bluuebunny/crossref_metadata_2025 huggingface dataset:
Effectiveness of different types of skin grafting for treating venous leg ulcers
Authors: Pan Junqing , Hu Xiangjun , Yin Hongwei , Zhang Congzhong , Yan Zhangren
Published: April 2021

Background:

Venous leg ulcers (VLUs) are the most common ulcer on the lower extremity, with 4% of patients over the age of 65 suffering from VLUs worldwide. As a recurrent, chronic, disabling disease, VLUs are associated with prolonged disability, substantial socioeconomic impact, and significant psychosocial morbidity. At present, Skin grating is one of the most effective treatments for non-healing ulcers. However, there are still no new studies based on the latest research and new research methods to evaluate and compare the effect of different types of skin grafts for treating venous leg ulcers. Therefore, a Bayesian network meta-analysis (NMA) will be conducted to systematically assess skin grafting efficacy for VLUs.

Methods:

We will include randomized controlled trials (RCTs) involving patients with VLUs treated by skin grafts. Electronic databases and clinical trials registries will be searched from their inception until June 2021, without language or publication restrictions on status. The search strategy mainly includes Medical Subject Headings (MeSH) and free-text terms. Two review authors will independently perform data extraction and assessment of study quality. And We will use Bayesian NMA to evaluate all available evidence in STATA 14.0 and WinBUGS software.

Results:

This protocol will use Bayesian NMA to assess the effectiveness of different types of skin grafting for treating venous leg ulcers.

Conclusion:

This study aims to synthesize the available evidence from RCTs in a network meta-analysis to summarize the best research available and provide consistency among treatment protocols given to patients, resulting in improved efficacy and the quality of care and reduced cost.
Improvement of Bone Marrow Necrosis by Tyrosine Kinase Inhibitor Substitution in a Pediatric Patient With Philadelphia Chromosome-positive Acute Lymphoblastic Leukemia
Authors: Mikami Takashi , Kato Itaru , Oiki Nanami , Okamoto Seiji , Kamitori Tatsuya , Tasaka Keiji , Ogata Hideto , Tanaka Kuniaki , Umeda Katsutsugu , Hiramatsu Hidefumi , Okamoto Takeshi , Adachi Souichi , Takita Junko
Published: April 2021

Bone marrow necrosis (BMN) describes necrosis of the myeloid tissues without cortical bone involvement. Imatinib, a tyrosine kinase inhibitor, can trigger BMN during the treatment of malignant disease. In such cases, it is necessary to reduce imatinib dose or discontinue its administration, which could influence treatment outcomes. Here, we report a 6-year-old boy with Philadelphia chromosome-positive acute lymphoblastic leukemia, who developed BMN in response to imatinib. We replaced imatinib with dasatinib, and necrotic lesions gradually disappeared and were never exacerbated. In Philadelphia chromosome-positive acute lymphoblastic leukemia with BMN, tyrosine kinase inhibitor replacement may allow continued chemotherapy without intensity reduction.
Does Iron Deficiency Affect the Heart in Children?
Authors: Demir Fadime , Kayali Seyma , Gokcebay Dilek G.
Published: April 2021

Introduction:

It is well known that serum iron parameters are closely related to cardiovascular health. Iron deficiency may lead to significant cardiac problems, such as atrioventricular conduction abnormalities, and systolic and/or diastolic dysfunction. Studies related to the effect of iron deficiency on cardiac functions are limited in children. Therefore, the aim of this study was to evaluate the effect of low iron stores on cardiac repolarization parameters which are used to predict arrhythmia and cardiac functions.

Materials and Methods:

Onehundred thirty-five children 2 to 18 years of age without structural heart disease who were referred to the Pediatric Cardiology Department for various reasons such as chest pain, heart murmur, or evaluation before sports participation were evaluated prospectively. The cases were separated into 3 groups according to ferritin levels (group 1: ferritin <15 ng/mL [n=48], group 2: ferritin 15 to 25 ng/mL [n=51], and group 3: ferritin >25 ng/mL [n=36]). Evaluations were made with detailed 12-lead surface electrocardiography (ECG) and transthoracic echocardiogram. Cardiac repolarization parameters were measured from surface ECG and systolic functions, left ventricular wall diameters were evaluated from transthoracic echocardiogram.

Results:

Eighty-four (62.2%) girls and 51 (37.8%) boys are included in the study. The average age of the groups was similar. In children with low ferritin levels (group 1); Pw, Pw max, and Pw dis; QT, QTc, and QTc dis; Tp-Te, Tp-Te dis, Tp-Te/QT, and Tp-Te/QTc were significantly longer compared with the group 3 (P<0.05). There was a negative correlation between ferritin level and Pw, P max, and Pw dis; QT, QT dis, QTc, and QTc dis; Tp-Te, Tp-Te dis, Tp-Te/QT, and Tp-Te/QTc (P<0.05). No correlation was found between ferritin level and Pw min. There was no difference between the groups in respect of ejection phase indices, heart wall measurements, and end-diastolic diameter measurements.

