bluuebunny/crossref_metadata_2025 huggingface dataset:
HLA-associated preadaptation in HIV Vif is associated with higher set point viral load and faster CD4+ decline in Zambian transmission pairs
Authors: Connolly Sarah , Carlson Jonathan M. , Schaefer Malinda , Bere Alfred , Kilembe William , Allen Susan , Hunter Eric
Published: March 2021

Objective (s):

We investigated the relationship between human leukocyte antigen (HLA)-associated preadaptation for the entire subtype C HIV-1 proteome of the transmitted founder virus and subsequent HIV-1 disease progression in a cohort of heterosexual linked transmission pairs in Zambia.

Design:

An adaptation model was used to calculate an adaptation score for each virus-HLA combination in order to quantify the degree of preadaptation of the transmitted virus to the linked recipient's HLA alleles. These scores were then assessed for their relationship to viral load and longitudinal CD4+ decline in the recipient.

Methods:

Viral RNA was extracted from the plasma of the donor partner and the linked recipient near the time of transmission, as well as longitudinally from the linked recipient. Viral adaptation scores were calculated for each individual and each protein in the subtype C HIV-1 proteome.

Results:

The majority of HLA-associated sites were located in Gag, Pol and Nef; however, proportional to protein length, the accessory and regulatory proteins contained a relatively high proportion of HLA-associated sites. Over the course of infection, HLA-mediated immune adaptation increased for all proteins except Vpu and gp120. Preadaptation was positively associated with higher early set point viral load and faster CD4+ decline. When examined by protein, preadaptation in Pol and Vif were statistically significantly associated with these markers of disease progression.

Conclusion:

Adaptation in Pol had the greatest impact on viral control. Despite containing a large proportion of HLA-associated sites, Vif was the only regulatory or accessory protein for which preadaptation significantly correlated with disease progression.
Load-Bearing Capacity and Design Advantages of a Custom-Made, Thin Pure-Titanium Cranioplasty (CranioTop)
Authors: Lewitz Marc , Salma Asem , Welzel Saravia Heinz , Sakellaropoulou Ioanna , Sarkis Hraq Mourad , Ewelt Christian , Fortmann Thomas , Wilbers Eike , Schipmann Stephanie , Suero Molina Eric , Santacroce Antonio , Zawy Alsofy Samer
Published: March 2021

Background:

Adequate and stable coverage of cranial contour and continuity defects of any origin is a common challenge in neurosurgical clinics. This study presents the results of investigations concerning the mechanical load-bearing capacity and design advantages of custom-made implants made from a thin, pure-titanium sheet (CranioTop) (CLinstruments, Attendorn, Germany) for covering complex cranial defects.

Methods:

In 9 test series, the stability of three differently shaped and sized thin titanium sheet implants was tested using vertical, uniaxial compression with 3 different compression stamps, to investigate the behaviour of these implants in relation to punctiform as well as planar forces.

Results:

All 9 model implants showed elastic behavior in the synchronously recorded force/displacement diagrams at an impression of up to 2 mm. The forces at 2 mm deformation were between 170.1 and 702.7 Newton.

Conclusion:

Cranioplasty using CranioTop is a stable procedure for covering skull defects, even those of large dimensions. An added advantage is the significant reduction in effort required to prepare the area of the bone margins compared to other current techniques of cranioplasty.
Anatomical Features in Lower-Lip Depressor Muscles for Optimization of Myectomies in Marginal Mandibular Nerve Palsy
Authors: Vejbrink Kildal Villiam , Jensson David , Weninger Wolfgang J. , Meng Stefan , Tzou Chieh-Han John , Rodriguez-Lorenzo Andrés
Published: March 2021

Introduction:

Myectomies of the lower-lip depressor muscles, with the aim to improve facial balance in unilateral facial paralysis, have unexplained high recurrence rates. A potential explanation is that these recurrences are due to inadequate resection through the muscle width, leaving lateral muscle fibers intact.

Aim:

Revisit the anatomy of the lower-lip depressor muscles and suggest an optimization of the surgical technique. Perform a literature review to identify recurrence rates and surgical technique of the procedure.

Materials and Methods:

Ten fresh hemifaces were dissected. The following measurements of depressor labii inferioris and depressor anguli oris were made: the widths of the muscles, the distance from the mandibular midline to the lateral borders of the muscles, and the intraoral distance from the lateral canine to the lateral border of depressor anguli oris. A literature review was performed.

Results:

The width of depressor labii inferioris was 20 ± 4 mm and depressor anguli oris 14 ± 3 mm. The distance from the midline to the lateral border of depressor labii inferioris was 32 ± 4 mm and 54 ± 4 mm for depressor anguli oris. The literature review revealed a mean recurrence rate of 21%.

