were excluded. We adjusted for baseline variables using propensity scores with inverse probability of treatment weighting. A sensitivity analysis was then conducted to determine the strength of an unmeasured confounder (e.g., unmeasured shock severity/response to resuscitation) that could explain the effect on mortality. Finally, lower extremity injury patterns of patients undergoing REBOA were inspected to distinguish amputation indicated for traumatic injury from complications of REBOA placement.

RESULTS

Of 1,392,482 patients meeting the inclusion criteria, 187 underwent REBOA. After inverse probability of treatment weighting, all covariates were balanced. The risk difference for mortality was 0.21 (0.14–0.29) and for AKI was 0.041 (−0.007 to 0.089). For the mortality effect to be explained by an unmeasured confounder, it would need to be stronger than any observed in terms of its relationship with mortality and with REBOA placement. Eleven REBOA patients underwent lower extremity amputation; however, they all suffered severe traumatic injury to the lower extremity.

CONCLUSION

There is no evidence in the TQIP data set to suggest that REBOA causes amputation, and the evidence for its effect on AKI is considerably weaker than previously reported. The increased mortality effect of REBOA is confirmed and could only be nullified by a potent confounder.

LEVEL OF EVIDENCE

Therapeutic/care management, level IV.
The art and craft of biliary T-tube Use
Authors: Padmore Greg , Sutherland Francis R. , Ball Chad G.
Published: May 2021

INTRODUCTION

Since the universal adoption of Hans Kehr’s biliary T-tube in the early twentieth century, use has shifted from routine towards highly selective. Improved interventional endoscopy, percutaneous techniques, and hepato-pancreato-biliary (HPB) training have resulted in less T-tube experience within general surgery. The aim of this technical review is to discuss T-tube indications, technical nuances, and management.

METHODS

Peer-reviewed literature, combined with high volume HPB experience by the authors, was utilized to construct a 10-step conceptual pathway for safe T-tube usage.

RESULTS

Essential concepts surrounding T-tube use include: 1. Contemporary indications for T-tube insertion (disease-, patient-, and anatomy-based); 2. Correct instrument availability (open and laparoscopic); 3. T-tube selection and mechanical preparation; 4. Atraumatic T-tube insertion and security; 5. Immediate postoperative management and meticulous T-tube care; 6. Imaging biliary T-tubes; 7. Optimal timing of T-tube removal; 8. Technical aspects of T-tube removal; 9. Management of potential T-tube inpatient complications; and 10. Management of T-tube complications in the outpatient setting.

CONCLUSIONS

Although their use has decreased substantially, the role of biliary T-tubes in some patients is essential. Given the reality of less frequent experience with T-tube insertion and management, this 10-step pathway will provide an adequate mental and technical framework for safe biliary T-tube use.

LEVEL OF EVIDENCE

Expert opinion, level V.
Association between the initial serum phosphate level and 30-day mortality in blunt trauma patients
Authors: Kim Dong Won , Jung Woo Jin , Lee Dong Keon , Lee Kui Ja , Choi Hyo Ju
Published: May 2021

BACKGROUND

Studies on patients with cardiac arrest or sepsis have reported that high initial phosphate levels are associated with poor outcomes. However, no previous study has investigated the association between initial phosphate levels and outcomes in blunt trauma patients.

METHODS

This study was a retrospective observational study conducted on blunt trauma patients who had been treated at the single regional trauma center between January 2016 and December 2017. Patients’ demographic data, initial vital signs, trauma scores, and laboratory parameters including phosphate levels were collected from the trauma registry. The primary outcome was set to 30-day mortality. The secondary outcomes were the total volume of blood transfused, 30-day hospital-free days, and 30-day intensive care unit–free days.