Conclusion:

Iron deficiency may be related to the tendency of arrhythmias in children without structural heart disease. Therefore, careful evaluation of ECG parameters of healthy children with low iron stores, and follow up with intermittent monitoring is highly important.
Prognostic factors for pain chronicity in low back pain: a systematic review
Authors: Nieminen Linda Karoliina , Pyysalo Liisa Maria , Kankaanpää Markku Juhani
Published: April 2021

Low back pain is the leading cause for years lived in disability. Most people with acute low back pain improve rapidly, but 4% to 25% of patients become chronic. Since the previous systematic reviews on the subject, a large number of new studies have been conducted. The objective of this article was to review the evidence of the prognostic factors behind nonspecific chronic low back pain. A systematic literature search was performed without date limitation from the MEDLINE, Cochrane library, and Medic databases. Specific inclusion criteria were used, and risk factors before the onset of chronic symptoms were searched. Study quality was assessed by 2 independent reviewers. One hundred eleven full articles were read for potential inclusion, and 25 articles met all the inclusion criteria. One study was rated as good quality, 19 studies were rated as fair quality, and 5 articles were rated as poor quality. Higher pain intensity, higher body weight, carrying heavy loads at work, difficult working positions, and depression were the most frequently observed risk factors for chronic low back pain. Maladaptive behavior strategies, general anxiety, functional limitation during the episode, smoking, and particularly physical work were also explicitly predictive of chronicity. According to this systematic review, several prognostic factors from the biomechanical, psychological and psychosocial point of view are significant for chronicity in low back pain.
Analysis of COVID-19 Patients With Acute Respiratory Distress Syndrome Managed With Extracorporeal Membrane Oxygenation at US Academic Centers
Authors: Nguyen Ninh T. , Sullivan Brittany , Sagebin Fabio , Hohmann Samuel F. , Amin Alpesh , Nahmias Jeffry
Published: April 2021

Objective:

This study analyzed the outcomes of COVID-19 patients with ARDS who were managed with extracorporeal membrane oxygenation (ECMO) across 155 US academic centers.

Summary Background Data:

ECMO has been utilized in COVID-19 patients with acute respiratory distress syndrome (ARDS) and refractory hypoxemia. Early case series with the use of ECMO in these patients reported high mortality exceeding 90%.

Methods:

Using ICD-10 codes, data of patients with COVID-19 with ARDS, managed with ECMO between April and September 2020, were analyzed using the Vizient clinical database. Outcomes measured included in-hospital mortality, hospital and ICU length of stay, and direct cost. For comparative purposes, the outcome of a subset of COVID-19 patients aged between 18 and 64 years and managed with versus without ECMO were examined.

Results:

1,182 patients with COVID-19 and ARDS received ECMO. In-hospital mortality was 45.9%, mean length of stay was 36.8 ± 24.9 days, and mean ICU stay was 29.1 ± 17.3 days. In-hospital mortality according to age group was 25.2% for 1 to 30 years; 42.2% for 31 to 50 years; 53.2% for 51 to 64 years; and 73.7% for ≥65 years. A subset analysis of COVID-19 patients, aged 18 to 64 years with ARDS requiring mechanical ventilation and managed with (n = 1113) vs without (n = 16,343) ECMO, showed relatively high in-hospital mortality for both groups (44.6% with ECMO vs 37.9% without ECMO).

Conclusions:

In this large US study of patients with COVID-19 and ARDS managed with ECMO, the in-hospital mortality is high but much lower than initial reports. Future research is needed to evaluate which patients with COVID-19 and ARDS would benefit from ECMO.
Surgical Decision-Making in Pancreatic Ductal Adenocarcinoma
Authors: Habib Joseph R. , Kinny-Köster Benedict , Bou-Samra Patrick , Alsaad Ranim , Sereni Elisabetta , Javed Ammar A. , Ding Ding , Cameron John L. , Lafaro Kelly J. , Burns William R. , He Jin , Yu Jun , Wolfgang Christopher L. , Burkhart Richard A.
Published: April 2021

Objective:

To develop a predictive model of oncologic outcomes for patients with pancreatic ductal adenocarcinoma (PDAC) undergoing resection after neoadjuvant or induction chemotherapy use.

Background:

Early recurrence following surgical resection for PDAC is common. The use of neoadjuvant chemotherapy prior to resection may increase the likelihood of long-term systemic disease control. Accurately characterizing an individual's likely oncologic outcome in the perioperative setting remains challenging.

Methods:

Data from patients with PDAC who received chemotherapy prior to pancreatectomy at a single high-volume institution between 2007 and 2018 were captured in a prospectively collected database. Core clinicopathologic data were reviewed for accuracy and survival data were abstracted from the electronic medical record and national databases. Cox-proportional regressions were used to model outcomes and develop an interactive prognostic tool for clinical decision-making.

Results:

A total of 581 patients were included with a median overall survival (OS) and recurrence-free survival (RFS) of 29.5 (26.5–32.5) and 16.6 (15.8–17.5) months, respectively. Multivariable analysis demonstrates OS and RFS were associated with type of chemotherapeutic used and

the number of chemotherapy cycles received preoperatively. Additional factors contributing to survival models included: tumor grade, histopathologic response to therapy, nodal status, and administration of adjuvant chemotherapy. The models were validated using an iterative bootstrap method and with randomized cohort splitting. The models were well calibrated with concordance indices of 0.68 and 0.65 for the final OS and RFS models, respectively.