Discussion:

A potential optimization of the surgical technique in lower-lip depressor myectomies is to extend the muscle resection laterally. To ensure inclusion of the whole width of the depressor muscles and decrease the recurrence rates of the procedure, the measurements presented in this study should be kept in mind during surgery.
Anatomical Findings and Short-term Efficacy of Fascial Anatomy-guided Infrapyloric Lymphadenectomy in Laparoscopic Radical Gastrectomy for Gastric Cancer
Authors: Xu Yanchang , Li Zhixiong , Pan Guofeng , Wu Haiyan , Li Junpeng , Lin Wenlin , Chen Jian , Cai Zhifeng
Published: March 2021

Objective:

The aim was to investigate the anatomical layers of the specific fascia involved in infrapyloric lymphadenectomy in laparoscopic radical gastrectomy for gastric cancer and to analyze the short-term efficacy of an anatomy-guided surgical approach.

Materials and Methods:

On the basis of many years of clinical practice in fascial anatomy-guided laparoscopic radical gastrectomy for gastric cancer, we proposed anatomical considerations for infrapyloric lymphadenectomy in this procedure and investigated the anatomy of the mesentery and mesenteric fusion in this region, including the specific starting and ending points and the plane of the operation. We also retrospectively analyzed the clinical data of 265 patients who underwent fascial anatomy-guided infrapyloric lymphadenectomy in laparoscopic radical gastrectomy for gastric cancer from January 2015 to January 2019 and compared the short-term efficacy between the fascial anatomy-guided laparoscopic infrapyloric lymphadenectomy plus mesogastric excision group and the laparoscopic infrapyloric lymphadenectomy group.

Results:

Extensive mesenteric fusion and folds exist in the infrapyloric region of the stomach, and removal of the medial fold (medial leg) and lateral fold (lateral leg) of the infrapyloric mesogastrium during surgery is easily missed, resulting in incomplete removal of the infrapyloric mesogastrium. Baseline data were comparable between the laparoscopic infrapyloric lymphadenectomy plus mesogastric excision group and the laparoscopic infrapyloric lymphadenectomy group. The mean operative time for infrapyloric lymphadenectomy, the number of positive lymph nodes harvested in the infrapyloric region, and the number of patients with mesenteric metastasis in the infrapyloric region were not significantly different (P>0.05). The number of harvested lymph nodes was higher in the laparoscopic infrapyloric lymphadenectomy plus mesogastric excision group than in the laparoscopic infrapyloric lymphadenectomy group (5.09±3.30 vs. 4.13±2.90, P<0.05), and intraoperative blood loss was lower in the former group than in the latter group (5.89±3.78 vs. 25.21±11.24 mL, P=0.000).

Conclusion:

Fascial anatomy-guided laparoscopic infrapyloric lymphadenectomy enables systematic and complete removal of the lymph nodes and mesentery of the infrapyloric region with less intraoperative blood loss.
Use of disease-modifying drugs during pregnancy and breastfeeding
Authors: Dobson Ruth , Hellwig Kerstin
Published: March 2021

Purpose of review

The fact that multiple sclerosis (MS) predominantly affects women has been recognized for many years. As the age at diagnosis is decreasing, and treatment options are becoming more complex, increasing numbers of women are facing decisions about the use of disease modifying therapy (DMT) in and around pregnancy.

Recent findings

New data are rapidly becoming available, particularly regarding the safety of therapies in both pregnancy and breastfeeding. Effective treatment and suppression of relapses is key to ensuring good outcomes in the longer term for the woman, however this must be balanced against individual risk of relapse and risks to the fetus. Women should be advised that it is possible to breastfeed while taking selected DMT.

In this review, we discuss evidence surrounding the safety of DMTs in both pregnancy and breastfeeding, and use this knowledge to suggest approaches to pregnancy and family planning in women with MS.
Validation of Automated Biventricular Myocardial Segmentation from Coronary Computed Tomographic Angiography for Multimodality Image Fusion
Authors: Piccinelli Marina , Dahiya Navdeep , Folks Russell D , Yezzi Anthony , Garcia Ernest V
Published: March 2021

Purpose

Image fusion strategies of myocardial perfusion imaging (MPI) and coronary CT angiography (CCTA) have shown increased diagnostic power. However, their clinical feasibility is hindered by the lack of efficient algorithms for the extraction of cardiac anatomy from CCTA datasets. The aim of this work was to validate our previously published algorithm for automated cardiac segmentation of CCTAs in a larger cohort of subjects while testing its application in clinical settings.

Methods

Three borders were automatically and manually extracted on sixty-three clinical CCTAs: left and right endocardia (LV, RV) and the biventricular epicardium (EPI). Impact of image resolutions and inter-operator variability on accuracy and robustness of automated processing were evaluated. Automated algorithm accuracy was assessed with the Dice Similarity Coefficient (DSC) and the surface-to-surface distance metric. Relevant quantities were compared for automated versus manual segmentations: LV and RV volumes, myocardial mass and LV myocardial mass.