RESULTS

Of the 1,907 included patients, 1,836 were in the survival group, and 71 were in the nonsurvival group. The nonsurvival group had a significantly higher phosphate level than the survival group. Patients in the hyperphosphatemia group had a higher 30-day mortality, fewer 30-day intensive care unit–free days, and higher transfusion volume than those in the other groups. In multivariable logistic regression analysis, hyperphosphatemia was independently associated with 30-day mortality. The receiver operating characteristic curve analysis showed that the area under the curve with the inclusion of phosphate in addition to Injury Severity Score, Revised Trauma Score, and age was 0.911. Area under the curve was also increased when phosphate was simply added to Injury Severity Score and Revised Trauma Score.

CONCLUSION

In blunt trauma patients, hyperphosphatemia was associated with an increased 30-day mortality.

LEVEL OF EVIDENCE

Prognostic, level III.
Genetic overlap between major depression, bipolar disorder and Alzheimer’s Disease
Authors: Dos Santos Fernanda C. , Mendes-Silva Ana Paula , Nikolova Yuliya S. , Sibille Etienne L. , Diniz Breno Satler
Published: May 2021

Background

Mood disorders, including major depression (MD) and bipolar disorder (BD), are risk factors for Alzheimer’s disease (AD) and possibly share an overlapping genetic architecture. However, few studies have investigated the shared loci and potential pleiotropy among these disorders.

Methods

We carried out a systematic analytical pipeline using GWAS data and three complementary (genome-wide, single variant, and gene-level) statistical approaches to investigate the genetic overlap among MD, BD, and AD.

Results

GWAS summary statistics data from 679,973 individuals were analyzed herein (59,851 MD cases and 113,154 controls; 20,352 BD cases and 31,358 controls; and 71,880 AD cases and 383,378 controls). We identified a significant positive genetic correlation between MD and AD (rG = 0.162; s.e. = 0.064; p = 0.012), and between BD and AD (rG = 0.162; s.e. = 0.068; p = 0.018). We also identified two pleiotropic candidate genes for MD and AD (TMEM106B and THSD7A) and three forBD and AD (MTSS2, VAC14, and FAF1), and reported candidate biological pathways associated with all three disorders.

Discussion

Our study identified genetic loci and mechanisms shared by mood disorders and AD. These findings could be relevant to better understand the higher risk for AD among individuals with mood disorders, and to propose new interventions.
A hemagglutination-based, semi-quantitative test for point-of-care determination of SARS-CoV-2 antibody levels
Authors: Kruse Robert L. , Huang Yuting , Lee Alyssa , Zhu Xianming , Shrestha Ruchee , Laeyendecker Oliver , Littlefield Kirsten , Pekosz Andy , Bloch Evan M. , Tobian Aaron A.R. , Wang Zack Z.
Published: May 2021

Serologic, point-of-care tests to detect antibodies against SARS-CoV-2 are an important tool in the COVID-19 pandemic. The majority of current point-of-care antibody tests developed for SARS-CoV-2 rely on lateral flow assays, but these do not offer quantitative information. To address this, we developed a new method of COVID-19 antibody testing employing hemagglutination tested on a dry card, similar to that which is already available for rapid typing of ABO blood groups. A fusion protein linking red blood cells (RBCs) to the receptor-binding domain (RBD) of SARS-CoV-2 spike protein was placed on the card. 200 COVID-19 patient and 200 control plasma samples were reconstituted with O-negative RBCs to form whole blood and added to the dried protein, followed by a stirring step and a tilting step, 3-minute incubation, and a second tilting step. The sensitivity for the hemagglutination test, Euroimmun IgG ELISA test and RBD-based CoronaChek lateral flow assay was 87.0%, 86.5%, and 84.5%, respectively, using samples obtained from recovered COVID-19 individuals. Testing pre-pandemic samples, the hemagglutination test had a specificity of 95.5%, compared to 97.3% and 98.9% for the ELISA and CoronaChek, respectively. A distribution of agglutination strengths was observed in COVID-19 convalescent plasma samples, with the highest agglutination score (4) exhibiting significantly higher neutralizing antibody titers than weak positives (2) (p<0.0001). Strong agglutinations were observed within 1 minute of testing, and this shorter assay time also increased specificity to 98.5%. In conclusion, we developed a novel rapid, point-of-care RBC agglutination test for the detection of SARS-CoV-2 antibodies that can yield semi-quantitative information on neutralizing antibody titer in patients. The five-minute test may find use in determination of serostatus prior to vaccination, post-vaccination surveillance and travel screening.
A polygenic score-based approach to identify gene-drug interactions stratifying breast cancer risk
Authors: Marderstein Andrew R. , Kulm Scott , Peng Cheng , Tamimi Rulla , Clark Andrew G. , Elemento Olivier
Published: May 2021