Conclusion:

We developed an intuitive and dynamic decision-making tool that can be useful in estimating OS, RFS, and location-specific disease recurrence rates. This prognostic tool may add value to patient care in discussing the benefits associated with surgical resection for PDAC.
‘Is there a Reader who can Handle it with any Comfort?’: A Brief Publication History of
the Works of Francis Bacon
Authors: Verburgt Lukas M.
Published: April 2021

With the Oxford Francis Bacon project yet to be completed, after more than 150 years the standard scholarly edition of Francis Bacon's (1561–1626) complete works is still
The works of Francis Bacon
. This great but now almost outdated Victorian edition was first published in London in seven volumes, 1857–1859. It has a rather complex publication history, often leading to confusion, which is well worth telling in full. The story is used here as an opportunity to look at some of the practical considerations and discussions behind this classic edition: the alternative plans for its arrangement and publication, and the conflict between the publisher and the editors relating to the scholarly implications of making the edition either as profitable or as readable as possible.
Extract, Transform, Load Framework for the Conversion of Health Databases to OMOP
Authors: Quiroz Juan C. , Chard Tim , Sa Zhisheng , Ritchie Angus , Jorm Louisa , Gallego Blanca
Published: April 2021

Objective

Develop an extract, transform, load (ETL) framework for the conversion of health databases to the Observational Medical Outcomes Partnership Common Data Model (OMOP CDM) that supports transparency of the mapping process, readability, refactoring, and maintainability.

Materials and Methods

We propose an ETL framework that is metadata-driven and generic across source datasets. The ETL framework reads mapping logic for OMOP tables from YAML files, which organize SQL snippets in key-value pairs that define the extract and transform logic to populate OMOP columns.

Results

We developed a data manipulation language (DML) for writing the mapping logic from health datasets to OMOP, which defines mapping operations on a column-by-column basis. A core ETL pipeline converts the DML in YAML files and generates an ETL script. We provide access to our ETL framework via a web application, allowing users to upload and edit YAML files and obtain an ETL SQL script that can be used in development environments.

Discussion

The structure of the DML and the mapping operations defined in column-by-column operations maximizes readability, refactoring, and maintainability, while minimizing technical debt, and standardizes the writing of ETL operations for mapping to OMOP. Our web application allows institutions and teams to reuse the ETL pipeline by writing their own rules using our DML.

Conclusion

The research community needs tools that reduce the cost and time effort needed to map datasets to OMOP. These tools must support transparency of the mapping process for mapping efforts to be reused by different institutions.
Early and ongoing importations of SARS-CoV-2 in Canada
Authors: McLaughlin Angela , Montoya Vincent , Miller Rachel L. , Mordecai Gideon J. , Worobey Michael , Poon Art F. Y. , Joy Jeffrey B.
Published: April 2021

Tracking the emergence and spread of SARS-CoV-2 is critical to inform public health interventions. Phylodynamic analyses have quantified SARS-CoV-2 migration on global and local scales1–5, yet they have not been applied to determine transmission dynamics in Canada. We quantified SARS-CoV-2 migration into, within, and out of Canada in the context of COVID-19 travel restrictions. To minimize sampling bias, global sequences were subsampled with probabilities corrected for their countries’ monthly contribution to global new diagnoses. A time-scaled maximum likelihood tree was used to estimate most likely ancestral geographic locations (country or Canadian province), enabling identification of sublineages, defined as introduction events into Canada resulting in domestic transmission. Of 402 Canadian sublineages identified, the majority likely originated from the USA (54%), followed by Russia (7%), India (6%), Italy (6%), and the UK (5%). International introductions were mostly into Ontario (39%) and Quebec (38%). Among Pango lineages6, B.1 was imported at least 191 separate times from 11 different countries. Introduction rates peaked in late March then diminished but were not eliminated following national interventions including restrictions on non-essential travel. We further identified 1,380 singleton importations, international importations that did not result in further sampled transmission, whereby representation of lineages and location were comparable to sublineages. Although proportion of international transmission decreased over time, this coincided with exponential growth of within-province transmission – in fact, total number of sampled transmission events from international or interprovincial sources increased from winter 2020 into spring 2020 in many provinces. Ontario, Quebec, and British Columbia acted as sources of transmission more than recipients, within the caveat of higher sequence representation. We present strong evidence that international introductions and interprovincial transmission of SARS-CoV-2 contributed to the Canadian COVID-19 burden throughout 2020, despite initial reductions mediated by travel restrictions in 2020. More stringent border controls and quarantine measures may have curtailed introductions of SARS-CoV-2 into Canada and may still be warranted.

Significance Statement

By analyzing SARS-CoV-2 genomes from Canada in the context of the global pandemic, we illuminate the extent to which the COVID-19 burden in Canada was perpetuated by ongoing international importations and interprovincial transmission throughout 2020. Although travel restrictions enacted in March 2020 reduced the importation rate and proportion of transmission from abroad across all Canadian provinces, SARS-CoV-2 introductions from the USA, India, Russia, and other nations were detectable through the summer and fall of 2020.
Lesion covariance networks reveal proposed origins and pathways of diffuse gliomas
Authors: Mandal Ayan S. , Romero-Garcia Rafael , Seidlitz Jakob , Hart Michael G. , Alexander-Bloch Aaron , Suckling John
Published: April 2021