Results

Lower resolution images offered an acceptable trade-off for accuracy and processing time (45 sec). DSC for LV, RV, EPI borders were 0.88, 0.80 and 0.89. Automated versus manual correlation coefficients for LV and RV vol, myo and LV mass were 0.96, 0.73, 0.84 and 0.67 with inter-operator agreement > 0.93 for three variables. Consistent and improved results were evidenced at higher resolutions.

Conclusion

Our algorithms allowed efficient automated cardiac segmentation from CT imagery with minimal user intervention, clinically acceptable times and accuracy. The reported results show promise for its use in a clinical environment, specifically in the context of image fusion.
SARS-CoV-2 antibody prevalence and determinants of six ethnic groups living in Amsterdam, the Netherlands: a population-based cross-sectional study, June-October 2020
Authors: Coyer Liza , Boyd Anders , Schinkel Janke , Agyemang Charles , Galenkamp Henrike , Koopman Anitra D M , Leenstra Tjalling , van Charante Eric P Moll , van den Born Bert-Jan H , Lok Anja , Verhoeff Arnoud , Zwinderman Aeilko H , Jurriaans Suzanne , van Vught Lonneke A , Stronks Karien , Prins Maria
Published: March 2021

Background

Ethnic minorities have higher rates of SARS-CoV-2 diagnoses, but little is known about ethnic differences in past exposure. We aimed to determine whether prevalence and determinants of SARS-CoV-2 exposure varied between six ethnic groups in Amsterdam, the Netherlands.

Methods

Participants aged 25-79 years enrolled in a population-based prospective cohort were randomly selected within ethnic groups and invited to test for SARS-CoV-2-specific antibodies and answer COVID-19 related questions. We estimated prevalence and determinants of SARS-CoV-2 exposure within ethnic groups using survey-weighted logistic regression adjusting for age, sex and calendar time.

Results

Between June 24-October 9, 2020, we included 2497 participants. Adjusted SARS-CoV-2 seroprevalence was comparable between ethnic-Dutch (25/498; 5.5%, 95%CI=3.2-7.9), South-Asian Surinamese (22/451; 4.8%, 95%CI=2.1-7.5), African Surinamese (22/400; 8.2%, 95%CI=3.0-13.4), Turkish (30/408; 7.8%, 95%CI=4.3-11.2) and Moroccan (32/391; 7.0%, 95%CI=4.0-9.9) participants, but higher among Ghanaians (95/327; 26.5%, 95%CI=18.7-34.4). 57.1% of SARS-CoV-2-positive participants did not suspect or were unsure of being infected, which was lowest in African Surinamese (18.2%) and highest in Ghanaians (90.5%). Determinants of SARS-CoV-2 exposure varied across ethnic groups, while the most common determinant was having a household member suspected of infection. In Ghanaians, seropositivity was associated with older age, larger household sizes, living with small children, leaving home to work and attending religious services.

Conclusions

No remarkable differences in SARS-CoV-2 seroprevalence were observed between the largest ethnic groups in Amsterdam after the first wave of infections. The higher infection seroprevalence observed among Ghanaians, which passed mostly unnoticed, warrants wider prevention efforts and opportunities for non-symptom-based testing.
A human multisystem disorder with autoinflammation, leukoencephalopathy and hepatopathy is caused by mutations in C2orf69
Authors: Lausberg Eva , Gießelmann Sebastian , Dewulf Joseph P , Wiame Elsa , Holz Anja , Salvarinova Ramona , Karnebeek Clara Van , Klemm Patricia , Ohl Kim , Mull Michael , Braunschweig Till , Weis Joachim , Sommer Clemens , Demuth Stephanie , Haase Claudia , Debray François-Guillaume , Libioulle Cecile , Choukair Daniela , Oommen Prasad T. , Borkhardt Arndt , Surowy Harald , Wieczorek Dagmar , Meyer Robert , Eggermann Thomas , Begemann Matthias , Schaftingen Emile Van , Häusler Martin , Tenbrock Klaus , den Heuvel Lambert van , Elbracht Miriam , Kurth Ingo , Kraft Florian
Published: March 2021

Background

Deciphering the function of the many genes previously classified as uncharacterized “open reading frame” (orf) completes our understanding of cell function and its pathophysiology.

Methods

Whole-exome sequencing, yeast 2-hybrid and transcriptome analyses together with molecular characterization are used here to uncover the function of the C2orf69 gene.

Results

We identify loss-of-function mutations in the uncharacterized C2orf69 gene in eight individuals with brain abnormalities involving hypomyelination and microcephaly, liver dysfunction and recurrent autoinflammation. C2orf69 contains an N-terminal signal peptide that is required and sufficient for mitochondrial localization. Consistent with mitochondrial dysfunction, patients show signs of respiratory chain defect and a CRISPR-Cas9 knockout cell model of C2orf69 shows comparable respiratory chain defects. Patient-derived cells reveal alterations in immunological signaling pathways. Deposits of PAS-positive material in tissues from affected individuals together with decreased glycogen branching enzyme 1 (GBE1) activity indicate an additional impact of C2orf69 on glycogen metabolism.