An individual’s genetics can dramatically influence breast cancer (BC) risk. While clinical measures for prevention do exist, non-invasive personalized measures for reducing BC risk are limited. Commonly-used medications are a promising set of modifiable factors, however no previous study has explored whether a range of widely-taken approved drugs modulate BC genetics. In this study, we describe a quantitative framework for exploring the interaction between the genetic susceptibility of BC and medication usage among UK Biobank women. We computed BC polygenic scores (PGS) that summarize BC genetic risk, and find that the PGS explains nearly three-times greater variation in disease risk within corticosteroid users compared to non-users. We map 35 genes significantly interacting with corticosteroid use (FDR < 0.1), highlighting the transcription factor NRF2 as a common regulator of gene-corticosteroid interactions in BC. Finally, we discover a novel regulatory variant strongly stratifying BC risk according to corticosteroid use. Within risk allele carriers, 18.2% of women taking corticosteroids developed BC, compared to 5.1% of the non-users (with a HR = 3.41 per-allele within corticosteroid users). Overall, this work highlights the clinical relevance of gene-drug interactions in disease risk, and provides a roadmap for repurposing biobanks in drug repositioning and precision medicine.
The impact of BNT162b2 mRNA vaccine on adaptive and innate immune responses
Authors: Föhse Konstantin , Geckin Büsra , Zoodsma Martijn , Kilic Gizem , Liu Zhaoli , Röring Rutger J. , Overheul Gijs J. , van de Maat Josephine S. , Bulut Ozlem , Hoogerwerf Jacobien J. , Oever Jaap ten , Simonetti Elles , Schaal Heiner , Adams Ortwin , Müller Lisa , Ostermann Philipp Niklas , van de Veerdonk Frank L. , Joosten Leo A.B. , Haagmans Bart L. , van Crevel Reinout , van Rij Ronald P. , GeurtsvanKessel Corine , de Jonge Marien I. , Li Yang , Domínguez-Andrés Jorge , Netea Mihai G.
Published: May 2021

The mRNA-based BNT162b2 protects against severe disease and mortality caused by SARS-CoV-2 through induction of specific antibody and T-cell responses. Much less is known about its broad effects on immune responses against other pathogens. In the present study, we investigated the specific adaptive immune responses induced by BNT162b2 vaccination against various SARS-CoV-2 variants, as well as its effects on the responsiveness of human immune cells upon stimulation with heterologous viral, bacterial, and fungal pathogens. BNT162b2 vaccination induced effective humoral and cellular immunity against SARS-CoV-2 that started to wane after six months. We also observed long-term transcriptional changes in immune cells after vaccination, as assessed by RNA sequencing. Additionally, vaccination with BNT162b2 modulated innate immune responses as measured by the production of inflammatory cytokines when stimulated with various microbial stimuli other than SARS-CoV-2, including higher IL-1/IL-6 release and decreased production of IFN-α. Altogether, these data expand our knowledge regarding the overall immunological effects of this new class of vaccines and underline the need of additional studies to elucidate their effects on both innate and adaptive immune responses.
Estimating vaccine efficacy against transmission via effect on viral load
Authors: Kennedy-Shaffer Lee , Kahn Rebecca , Lipsitch Marc
Published: May 2021