Diffuse gliomas have been hypothesized to originate from neural stem cells in the subventricular zone. Here, we evaluated this hypothesis by mapping independent sources of glioma localization and determining their relationships with neurogenic niches, genetic markers, and large-scale connectivity networks. Using lesion data from a total of 410 patients with glioma, we identified -- and replicated in an independent sample -- three lesion covariance networks (LCNs), which reflect clusters of frequent glioma co-localization. Each LCN overlapped with a distinct horn of the lateral ventricles. The first LCN, which overlapped with the anterior horn, was associated with low-grade, IDH-mutated/1p19q-codeleted tumors, as well as a neural transcriptomic signature and improved overall survival. Each LCN significantly corresponded with multiple brain networks, with LCN1 bearing an especially strong relationship with structural and functional connectivity, consistent with its neural transcriptomic profile. Finally, we identified subcortical, periventricular structures with functional connectivity patterns to the cortex that significantly matched each LCN. Cumulatively, our findings support a model wherein periventricular brain connectivity guides tumor development.
Effectiveness of An Impedance Cardiography Guided Treatment Strategy to Improve Blood Pressure Control in A Real-World Setting: Results from A Pilot Pragmatic Clinical Trial
Authors: Wang Luyan , Lu Yuan , Wang Hongyi , Gu Jianlei , Ma Zheng J. , Lian Zheng , Zhang Zhiying , Krumholz Harlan M. , Sun Ningling
Published: April 2021

Background

Hypertension is a hemodynamic-related disorder characterized by abnormalities of the cardiac output (CO) and/or systemic vascular resistance (SVR). We hypothesized that selecting antihypertensive therapy based on patients’ hemodynamic profile could improve blood pressure (BP) control more effectively than standard care in hypertensive patients in real-world clinical practice.

Methods

We conducted a pilot single-center, pragmatic randomized trial involving adults with uncontrolled hypertension who sought outpatient care at a hypertension clinic of the Peking University People’s Hospital, the largest teaching hospital of Peking University, in Beijing China, between December 2018 and December 2019. Participants were randomly assigned to the standard care group or the hemodynamic group in a 1:1 ratio. Impedance cardiography (ICG) was performed with all participants to measure hemodynamic parameters. Only physicians in the hemodynamic group were provided with patients’ ICG findings and a computerized clinical decision support of recommended treatment choices based on patients’ hemodynamic profiles. The primary outcomes were the changes in systolic BP (SBP) and diastolic BP (DBP) levels at the follow-up visit 4-12 weeks after baseline. Secondary outcomes included achievement of BP goal of <140/ 90 mmHg and the changes in BP by baseline BP, age, sex, and BMI.

Results

A total 102 adults (mean age was 54±14 years; 41% were women) completed the study. The mean baseline SBP was 150.9 (±11.5) mmHg and mean baseline DBP was 91.1 (±11.3) mmHg. At the follow-up visit, the mean SBP and DBP decreased by 19.9 and 11.3 mmHg in the hemodynamic group, as compared with 12.0 and 4.9 mmHg in the standard care group (P value for difference between groups <0.001 for both SBP and DBP). The proportion of patients achieving BP goal of <140/ 90 mmHg in the hemodynamic group was 67%, as compared with 41% in the standard care group (P=0.017). The hemodynamic group had a larger effect on BP reduction consistently across subgroups by age, sex, BMI, and baseline BP.

Conclusions

An ICG-guided treatment strategy led to greater reductions in BP levels than were observed with standard care in a real-world population of outpatients with hypertension. There is a need for further validation of this strategy for improving blood pressure treatment selection. (Funded by internal research grant from the Peking University People’s Hospital; ClinicalTrials.gov number: NCT04715698.)
GRAd-COV2, a gorilla adenovirus based candidate vaccine against COVID-19, is safe and immunogenic in young and older adults
Authors: Lanini Simone , Capone Stefania , Antinori Andrea , Milleri Stefano , Nicastri Emanuele , Camerini Roberto , Agrati Chiara , Castilletti Concetta , Mori Federica , Sacchi Alessandra , Matusali Giulia , Gagliardini Roberta , Ammendola Virginia , Cimini Eleonora , Grazioli Fabiana , Scorzolini Laura , Napolitano Federico , Piazzi Maria Maddalena , Soriani Marco , De Luca Aldo , Battella Simone , Sommella Andrea , Contino Alessandra M. , Barra Federica , Gentile Michela , Raggioli Angelo , Shi Yufang , Girardi Enrico , Maeurer Markus , Capobianchi Maria R. , Vaia Francesco , Piacentini Mauro , Kroemer Guido , Vitelli Alessandra , Colloca Stefano , Folgori Antonella , Ippolito Giuseppe
Published: April 2021

Safe and effective vaccines against coronavirus disease 2019 (COVID-19) are urgently needed to control the ongoing pandemic. Although impressive progress has been made with several COVID-19 vaccines already approved, it is clear that those developed so far cannot meet the global vaccine demand. We have developed a COVID-19 vaccine based on a replication-defective gorilla adenovirus expressing the stabilized pre-fusion SARS-CoV-2 Spike protein, named GRAd-COV2. We aimed to assess the safety and immunogenicity of a single-dose regimen of this vaccine in healthy younger and older adults to select the appropriate dose for each age group. To this purpose, a phase 1, dose-escalation, open-label trial was conducted including 90 healthy subjects, (45 aged 18-55 years and 45 aged 65-85 years), who received a single intramuscular administration of GRAd-CoV2 at three escalating doses. Local and systemic adverse reactions were mostly mild or moderate and of short duration, and no serious AE was reported. Four weeks after vaccination, seroconversion to Spike/RBD was achieved in 43/44 young volunteers and in 45/45 older subjects. Consistently, neutralizing antibodies were detected in 42/44 younger age and 45/45 older age volunteers. In addition, GRAd-COV2 induced a robust and Th1-skewed T cell response against the S antigen in 89/90 subjects from both age groups. Overall, the safety and immunogenicity data from the phase 1 trial support further development of this vaccine.