Conclusion

Our study identifies C2orf69 as an important regulator of human mitochondrial function and suggests an additional influence on other metabolic pathways.

Graphical Abstract
Evolutionary and phenotypic characterization of spike mutations in a new SARS-CoV-2 Lineage reveals two Variants of Interest
Authors: Ruiz-Rodriguez Paula , Francés-Gómez Clara , Chiner-Oms Álvaro , López Mariana G. , Jiménez-Serrano Santiago , Cancino-Muñoz Irving , Ruiz-Hueso Paula , Torres-Puente Manuela , Bracho Maria Alma , D’Auria Giuseppe , Martinez-Priego Llúcia , Guerreiro Manuel , Montero-Alonso Marta , Gómez María Dolores , Piñana José Luis ,   SeqCOVID-SPAIN consortium, González-Candelas Fernando , Comas Iñaki , Marina Alberto , Geller Ron , Coscolla Mireia
Published: March 2021

Molecular epidemiology of SARS-CoV-2 aims to monitor the appearance of new variants with the potential to change the virulence or transmissibility of the virus. During the first year of SARS-CoV-2 evolution, numerous variants with possible public health impact have emerged. We have detected two mutations in the Spike protein at amino acid positions 1163 and 1167 that have appeared independently multiple times in different genetic backgrounds, indicating they may increase viral fitness. Interestingly, the majority of these sequences appear in transmission clusters, with the genotype encoding mutations at both positions increasing in frequency more than single-site mutants. This genetic outcome that we denote as Lineage B.1.177.637, belongs to clade 20E and includes 12 additional single nucleotide polymorphisms but no deletions with respect to the reference genome (first sequence in Wuhan). B.1.177.637 appeared after the first wave of the epidemic in Spain, and subsequently spread to eight additional countries, increasing in frequency among sequences in public databases. Positions 1163 and 1167 of the Spike protein are situated in the HR2 domain, which is implicated in the fusion of the host and viral membranes. To better understand the effect of these mutations on the virus, we examined whether B.1.177.637 altered infectivity, thermal stability, or antibody sensitivity. Unexpectedly, we observed reduced infectivity of this variant relative to the ancestral 20E variantin vitrowhile the levels of viral RNA in nasopharyngeal swabs did not vary significantly. In addition, we found the mutations do not impact thermal stability or antibody susceptibility in vaccinated individuals but display a moderate reduction in sensitivity to neutralization by convalescent sera from early stages of the pandemic. Altogether, this lineage could be considered a Variant of Interest (VOI), we denote VOI1163.7. Finally, we detected a sub-cluster of sequences within VOI1163.7 that have acquired two additional changes previously associated with antibody escape and it could be identified as VOI1163.7.V2. Overall, we have detected the spread of a new Spike variant that may be advantageous to the virus and whose continuous transmission poses risks by the acquisition of additional mutations that could affect pre-existing immunity.
Ensemble Forecasts of Seasonal Dengue Epidemics
Authors: Chen Yuliang , Liu Tao , Pei Sen , Yu Xiaolin , Zeng Qinghui , Wu Haisheng , Xiao Jianpeng , Ma Wenjun , Guo Pi
Published: March 2021

As a common vector-borne disease, dengue fever still remains a lot of challenges to forecast for which the significant distinction of epidemic scale is affected by multiple factors, such as mosquito density, meteorological conditions, geographical environment, travel and so on. To track down the epidemic scale and forecast the remaining time of epidemic season, the population size affected by the epidemic is evaluated before the compartmental model is optimized by assimilation observation with filtering method. In retrospective forecast of dengue pandemic for Guangzhou from 2014-2015 seasons, accurate forecast of dengue cases is generated with an accurate prediction of peak time in all time periods. The real-time forecast system shows a good performance on capturing the trajectory of dengue transmission and scale of epidemic.
Cumulative incidence of SARS-CoV-2 infection and associated risk factors among frontline health care workers in Paris, France: the SEROCOV prospective cohort study
Authors: Hausfater Pierre , Boutolleau David , Lacombe Karine , Beurton Alexandra , Dumont Margaux , Constantin Jean-Michel , Ghosn Jade , Combes Alain , Cury Nicolas , Guedj Romain , Djibré Michel , Bompard Rudy , Mazerand Sandie , Pourcher Valérie , Gimeno Linda , Marois Clemence , Teyssou Elisa , Marcelin Anne-Geneviève , Hajage David , Tubach Florence
Published: March 2021

Background

With the COVID-19 pandemic, documenting whether health care workers (HCWs) are at increased risk of SARS-CoV-2 contamination and identifying risk factors is of major concern.