Determining policies to end the SARS-CoV-2 pandemic will require an understanding of the efficacy and effectiveness (hereafter, efficacy) of vaccines. Beyond the efficacy against severe disease and symptomatic and asymptomatic infection, understanding vaccine efficacy against transmission will help model epidemic trajectory and determine appropriate control measures. Recent studies have proposed using random virologic testing in individual randomized controlled trials to improve estimation of vaccine efficacy against infection. We propose to further use the viral load measures from these tests to estimate efficacy against transmission. This estimation requires a model of the relationship between viral load and transmissibility and assumptions about the vaccine effect on transmission and the progress of the epidemic. We describe these key assumptions, potential violations of them, and solutions that can be implemented to mitigate these violations. Assessing these assumptions and implementing this random sampling, with viral load measures, will enable better estimation of the crucial measure of vaccine efficacy against transmission.
Derivation and external validation of a simple risk score to predict in-hospital mortality in patients hospitalized for COVID-19
Authors: Mann Charlotte Z. , Abshire Chelsea , Yost Monica , Kaatz Scott , Swaminathan Lakshmi , Flanders Scott A. , Prescott Hallie C. , Gagnon-Bartsch Johann A.
Published: May 2021

Background

As SARS-CoV-2 continues to spread, and hospitals are treating a large number of patients with COVID-19, easy-to-use risk models that predict hospital mortality can assist in clinical decision making and triage.

Objective

As SARS-CoV-2 continues to spread, easy-to-use risk models that predict hospital mortality can assist in clinical decision making and triage. We aimed to develop a risk score model for in-hospital mortality in patients hospitalized with COVID-19 that was robust across hospitals and used clinical factors that are readily available and measured standardly across hospitals.

Methods

In this observational study we developed a risk score model using data collected by trained abstractors for patients in 20 diverse hospitals across the state of Michigan (Mi-COVID19) who were discharged between March 5, 2020 and August 14, 2020. Patients who tested positive for SARS-CoV-2 during hospitalization or were discharged with an ICD-10 code for COVID-19 (U07.1) were included. We employed an iterative forward selection approach to consider the inclusion of 145 potential risk factors available at hospital presentation. Model performance was externally validated with patients from 19 hospitals in the Mi-COVID19 registry not used in model development. We shared the model in an easy-to-use online application that allows the user to predict in-hospital mortality risk for a patient if they have any subset of the variables in the final model.

Results

Our final model includes the patient’s age, first recorded respiratory rate, first recorded pulse oximetry, highest creatinine level on day of presentation, and hospital’s COVID-19 mortality rate. No other factors showed sufficient incremental model improvement to warrant inclusion. The AUC for the derivation and validation sets were .796 and .829 respectively.

Conclusions

Risk of in-hospital mortality in COVID-19 patients can be reliably estimated using a few factors, which are standardly measured and available to physicians very early in a hospital encounter.
Quantifying the impact of UVC in reducing airborne pathogen transmission and improving energy efficiency for healthy buildings: Kahn-Mariita equivalent ventilation model
Authors: Kahn Kevin , Mariita Richard M.
Published: May 2021