One Sentence Summary

GRAd-COV2, a candidate vaccine for COVID-19 based on a novel gorilla adenovirus, is safe and immunogenic in younger and older adults
Increased serum thromboxane A2 and prostacyclin but lower complement C3 and C4 levels in COVID-19: associations with chest CT-scan anomalies and lowered peripheral oxygen saturation
Authors: Al-Hakeim Hussein Kadhem , Al-Hamami Shaymaa Ali , Maes Michael
Published: April 2021

Background

COVID-19 patients suffer from hypercoagulation and activated immune-inflammatory pathways. This study was performed to assay serum complement C3 and C4, and thromboxane A2 (TxA2) and prostacyclin (PGI2) in association with chest CT scan anomalies (CCTAs) and peripheral oxygen saturation (SpO2)

Methods

Serum levels of C3, C4, TxA2, and PGI2 were measured by ELISA and albumin, calcium, and magnesium by spectrophotometric method in 60 COVID-19 patients and 30 controls.

Results

C3 and C4 are significantly decreased and TxA2 and PGI2 significantly increased in COVID-19 patients as compared with controls. Neural networks showed that a combination of C3, albumin, and TxA2 yielded a predictive accuracy of 100% in detecting COVID-19 patients. SpO2 was significantly decreased in COVID-19 patients and was inversely associated with TxA2 and PGI2, and positively with C3, C4, albumin, and calcium. CCTAs were accompanied by lower SpO2 and albumin, and increased PGI2 levels. Patients with positive IgG results show significantly higher SpO2, TxA2, PGI2, and C4 levels than IgG negative patients.

Conclusion

Hypoalbuminemia, which is strongly associated with lung lesions and lowered peripheral oxygen saturation, is characterized by increased TxA2, suggesting that interactions between immune-inflammatory pathways and platelet hyperactivity participate in the pathophysiology of COVID-19 and consequently may play a role in enhanced risk of hypercoagulability and venous thromboembolism. These mechanisms are aggravated by lowered calcium and magnesium levels.
Cascade screening following a polygenic risk score test: what is the risk of a relative conditional on a high score of a proband?
Authors: Carmi Shai
Published: April 2021

Polygenic risk scores (PRSs) for predicting disease risk have become increasingly accurate, leading to rising popularity of PRS tests. Consider an individual whose PRS test has placed him/her at the top q-quantile of genetic risk. Recently, Reid et al. (Circ Genom Precis Med. 2021;14:e003262) have investigated whether such a finding should motivate cascade screening in the proband’s siblings. Specifically, using data from the UK biobank, Reid et al. computed the empirical probability of a sibling of the proband to also have a PRS at the top q-quantile. In this short note, I use the liability threshold model to compute this probability analytically (for either a sibling of the proband or for a more distant relative), showing excellent agreement with the empirical results of Reid et al., including that this probability is disease-independent. Further, I compute the probability of the relative of the proband to be affected, as a function of the quantile threshold q, the proportion of variance explained by the score, and the disease prevalence.
Depression and anxiety among the University community during the Covid-19 pandemic: a study in Southern Brazil
Authors: Schuch Helena S. , Cademartori Mariana G. , Dias Valesca Doro , Levandowski Mateus L. , Munhoz Tiago N , Hallal Pedro R. C. , Demarco Flávio F.
Published: April 2021

Background

The COVID-19 pandemic has disrupted people’s routine in several ways, including the temporary cessation of face-to-face teaching activities, which may affect the mental health of the population. This study aimed to assess the mental health of the academic community of a University in South Brazil during the Covid-19 pandemic.

Methods

Cross-sectional web-based survey conducted between July-August 2020 through a self-administered online questionnaire. All University staff and students were eligible. Depression was assessed using the Patient Health Questionnaire-9 and anxiety by the Generalized Anxiety Disorder-7. All analyses were stratified by academic or administrative staff, undergraduate and graduate students.

Results

2,785 individuals participated in the study. Prevalence of depression and anxiety were 39.2% (95% Confidence Interval (CI) 37.3-41.1) and 52.5% (95% CI 50.6-54.4), respectively. On stratified analyses, undergraduate students showed a higher prevalence of the outcomes compared to other groups. In relation to social distancing, higher prevalence of mental illness was associated to strictly following the authority’s guidelines and with not leaving the house routinely, but these associations were restricted to some subgroups. Mental health care and previous diagnosis of mental illness were associated with higher rates of anxiety and depression.

Limitations

The main concerns were the representativeness of the sample and the response rate.

Conclusions

An alarming prevalence of mental illness was observed in this academic community. Despite the well-known benefits of social distancing and quarantine to public health, it requires a special surveillance on the mental health of the population, especially students and those with previous mental illness diagnosis.
Cannabidiol (CBD) repurposing as antibacterial: promising therapy of CBD plus polymyxin B against superbugs
Authors: Abichabki Nathália , Zacharias Luísa V. , Moreira Natália C. , Bellissimo-Rodrigues Fernando , Moreira Fernanda L. , Benzi Jhohann R. L. , Ogasawara Tânia M. C. , Ferreira Joseane C. , Pereira Leonardo R. L. , Braga Gilberto Ú. L. , Ribeiro Camila M. , Pavan Fernando R. , Zuardi Antonio W. , Hallak Jaime E. C. , Crippa José A. S. , Lanchote Vera L. , Cantón Rafael , Darini Ana Lúcia C. , Andrade Leonardo N.
Published: April 2021