Methods

In this multicenter prospective cohort study, HCWs from frontline departments were included in March and April 2020 and followed for 3 months. SARS-CoV-2 serology was performed at month 0 (M0), M1, and M3 and RT-PCR in case of symptoms. The primary outcome was laboratory-confirmed SARS-CoV-2 infection at M3. Risk factors of laboratory-confirmed SARS-CoV-2 infection at M3 were identified by multivariate logistic regression.

Results

Among 1,062 HCWs (median [interquartile range] age, 33 [28-42] years; 758 [71.4%] women; 321 [30.2%] physicians), the cumulative incidence of SARS-CoV-2 infection at M3 was 14.6% (95% confidence interval [CI] [12.5; 16.9]). Risk factors were the working department specialty, with increased risk for intensive care units (odds ratio 1.80, 95%CI [0.38; 8.58]), emergency departments (3.91 [0.83; 18.43]) and infectious diseases departments (4.22 [0.92; 18.28]); active smoking was associated with reduced risk (0.36 [0.21; 0.63]). Age, sex, professional category, number of years of experience in the job or department, and public transportation use were not significantly associated with laboratory-confirmed SARS-CoV-2 infection at M3.

Conclusion

The rate of SARS-CoV-2 infection in frontline HCWs was 14.6% at the end of the first COVID-19 wave in Paris and occurred mainly early. The study argues for an origin of professional in addition to private life contamination and therefore including HCWs in the first-line vaccination target population. It also highlights that smokers were at lower risk.

Key messages

During the first epidemic wave, 14.6% of 1,062 first-line Health Care Workers had a positive serology and/or RT-PCR test for SARS-CoV-2.

Most infections occurred early

Risk was increased by working in infectious diseases (OR 4.22, 95% confidence interval [0.92; 18.28]), emergency (3.91 [0.83; 18.43]) and intensive care units (1.80, [0.38; 8.58])

Being an active smoker was protective (0.36 [0.21; 0.3]).
Antibody response to SARS-CoV-2 vaccination is extremely vivacious in subjects with previous SARS-CoV-2 infection
Authors: Callegaro Annapaola , Borleri Daniela , Farina Claudio , Napolitano Gavino , Valenti Daniela , Rizzi Marco , Maggiolo Franco
Published: March 2021

Background

The SARS-CoV-2 pandemic calls for rapid actions, now principally oriented to a world-wide vaccination campaign.

In this study we verified if, in individuals with a previous SARS-CoV-2 infection, a single dose of mRNA vaccine would be immunologically equivalent to a full vaccine schedule in naïve individuals.

Methods

Health care workers (184) with a previous SARS-CoV-2 infection were sampled soon before the second dose of vaccine and between 7 and 10 days after the second dose, the last sampling time was applied to SARS-CoV-2 naïve individuals, too.

Antibodies against SARS-CoV-2 were measured using Elecsys® Anti-SARS-CoV-2 S immunoassay.

The study was powered for non-inferiority. We used non parametric tests and Pearson correlation test to perform inferential analysis.

Results

After a single vaccine injection, the median titer of specific antibodies in individuals with previous COVID-19 was 30,527 U/ml (IQR 19,992-39,288) and in subjects with previous SARS-CoV-2 asymptomatic infection was 19,367.5 U/ml (IQR 14,688-31,353) (P=0.032). Both results were far above the median titer in naïve individuals after a full vaccination schedule: 1,974.5 U/ml (IQR 895-3,455) (P<0.0001). Adverse events after vaccine injection were more frequent after the second dose of vaccine (mean 0.95, 95%CI from 0.75 to 1.14 versus mean 1.91, 95%CI from 1.63 to 2.19)(P<0.0001) and in exposed compared to naïve (mean 1.63; 95%CI from 1.28 to 1.98 versus mean 2.35; 95%CI from 1.87 to 2.82)(P=0.015).

Conclusion

In SARS-CoV-2 naturally infected individuals a single mRNA vaccine dose seems sufficient to reach immunity. Modifying current dosing schedules would speed-up vaccination campaigns.
Global association of obesity and COVID-19 death rates
Authors: Adams Mary L.
Published: March 2021

Importance

COVID-19 was responsible for an enormous global death toll with large variation among countries.

Objective

To examine the possible impact of obesity on COVID-19 death rates.

Design

Measure associations between obesity rates in 2016 and COVID-19 deaths/million population through 2/25/2021, across countries.

Setting

Global

Participants

167 countries for which obesity and death data were available, grouped by population size, with multiples of 10 countries in each of 8 groups plus a group including all 57 countries with obesity rates <15%.

Outcome and measures

Using Excel, COVID-19 deaths/million were regressed on the obesity rate for each country, based on obesity being a key factor in COVID hospitalizations and deaths. Using the least squares formula for the best fit for each model, R2, components of the formula, and the percentage of world population represented, were recorded for each group.