There is growing evidence that viruses responsible for pandemics, such as MERS and SARS, are mainly spread through aerosols. Recommendations have been introduced to reduce the transmission risk of virulent airborne viral particles by increasing ventilation rates, expressed in air-changes-per-hour (ACH), effectively improving the dilution of airborne pathogens via mechanical ventilation. However, the infrastructural and operational costs associated with upgrades of Heating, Ventilation, and Air Conditioning (HVAC) systems make these solutions expensive. It is well documented that UVC disinfection can help lower exposure risks by inactivating viruses in shared enclosed spaces, and the performances of such solutions be translated into equivalent ventilation (equivalent ACH or eACH). Here, we present the first framework to extract the optimum UVC output requirements for a target eACH, and improve facilities ability to comply with ventilation guidelines at lower energy costs. The Kahn-Mariita (KM) model considers the air quality of a shared enclosed space over time by supplementing existing mechanical ventilation with localized UVC air treatment, whether in recirculating units or upper-air systems, and extracts the systems requirements based on end-user needs by incorporating variables such as room size, occupancy, existing ventilation, and target eACH. An example of a conference room shows that a UVC chamber with an air recirculation rate of 160m3/h increases the ventilation from ACH=3 to eACH=7.9 and reduce down-time from 46 minutes to <10 minutes with as little 1W of UVC output. A recirculation rate of 30m3/h however offers no noticeable benefits above 200mW, with a maximum reachable eACH=3.9 and down-time of approximately 31 minutes. The KM model is unique in that it allows for the first time to find the optimum UVC output needs to ensure air quality is maintained and transmission risk minimized, while increasing energy savings. Recent studies suggest mechanically increasing fresh air supply will more than double the energy costs of HVAC systems, while the use of UVC reduces energy demand as much as by 50%. The KM model approaches air quality and energy efficiency in a unified way by incorporating UVC as a supplement to existing ventilation to increase eACH, reduce down-time, and increase the closed space occupancy.
Unbiased and UMI-informed sequencing of cell-free miRNAs at single-nucleotide resolution
Authors: van Eijndhoven M.A.J. , Aparicio-Puerta E. , Gómez-Martín C. , Medina J.M. , Drees E.E.E. , Bradley E.J. , Bosch L. , Scheepbouwer C. , Hackenberg M. , Pegtel D.M.
Published: May 2021

Terminal nucleotidyl transferases are enzymes that add non-templated nucleotides to RNA molecules. In the case of microRNAs, this process was shown to be functionally relevant for their maturation process and generation of isomiRs with non-canonical mRNA targets. Deconvolution of these posttranscriptional modifications is challenging in particular for extracellular miRNAs that are considered as a target for minimally-invasive diagnostics. Massively parallel RNA sequencing is the only method that can truthfully reveal isomiR diversity in biological samples and determine relative quantities. Improvements aside, current small RNA sequencing strategies remain imprecise. We developed IsoSeek that diverges from these methods by making use of randomized 5’- and 3’-adapters combined with a 10N unique molecular identifier (UMI). Using synthetic miRNA and isomiR spike-in sets and testing depletion and RNA competition strategies in 7 sequencing rounds of >100 samples, we rigorously optimized and validated the technical accuracy of the IsoSeek method. In genetically-altered HEK293, we characterized the terminal uridylase (TUT4/TUT7) dependent miRNA uridylome and discovered extensive uridylation of disease-associated miRNAs. Notably, 3’-uridylated isomiR profiles of plasma extracellular vesicles (EVs) rely on UMI-correction. Thus, IsoSeek advances our knowledge of cell-free miRNAs and supports development into non-invasive biomarkers.
Phonological and temporal regularities lead to differential ERP effects in self- and externally generated speech
Authors: Emmendorfer Alexandra K. , Bonte Milene , Jansma Bernadette M. , Kotz Sonja A.
Published: May 2021

Some theories of predictive processing propose reduced sensory and neural responses to anticipated events. Support comes from M/EEG studies, showing reduced auditory N1 and P2 responses to self-compared to externally generated events, or when stimulus properties are more predictable (e.g. prototypical). The current study examined the sensitivity of N1 and P2 responses to statistical regularities of speech. We employed a motor-to-auditory paradigm comparing ERP responses to externally and self-generated pseudowords, varying in phonotactic probability and syllable stress. We expected to see N1 and P2 suppression for self-generated stimuli, with greater suppression effect for more predictable features such as high phonotactic probability and first syllable stress in pseudowords. We observe an interaction between phonotactic probability and condition on the N1 amplitude, with an enhanced effect of phonotactic probability in processing self-generated stimuli. However, the directionality of this effect was reversed compared to what was expected, namely a larger N1 amplitude for high probability items, possibly indicating a perceptual bias toward the more predictable item. We further observed an effect of syllable stress on the P2 amplitude, with greater amplitudes in response to first syllable stress items. The current results suggest that phonotactic probability plays an important role in processing self-generated speech, supporting feedforward models involved in speech production.
Controlled bio-inspired self-organised criticality
Authors: olde Scheper Tjeerd V.
Published: May 2021