Abstract

Multidrug-resistant (MDR) and extensively drug-resistant (XDR) bacteria are a major worldwide public health problem. In the last decades, resistance to last-resort antibiotics such as polymyxin B (PB) have been increasingly observed among these superbugs, compromising the effectiveness of antimicrobial therapy. The present study aimed (i) to assess the ultrapure Cannabidiol (CBD) antibacterial activity against a broad diversity of Gram-negative (GN) and Gram-positive (GP) bacteria (44 different species, 95 strains), comprising standard strains and clinical isolates, and (ii) to investigate the antibacterial activity of the combination CBD + PB against GN bacteria, including chromosomal- and plasmid-acquired PB-resistant and intrinsically PB-resistant GNB. We evaluated CBDin vitroantibacterial activity using the standard broth microdilution method, and the antibacterial activity of the combination CBD + PB was screened using the standard broth microdilution and confirmed by checkerboard assay. CBD exhibited antibacterial activity against different GP bacterial species, lipooligosaccharide (LOS)-expressing GN diplococcus (GND) (Neisseria gonorrhoeae,Neisseria meningitidis, andMoraxella catarrhalis), andMycobacterium tuberculosis. The combination CBD + PB exhibited antibacterial activity against PB-resistant GNB (e.g.,Klebsiella pneumoniae) as well as additive and/or synergistic effect against LOS-expressing GND. The antibacterial activity of the combination CBD + PB againstPseudomonas aeruginosaand plasmid-mediated colistin-resistant (MCR-1)E. colistrains could be only demonstrated in the presence of phenylalanine-arginine-β-naphthylamide (PAβN). In conclusion, our results show promising translational potential of the combination CBD + PB against MDR and XDR GNB, including PB-resistantK. pneumoniae, highlighting its potential as a rescue treatment for life-threatening infections caused by these superbugs.

One Sentence Summary

Promising combination of cannabidiol (CBD) + polymyxin B (PB) against superbugs (e.g., PB-resistant Gram-negative bacilli): Repurposing CBD
Mechanism of riboregulation of p62 protein oligomerisation by vault RNA1-1 in selective autophagy
Authors: Büscher Magdalena , Horos Rastislav , Haubrich Kevin , Dobrev Nikolay , Baudin Florence , Hennig Janosch , Hentze Matthias W.
Published: April 2021

Macroautophagy ensures the clearance of intracellular substrates ranging from single ubiquitinated proteins to large proteotoxic aggregates and defective organelles. The selective autophagy receptor p62 binds these targets and recruits them to double-membrane vesicles, which fuse with lysosomes to degrade their content. We recently uncovered that p62 function is riboregulated by the small non-coding vault RNA1-1. Here, we present detailed insight into the underlying mechanism. We show that the PB1 domain and adjacent linker region of p62 (aa 1-122) are necessary and sufficient for specific vault RNA1-1 binding, and identify lysine 7 and arginine 21 as key hinges for p62 riboregulation. Chemical structure probing of vault RNA1-1 further reveals a central flexible loop within the RNA that mediates the specific p62 interaction. Our data define molecular determinants that govern mammalian autophagy via the p62-vault RNA1-1 riboregulatory pair.
Beneficial substrate partitioning boosts non-aqueous catalysis in de novo enzyme-alginate beads
Authors: Stenner Richard , Adrian Bunzel H. , Mulholland Adrian J. , Ross Anderson J. L.
Published: April 2021

Synthetic reactions often require solvents incompatible with biocatalysts. Here, we encapsulate ade novoheme-containing enzyme, C45, in calcium-alginate hydrogel beads to facilitate heterogeneous biocatalysis in neat organic solvents. Post-encapsulation, C45 retains activity even when the beads are suspended in organic solvents. In particular, the carbene transferase activity of C45 is enhanced when reactions are performed in aprotic, non-polar solvents such as hexane and toluene. Activity-solvent dependencies reveal that this activity boost is likely due to beneficial partitioning of the substrate into the beads from the organic phase. Furthermore, encapsulation facilitates enzyme recovery and recycling after the reaction. Such encapsulation opens up novel opportunities for biocatalysis in organic solvent systems, combining desired solvent properties of organic chemistry with enzymatic selectivity and proficiency.
Renalase is a novel tissue and serological biomarker in pancreatic ductal adenocarcinoma
Authors: Gao Yasheen , Wang Melinda , Guo Xiaojia , Hu Joanna , Chen Tian-min , Finn Sade’ M.B. , Lacy Jill , Kunstman John W. , Cha Charles H. , Bellin Melena D. , Robert Marie E. , Desir Gary V. , Gorelick Fred S.
Published: April 2021