Results

Obesity rates ranged from 2.1% to 37.9% and death rates ranged from 0.4/million to 1,892/million for groups representing up to 91% of global population. Results for the 8 population groups had R2 from 0.30 to 0.90 with slopes of the fitted line ranging from 27.9-51.0. Countries with obesity rates <15% had consistently low death rates (≤233/million), R2 of 0.003 and slope of the line=1.01.

Conclusions

For most countries about one-third of the difference in COVID death rates was due to obesity while in countries with obesity <15%, consistently low death rates were not associated with obesity. Reduced obesity rates could potentially have lowered the COVID death toll.
What role for asbestos in idiopathic pulmonary fibrosis? Findings from the IPF job exposures study
Authors: Reynolds Carl J , Sisodia Rupa , Barber Chris , Minelli Cosetta , Matteis Sara De , Moffatt Miriam , Cherrie John , Taylor Anthony Newman , Cullinan Paul , Fletcher Sophie , Walters Gareth , Spenser Lisa , Parfrey Helen , Saini Gauri , Chaudhuri Nazia , West Alex , Adamali Huzaifa , Beirne Paul , Forrest Ian , Gibbons Michael , Pepperell Justin , Hirani Nik , Harrison Kim , Dempsey Owen , O’Hickey Steve , Thickett David , Parekh Dhruv , Babu Suresh , Wilson Andrew , Chalmers George , Wickremasinghe Melissa , Coker Robina
Published: March 2021

Rationale

Asbestos is posited to cause otherwise ‘idiopathic’ pulmonary fibrosis (IPF); establishing this has important diagnostic and therapeutic implications.

Objectives

To determine the association between occupational asbestos exposure and IPF; to investigate interaction with MUC5B rs35705950 genotype.

Methods

Multi-centre, incident case-control study. Cases (n=494) were men diagnosed with IPF at 21 United Kingdom hospitals. Controls (n=466) were age-matched men who attended a hospital clinic in the same period. Asbestos exposure was measured using a validated job exposure matrix and a source-receptor model. The primary outcome was the association between asbestos exposure and IPF, estimated using logistic regression adjusted for age, smoking and centre. Interaction with MUC5B rs3570950 was investigated using a genetic dominant model.

Measurements and Main Results

327 (66%) cases and 293 (63%) controls ever had a high or medium asbestos exposure risk job; 8% of both cases and controls, had cumulative exposure estimates ≥ 25 fibre.ml−1.years. Occupational asbestos exposure was not associated with IPF, adjusted OR 1.1(95%CI 0.8-1.4; p=0.6) and there was no gene-environment interaction (p=0.2). Ever smoking was associated with IPF, OR 1.4 (95%CI 1-1.9; p=0.04). When stratifying for genotype there was significant interaction between smoking and work in an exposed job (p<0.01) for carriers of the minor allele of MUC5B rs3570950.

Conclusions

Occupational asbestos exposure alone, or through interaction with MUC5B rs35705950 genotype, was not associated with IPF. However, exposure to asbestos and smoking interact to increase IPF risk in carriers of the minor allele of MUC5B rs3570950.

Clinical trial registered with www.clinicaltrials.gov (NCT03211507).
A Data-driven Framework for Learning and Visualizing Characteristics of Thrombotic Event Phenotypes from Clinical Texts
Authors: Davoudi Anahita , Yang Audrey , Hwang Sy , Mowery Danielle L.
Published: March 2021

Automatically identifying thrombotic phenotypes based on clinical data, particularly clinical texts, can be challenging. Although many investigators have developed targeted information extraction methods for identifying thrombotic phenotypes from radiology notes, these methods can be time consuming to train, require large amounts of training data, and may miss subtle textual clues predictive of a thrombotic phenotype from notes beyond the radiology note. We developed a generalizable, data-driven framework for learning, characterizing, and visualizing clinical concepts from both radiology and discharge summaries predictive of thrombotic phenotypes.
Environmental drivers of SARS-CoV-2 lineage B.1.1.7 transmission intensity
Authors: Smith Thomas P. , Dorigatti Ilaria , Mishra Swapnil , Volz Erik , Walker Patrick G. T. , Ragonnet-Cronin Manon , Tristem Michael , Pearse William D.
Published: March 2021

Previous work has shown that environment affects SARS-CoV-2 transmission, but it is unclear whether emerging strains show similar responses. Here we show that, like other SARS-CoV-2 strains, lineage B.1.1.7 spread with greater transmission in colder and more densely populated parts of England. However, we also find evidence of B.1.1.7 having a transmission advantage at warmer temperatures compared to other strains. This implies that spring and summer conditions are unlikely to slow B.1.1.7’s invasion in Europe and across the Northern hemisphere - an important consideration for public health interventions.
The fast-slow continuum is not the end-game of life history evolution, human or otherwise
Authors: Salguero-Gómez Roberto
Published: March 2021