The control of extensive complex biological systems is considered to depend on feedback mechanisms. Reduced systems modelling has been effective to describe these mechanisms, but this approach does not sufficiently encompass the required complexity that is needed to understand how localised control in a biological system can provide global stable states. Self-Organised Criticality (SOC) is a characteristic property of locally interacting physical systems which readily emerges from changes to its dynamic state due to small nonlinear perturbations. Small changes in the local states, or in local interactions, can greatly affect the total system state of critical systems. It has long been conjectured that SOC is cardinal to biological systems that show similar critical dynamics and also may exhibit near power-law relations. Rate Control of Chaos (RCC) provides a suitable robust mechanism to generate SOC systems which operates at the edge of chaos. The bio-inspired RCC method requires only local instantaneous knowledge of some of the variables of the system, and is capable of adapting to local perturbations. Importantly, connected RCC controlled oscillators can maintain global multi-stable states, and domains with power-law relations may emerge. The network of oscillators deterministically stabilises into different orbits for different perturbations and the relation between the perturbation and amplitude can show exponential and power-law correlations. This is representative of a basic mechanism of protein production and control, that underlies complex processes such as homeostasis. Providing feedback from the global state, the total system dynamic behaviour can be boosted or reduced. Controlled SOC can provide much greater understanding of biological control mechanisms, that are based on distributed local producers, remote consumers of biological resources, with globally defined control.

Author summary

Using a nonlinear control method inspired by enzymatic control, which is capable of stabilising chaotic systems into periodic orbits or steady-states, it is shown that a controlled system can be created that is scale-free and in a critical state. This means that the system can easily move from one stable orbit to another using only a small local perturbation. Such a system is known as self-organised criticality, and is shown in this system to be deterministic. Using a known perturbation, it will result in a scale-free response of the system that can be in a power law relation. It has been conjectured that biosystems are in a self-organised critical state, and these models show that this is a suitable approach to allow local systems to control a global state, such as homeostatic control. The underlying principle is based on rate control of chaos, and can be used to understand how biosystems can use localised control to ensure stability at different dynamic scales without supervising mechanisms.
Dog10K_Boxer_Tasha_1.0: A long-read assembly of the dog reference genome
Authors: Jagannathan Vidhya , Hitte Christophe , Kidd Jeffrey M. , Masterson Patrick , Murphy Terence D. , Emery Sarah , Davis Brian , Buckley Reuben M. , Liu Yanhu , Zhang Xiangquan , Leeb Tosso , Zhang Ya-ping , Ostrander Elaine A. , Wang Guo-dong
Published: May 2021

The domestic dog has evolved to be an important biomedical model for studies regarding the genetic basis of disease, morphology and behavior. Genetic studies in the dog have relied on a draft reference genome of a purebred female boxer dog named “Tasha” initially published in 2005. Derived from a Sanger whole genome shotgun sequencing approach coupled with limited clone-based sequencing, the initial assembly and subsequent updates have served as the predominant resource for canine genetics for 15 years. While the initial assembly produced a good quality draft, as with all assemblies produced at the time it contained gaps, assembly errors and missing sequences, particularly in GC-rich regions, which are found at many promoters and in the first exons of protein coding genes. Here we present Dog10K_Boxer_Tasha_1.0, an improved chromosome-level highly contiguous genome assembly of Tasha created with long-read technologies, that increases sequence contiguity >100-fold, closes >23,000 gaps of the Canfam3.1 reference assembly and improves gene annotation by identifying >1200 new protein-coding transcripts. The assembly and annotation are available at NCBI under the accession GCF_000002285.5.
Fine-scale quantification of GC-biased gene conversion intensity in mammals
Authors: Galtier Nicolas
Published: May 2021