Dysregulated expression of the secretory protein renalase (RNLS) can promote pancreatic ductal adenocarcinoma (PDAC) growth in animal models. We characterized RNLS expression in premalignant and malignant PDAC tissue and investigated whether plasma RNLS levels corresponded to clinical PDAC characteristics. RNLS immunohistochemistry was used to determine the presence and distribution of RNLS in normal pancreas, chronic pancreatitis, PDAC precursor lesions, and PDAC tissues. Associations between pretreatment plasma RNLS and PDAC clinical status were assessed in patients with varied clinical stages of PDAC and included tumor characteristics, surgical resection in locally advanced/borderline resectable PDAC, and overall survival. Data were retrospectively obtained and correlated using non-parametric analysis. Mild to no RNLS was detected by histochemistry in the normal pancreas in the absence of abdominal trauma. In chronic pancreatitis, RNLS immunoreactivity localized to peri-acinar spindle-shaped cells in some samples. It was also widely present in PDAC precursor lesions and PDAC tissue. Among 240 patients with PDAC, elevated plasma RNLS levels were associated with worse tumor characteristics, including greater angiolymphatic invasion (80.0% vs. 58.1%, p = 0.012) and greater node positive disease (76.5% vs. 56.5%, p = 0.024). Overall survival was worse in patients with high plasma RNLS levels with median follow-up of 27.70 months vs. 65.03 months (p < 0.001). RNLS levels also predicted whether patients with locally advanced/borderline resectable (LA/BR) PDAC underwent resection (AUC 0.674; 95%CI 0.42-0.82, p = 0.04). Overall tissue RNLS was increased in both premalignant and malignant PDAC tissues compared to normal pancreas. Elevated plasma RNLS levels were associated with advanced tumor characteristics, decreased overall survival, and reduced resectability in patients with LA/BR PDAC. These studies show that RNLS levels are increased in premalignant pancreatic tissues and that its levels in plasma correspond to the clinical behavior of PDAC.
Cold-triggered induction of ROS- and raffinose-related metabolism in freezing-sensitive taproot tissue of sugar beet
Authors: Keller Isabel , Müdsam Christina , Rodrigues Cristina Martins , Kischka Dominik , Zierer Wolfgang , Sonnewald Uwe , Harms Karsten , Czarnecki Olaf , Fiedler-Wiechers Karin , Koch Wolfgang , Neuhaus H. Ekkehard , Ludewig Frank , Pommerrenig Benjamin
Published: April 2021

Sugar beet (Beta vulgaris subsp. vulgaris) is the exclusive source of sugar in the form of sucrose in temperate climate zones. There, sugar beet is grown as an annual crop from spring to autumn because of the damaging effect of freezing temperatures to taproot tissue. Natural and breeded varieties display variance in the degree of tolerance to freezing temperatures and genotypes with elevated tolerance to freezing have been isolated. Here we compare initial responses to frost between genotypes with either low and high winter survival rates. The selected genotypes differed in the severity of frost injury. We combined transcriptomic and metabolite analyses of leaf- and taproot tissues from such genotypes to elucidate mechanisms of the early freezing response and to dissect genotype- and tissue-dependent responses. Freezing temperatures induced drastic downregulation of photosynthesis-related genes in leaves but upregulation of genes related to minor carbohydrate metabolism, particularly of genes involved in raffinose metabolism in both, leaf and taproot tissue. In agreement with this, it has been revealed that raffinose and the corresponding intermediates, inositol and galactinol, increased markedly in these tissues. We found that genotypes with improved tolerance to freezing, showed higher accumulation of raffinose in a defined interior region within the upper part of the taproot, the pith, representing the tissue most susceptible to freeze damages. This accumulation was accompanied by specific upregulation of raffinose synthesizing enzymes in taproots, suggesting a protective role for raffinose and its precursors for freezing damage in sugar beet.
In vivo genome-wide CRISPR screens identify SOCS1 as a major intrinsic checkpoint of CD4+Th1 cell response
Authors: Del Galy Aurélien Sutra , Menegatti Silvia , Fuentealba Jaime , Perrin Laetitia , Lucibello Francesca , Helft Julie , Darbois Aurélie , Saitakis Michael , Tosello Jimena , Rookhuizen Derek , Deloger Marc , Gestraud Pierre , Socié Gérard , Amigorena Sebastian , Lantz Olivier , Menger Laurie
Published: April 2021

The expansion of antigen experienced CD4+T cells is limited by intrinsic factors. Usingin vivogenome-wide CRISPR-Cas9 screens, we identified SOCS1 as a non-redundant checkpoint imposing a brake on CD4+T-cell proliferation upon rechallenge. We show here that SOCS1 is a critical node integrating both IL-2 and IFN-γ signals and blocking multiple signaling pathways to abrogate CD4+Th1 cell response. In CD8+T-cell, SOCS1 does not impact the proliferation but rather reduces survival and effector functions. By targeting SOCS1, both murine and human CD4+T-cell antitumor adoptive therapies exhibit a restored intra-tumor accumulation, proliferation/survival, persistence and polyfunctionality, promoting long term rejection of established tumors. These findings identify SOCS1 as a major intracellular checkpoint inhibitor of primed CD4+T cells, opening new possibilities to optimize CAR-T cell therapies composition and efficacy.
Cortical tracking of a background speaker modulates the comprehension of a foreground speech signal
Authors: Keshavarzi Mahmoud , Varano Enrico , Reichenbach Tobias
Published: April 2021

Understanding speech in background noise is a difficult task. The tracking of speech rhythms such as the rate of syllables and words by cortical activity has emerged as a key neural mechanism for speech-in-noise comprehension. In particular, recent investigations have used transcranial alternating current stimulation (tACS) with the envelope of a speech signal to influence the cortical speech tracking, demonstrating that this type of stimulation modulates comprehension and therefore evidencing a functional role of the cortical tracking in speech processing. Cortical activity has been found to track the rhythms of a background speaker as well, but the functional significance of this neural response remains unclear. Here we employ a speech-comprehension task with a target speaker in the presence of a distractor voice to show that tACS with the speech envelope of the target voice as well as tACS with the envelope of the distractor speaker both modulate the comprehension of the target speech.