Life history human evolution places a strong emphasis on the fast-slow continuum and pace-of-life continuum. Papers in this area frequently make a call for more integrative research to explore the relationships between the fast-slow continuum (population-level variation in traits) and pace-of-life continuum (ditto at the individual level). Here, using high-resolution demographic models from natural populations of 41 modern human populations, and hundreds of non-human animal populations and plant populations, I show that the fast-slow continuum, while of interest to explore variation in human strategies, should not be the sole focus of attention. Using a phylogenetically corrected principal component analysis, I show that other axes of life history variation show great promise. Specifically, understanding of the mechanisms of inter-specific and intra-specific differences in senescence rates in reproduction and survival, and how species respond to stochastic variation, I argue, should become the focus of my interdisciplinary research. The proposed new axis of demographic buffering-lability emerges as an important one to explain over 20% of variation in human and non-human populations. I show that these axes help predict demographic resilience, and also correlates with human nation per capita GDP and population growth rates.
Contribution of SARS-CoV-2 accessory proteins to viral pathogenicity in K18 hACE2 transgenic mice
Authors: Silvas Jesus , Morales-Vasquez Desarey , Park Jun-Gyu , Chiem Kevin , Torrelles Jordi B. , Platt Roy Neal , Anderson Tim , Ye Chengjin , Martinez-Sobrido Luis
Published: March 2021

Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) is the viral pathogen responsible for the current coronavirus disease 2019 (COVID-19) pandemic. To date, it is estimated that over 113 million individuals have been infected with SARS-CoV-2 and over 2.5 million human deaths have been recorded worldwide. Currently, three vaccines have been approved by the Food and Drug Administration for emergency use only. However much of the pathogenesis observed during SARS-CoV-2 infection remains elusive. To gain insight into the contribution of individual accessory open reading frame (ORF) proteins in SARS-CoV-2 pathogenesis, we used our recently described reverse genetics system approach to successfully engineer recombinant (r)SARS-CoV-2, where we individually removed viral 3a, 6, 7a, 7b, and 8 ORF proteins, and characterized these recombinant virusesin vitroandin vivo. Our results indicate differences in plaque morphology, with ORF deficient (ΔORF) viruses producing smaller plaques than those of the wild-type (rSARS-CoV-2/WT). However, growth kinetics of ΔORF viruses were like those of rSARS-CoV-2/WT. Interestingly, infection of K18 human angiotensin converting enzyme 2 (hACE2) transgenic mice with the ΔORF rSARS-CoV-2 identified ORF3a and ORF6 as the major contributors of viral pathogenesis, while ΔORF7a, ΔORF7b and ΔORF8 rSARS-CoV-2 induced comparable pathology to rSARS-CoV-2/WT. This study demonstrates the robustness of our reverse genetics system to generate rSARS-CoV-2 and the major role for ORF3a and ORF6 in viral pathogenesis, providing important information for the generation of attenuated forms of SARS-CoV-2 for their implementation as live-attenuated vaccines for the treatment of SARS-CoV-2 infection and associated COVID-19.

IMPORTANCE

Despite great efforts put forward worldwide to combat the current coronavirus disease 2019 (COVID-19) pandemic, Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) continues to be a human health and socioeconomic threat. Insights into the pathogenesis of SARS-CoV-2 and contribution of viral proteins to disease outcome remains elusive. Our study aims to determine the contribution of SARS-CoV-2 accessory open reading frame (ORF) proteins in viral pathogenesis and disease outcome, and develop a synergistic platform combining our robust reverse genetics system to generate recombinant (r)SARS-CoV-2 with a validated rodent model of infection and disease. We demonstrated that SARS-CoV-2 ORF3a and ORF6 contribute to lung pathology and ultimately disease outcome in K18 hACE2 transgenic mice, while ORF7a, ORF7b, and ORF8 have little impact on disease outcome. Moreover, our combinatory platform serves as the foundation to generate attenuated forms of the virus to develop live-attenuated vaccines for the treatment of SARS-CoV-2.
The BioNTech / Pfizer vaccine BNT162b2 induces class-switched SARS-CoV-2-specific plasma cells and potential memory B cells as well as IgG and IgA serum and IgG saliva antibodies upon the first immunization
Authors: Lixenfeld Anne S. , Künsting Inga , Martin Emily L. , Kopylow Vera von , Lehrian Selina , Lunding Hanna B. , Buhre Jana S. , Quack Janna , Steinhaus Moritz , Graf Tobias , Ehlers Marc , Rahmöller Johann
Published: March 2021

To treat the SARS-CoV-2 virus, that enters the body through the respiratory tract, different vaccines in particular against the SARS-CoV-2 spike (S)-protein have been developed or are in the development process. For the BioNTech / Pfizer mRNA vaccine BNT162b2, which is injected twice, protection against COVID-19 has been described for the first weeks after the second vaccination. The underlying mechanisms of defense and the long-term effectiveness of this vaccine against COVID-19 are currently under investigation.