GC-biased gene conversion (gBGC) is a molecular evolutionary force that favours GC over AT alleles irrespective of their fitness effect. Quantifying the variation in time and across genomes of its intensity is key to properly interpret patterns of molecular evolution. In particular, the existing literature is unclear regarding the relationship between gBGC strength and species effective population size,Ne. Here we analysed the nucleotide substitution pattern in coding sequences of closely related species of mammals, thus accessing a high resolution map of the intensity of gBGC. Our maximum likelihood approach shows that gBGC is pervasive, highly variable among species and genes, and of strength positively correlated withNein mammals. We estimate that gBGC explains up to 60% of the total amount of synonymous AT→GC substitutions. We show that the fine-scale analysis of gBGC-induced nucleotide substitutions has the potential to inform on various aspects of molecular evolution, such as the distribution of fitness effects of mutations and the dynamics of recombination hotspots.
Screening bioactive food compounds in honey bees suggests curcumin blocks alcohol-induced damage to longevity and DNA methylation
Authors: Rasmussen Erik M. K. , Seier Kristine L. , Pedersen Ingrid K. , Kreibich Claus , Amdam Gro V. , Münch Daniel , Dahl John Arne
Published: May 2021

Various bioactive food compounds may confer health and longevity benefits, possibly through altering or preserving the human epigenome. While bioactive food compounds are widely being marketed as ‘improving health and longevity’ by counteracting harmful effects of poor nutrition and lifestyle, claimed effects are often not adequately documented. Using the honey bee (Apis mellifera) as a model species, we here employed a multi-step screening approach to investigate seven compounds for effects on lifespan and DNA methylation using ELISA and whole genome bisulfite sequencing (WGBS). A positive longevity effect was detected for valproic acid, isovaleric acid, and cyanocobalamin. For curcumin, we found that lifespan shortening caused by ethanol intake, was restored when curcumin and ethanol were co-administered. Furthermore, we identified region specific DNA methylation changes as a result of ethanol intake. Ethanol specific changes in DNA methylation were fully or partially blocked in honey bees receiving ethanol and curcumin together. Ethanol-affected and curcumin-blocked differentially methylated regions covered genes involved in fertility, temperature regulation and tubulin transport. Our results demonstrate fundamental negative effects of low dose ethanol consumption on lifespan and associated DNA methylation changes and present a proof-of-principle on how longevity and DNA methylation changes can be negated by the bioactive food component curcumin. Our findings provide a fundament for further studies of curcumin in mice and humans and offer an avenue to explore regarding possible prevention of health issues related to alcohol consumption.
The ICP22 protein of Herpes Simplex Virus 1 promotes RNA Polymerase II activity on Viral Immediate Early Genes
Authors: Birkenheuer Claire H. , Baines Joel D.
Published: May 2021

To determine the role of herpes simplex virus (HSV-1) ICP22 in viral transcription we performed precise nuclear run-on followed by deep sequencing (PRO-Seq) to map active RNA polymerase II (Pol II) on viral and cellular genomes in cells infected with a viral mutant lacking the entire ICP22-encoding α22 (US1/US1.5) gene, or a virus derived from the deletion mutant but bearing a restored α22 gene. At 3 hours post infection (hpi), the lack of ICP22 reduced Pol II activity at promoter proximal pause (PPP) sites on the α4 and α0 genes, and on the bodies of the α4, α0, and α27 genes. The decreased activity at α0 and α4 PPP sites at 3 hpi was distinguishable from effects caused by treatment with a viral DNA polymerase inhibitor. The ICP22 mutant had multiple defects at 6 hpi, including lower viral DNA replication and reduced Pol II activity on viral genes of all temporal classes. Between 3 and 6 hpi the repair virus, like wild type HSV-1, redirected Pol II activity from cellular genes to viral genes. In the absence of ICP22, the opposite occurred inasmuch as Pol II activity returned from the viral genome to cellular genes. These data indicate that ICP22 acts to increase Pol II activity at the PPP sites and bodies of viral immediate early genes at early times post infection, and directly or indirectly helps retain Pol II activity on the viral genome later in infection.