Because the envelope of the distractor speech does not carry information about the target speech stream, the modulation of speech comprehension through tACS with this envelope evidences that the cortical tracking of the background speaker affects the comprehension of the foreground speech signal. The phase dependency of the resulting modulation of speech comprehension is, however, opposite to that obtained from tACS with the envelope of the target speech signal. This suggests that the cortical tracking of the ignored speech stream and that of the attended speech stream may compete for neural resources.

Significance Statement

Loud environments such as busy pubs or restaurants can make conversation difficult. However, they also allow us to eavesdrop into other conversations that occur in the background. In particular, we often notice when somebody else mentions our name, even if we have not been listening to that person. However, the neural mechanisms by which background speech is processed remain poorly understood. Here we employ transcranial alternating current stimulation, a technique through which neural activity in the cerebral cortex can be influenced, to show that cortical responses to rhythms in the distractor speech modulate the comprehension of the target speaker. Our results evidence that the cortical tracking of background speech rhythms plays a functional role in speech processing.
Critical evaluation of kinetic schemes for coagulation
Authors: Ranc Alexandre , Bru Salome , Mendez Simon , Giansily-Blaizot Muriel , Nicoud Franck , Méndez Rojano Rodrigo
Published: April 2021

Computational models of the coagulation cascade are used for a wide range of applications in bio-medical engineering such as drug and bio-medical device developments. However, a lack of robustness of numerical models has been highlighted when studying clinically relevant scenarios. In order to develop more robust models, numerical simulations need to be confronted with realistic situations relevant to clinical practice. In this work, two well-established numerical representations of the coagulation cascade initiated by the intrinsic and extrinsic systems, respectively, were compared with thrombin generation assays considering realistic pathological conditions. Proper modifications were needed to align thein vitroandin silicodata, namely; adapting initial conditions to the thrombin assay system, omitting reactions irrelevant to our case study, and improving the fitting of some reaction rates. The modified models were able to capture the experimental trends of thrombin generation for a range of concentrations of factors XII, XI, and VIII for cases in which the coagulation cascade is triggered through the extrinsic and intrinsic systems. Our work emphasizes that when existing coagulation cascade models are extrapolated to experimental settings for which they were not calibrated, careful adjustments must be made. We show that the two coagulation models used in this work can predict physiological conditions, but when studying pathological conditions, proper modifications are needed to improve the numerical results.
The Kinship Matrix: Inferring the Kinship Structure of a Population from its Demography
Authors: Coste Christophe F. D. , Bienvenu François , Ronget Victor , Ramirez-Loza Juan-Pablo , Cubaynes Sarah , Pavard Samuel
Published: April 2021

The familial structure of a population and the relatedness of its individuals are determined by its demography. There is, however, no general method to infer kinship directly from the life-cycle of a structured population. Yet this question is central to fields such as ecology, evolution and conservation, especially in contexts where there is a strong interdependence between familial structure and population dynamics. Here, we give a general formula to compute, from any matrix population model, the expected number of arbitrary kin (sisters, nieces, cousins, etc) of a focal individualego, structured by the class ofegoand of its kin. Central to our approach are classic but little-used tools known as genealogical matrices. Our method can be used to obtain both individual-based and population-wide metrics of kinship, as we illustrate. It also makes it possible to analyze the sensitivity of the kinship structure to the traits implemented in the model.
Developmental changes in story-evoked responses in the neocortex and hippocampus
Authors: Cohen Samantha S. , Tottenham Nim , Baldassano Christopher
Published: April 2021

How does the representation of naturalistic life events change with age? Here we analyzed fMRI data from 414 children and adolescents (5 - 19 years) as they watched a narrative movie. In addition to changes in the degree of inter-subject correlation (ISC) with age in sensory and medial parietal regions, we used a novel measure (between-group ISC) to reveal age-related shifts in the responses across the majority of the neocortex. Over the course of development, brain responses became more discretized into stable and coherent events and shifted earlier in time to anticipate upcoming perceived event transitions, measured behaviorally in an age-matched sample. However, hippocampal responses to event boundaries actually decreased with age, suggesting a shifting division of labor between episodic encoding processes and schematic event representations between the ages of 5 and 19.
A counter-enzyme complex regulatesglutamate metabolism inBacillus subtilis
Authors: Jayaraman Vijay , Lee D. John , Elad Nadav , Vimer Shay , Sharon Michal , Fraser James S. , Tawfik Dan S.
Published: April 2021

Multi-enzyme assemblies composed of metabolic enzymes catalyzing sequential reactions are being increasingly studied. Here, we report the discovery of a 1.6 megadalton multi-enzyme complex fromBacillus subtiliscomposed of two enzymes catalyzing opposite rather than sequential reactions (“counter-enzymes”): glutamate synthase (GltAB), and glutamate dehydrogenase (GudB), that make and break glutamate, respectively.In vivoandin vitrostudies show that the primary role of complex formation is to inhibit GudB’s activity as this enzyme is constitutively expressed including in glutamate-limiting conditions. Using cryo-electron microscopy, we elucidated the structure of the complex and the basis of GudB’s inhibition. Finally, we show that this complex that exhibits unusual oscillatory progress curves is a necessity for planktonic growth in glutamate-limiting conditions, but is also essential for biofilm growth in glutamate-rich media, suggesting a regulatory role at fluctuating glutamate concentrations.