Importance

Using a mutant lacking the full US1/US1.5 gene, this study establishes a role for ICP22 in increasing Pol II activity on viral immediate early genes by enhancing transcription initiation and/or elongation onto immediate early gene bodies. Unlike truncation mutants studied previously, the full null virus is unable to sustain DNA replication and Pol II activity on late genes, precluding later stages of the viral life cycle.
CREB regulates the expression of Type 1 Inositol 1,4,5-trisphosphate receptors
Authors: Arige Vikas , Terry Lara E. , Knebel Taylor R. , Wagner Larry E. , Yule David I.
Published: May 2021

Inositol 1,4,5-trisphosphate (IP3) receptors (IP3Rs) play a central role in regulating intracellular calcium signals in response to a variety of internal/external cues. Dysregulation of IP3R signaling is the underlying cause for numerous pathological conditions. It is also well established that the activity of IP3Rs is governed by several post-translational modifications including phosphorylation by protein kinase A (PKA). However, the long-term effects of PKA activation on expression of IP3R sub-types, remains largely unexplored. In this report, we investigate the effect of chronic activation of PKA on expression of IP3R sub-types. We demonstrate that expression of IP3R1 is augmented upon prolonged activation of PKA or upon ectopic over-expression of CREB but does not alter IP3R2 and IP3R3 sub-type abundance. Conversely, inhibition of PKA or blocking endogenous CREB diminished IP3R1 expression. We also demonstrate that agonist-induced Ca2+-release mediated by IP3R1 is significantly attenuated upon blocking endogenous CREB. Moreover, CREB by regulating the expression of KRAS-induced actin-interacting protein (KRAP) ensures proper localization and licensing of IP3R1. Overall, we report a crucial role for CREB in governing both the expression and proper localization of IP3R1.

Summary statement

We report a critical role of CREB in regulating the expression and proper localization of IP3R1. Agonist-induced Ca2+release and Ca2+puffs generated by IP3R1 are diminished upon blocking the function of endogenous CREB.
Thiolutin has complex effects in vivo but is a direct inhibitor of RNA Polymerase II in vitro
Authors: Qiu Chenxi , Arora Payal , Malik Indranil , Laperuta Amber J. , Pavlovic Emily M. , Ugochukwu Scott , Naik Mandar , Kaplan Craig
Published: May 2021

Thiolutin is a natural product transcription inhibitor with an unresolved mode of action. Thiolutin and the related dithiolopyrrolone holomycin chelate Zn2+and previous studies have concluded that RNA Polymerase II (Pol II) inhibitionin vivois indirect. Here, we present chemicogenetic and biochemical approaches to investigate thiolutin’s mode of action inSaccharomyces cerevisiae. We identify mutants that alter sensitivity to thiolutin. We provide genetic evidence that thiolutin causes oxidation of thioredoxinsin vivoand that thiolutin both induces oxidative stress and interacts functionally with multiple metals including Mn2+and Cu2+, and not just Zn2+. Finally, we show direct inhibition of RNA polymerase II (Pol II) transcription initiation by thiolutinin vitroin support of classical studies that thiolutin can directly inhibit transcriptionin vitro. Inhibition requires both Mn2+and appropriate reduction of thiolutin as excess DTT abrogates its effects. Pause prone, defective elongation can be observedin vitroif inhibition is bypassed. Thiolutin effects on Pol II occupancyin vivoare widespread but major effects are consistent with prior observations for Tor pathway inhibition and stress induction, suggesting that thiolutin usein vivoshould be restricted to studies on its modes of action and not as an experimental tool.