In addition to the induction of systemic antibodies (Abs), Ab responses in the respiratory tract would help to form a first line of defense against SARS-CoV-2. Furthermore, protection depends on Fab-part-dependent neutralizing capacities, however, Fc-part-mediated effector mechanisms might also be important. Long-term defense would be based on the induction of long-lived antibody-producing plasma cells (PCs) and memory B cells.

Here, we established different assays to analyze anti-SARS-CoV-2-S IgG and IgA Abs in blood serum and saliva as well as SARS-CoV-2-S1-reactive IgG and IgA PCs and potential memory B cells in the blood of individuals upon their first immunization with BNT162b2.

We show that the vaccine induces in particular anti-SARS-CoV-2-S IgG1 and IgG3 as well as IgA1 and in some individuals also IgG2 and IgA2 serum Abs. In the saliva, we found no anti-SARS-CoV-2-S IgA, but instead IgG Abs. Furthermore, we found SARS-CoV-2-S reactive IgG+ blood PCs and potential memory B cells as well as SARS-CoV-2-S reactive IgA+ PCs and/or potential memory B cells in some individuals.

Our data suggest that the vaccine induces a promising CD4+ T cell-dependent systemic IgG1 and IgG3 Ab response with IgG+ PCs and potential memory B cells. In addition to the systemic IgG response, the systemic IgA and saliva IgG response might help to improve a first line of defense in the respiratory tract against SARS-CoV-2 and its mutants.
KAP survey of practicing doctors on antimicrobial stewardship based on openWHO course
Authors: Kaur Simerdeep , Sethi Prativa , Panda Prasan Kumar
Published: March 2021

Synopsis

Background

The overwhelming, irrational behaviour of using antimicrobial (AM) has added to the amplification and spread of antimicrobial resistance (AMR) burden. Healthcare professionals can curtail the AMR by practicing antimicrobial stewardship (AMS). Keeping this in view WHO has laid down a global action plan to combat AMR including free online availability of openWHO course. So, our study aimed at accessing the knowledge, attitude, and practice (KAP) of practicing doctors towards AMS based on this course in a tertiary care hospital.

Methods

The study was conducted among practitioners (faculty, senior residents, junior residents) in different clinical departments. The study was designed as a KAP survey. A validated self-administered questionnaire consisting of 29 questions was designed and shared among 200 participants through the mail and physically. Apart from observing knowledge/attitude/practice gaps, the difference in response to questions was evaluated among various groups (surgeon vs physician, faculty vs senior resident vs junior resident, openWHO course participant vs openWHO course aware non-participant vs openWHO course unaware non-participants.

Results

Response rate was 62.5% (n=200). Knowledge on AMS was observed among doctors’ with >50% near correct responses in each question except for the question asking on IV route of AM administration. A significant knowledge gap was found when a comparison was made between faculty members, senior residents, and junior residents (p <0.001) in the spectrum of activity of AM. Almost all the participants agreed that ASP is a necessity in the hospital and believed that ASP reduces healthcare costs and adverse effects of inappropriate AM prescription. A significant difference between the various groups’ aspects was also observed.

Conclusion

Knowledge gap on ASP is observed among all HCPs but significant differences among faculty, senior residents, and junior residents, among openWHO course vs unaware openWHO course participant. This shows faculty has to take the lead including more and more practice and education in ASP. The openWHO course may help in achieving this.
Acceptability of a nurse-led non-pharmacological complex intervention for knee pain: Nurse and patient views and experiences
Authors: Nomikos Polykarpos Angelos , Hall Michelle C , Fuller Amy , Ogollah Reuben , Valdes Ana M , Doherty Michael , Walsh David Andrew , Nair Roshan das , Abhishek Abhishek
Published: March 2021

Objectives

The overall purpose of this research programme is to develop and test the feasibility of a complex intervention for knee pain delivered by a nurse, and comprising both non-pharmacological and pharmacological interventions. In this first phase, we examined the acceptability of the non-pharmacological component of the intervention, issues faced in delivery, and resolve possible challenges.

Methods

Eighteen adults with chronic knee pain were recruited from the community. The intervention comprised holistic assessment, education, exercise, weight-loss advice (where appropriate) and advice on adjunctive treatments such as hot/cold treatments, footwear modification and walking aids. After nurse training, the intervention was delivered in four sessions spread over five weeks. Participants had one to one semi-structured interview at the end of the intervention. The nurse was interviewed after the last visit of the last participant. These were audio recorded and transcribed verbatim. Themes were identified by one author through framework analysis of the transcripts, and cross-checked by another.

Results

Most participants found the advice from the nurse easy to follow and were satisfied with the package, though some felt that too much information was provided too soon. The intervention changed their perception of managing knee pain, learning that it can be improved with self-management. However, participants thought that the most challenging part of the intervention was fitting the exercise regime into their daily routine. The nurse found discussion of goal setting to be challenging.

Conclusion

The nurse-led package of care is acceptable within a research setting. The results are promising and will be applied in a feasibility randomised-controlled trial.
Analytical and clinical performances of a SARS-CoV-2 S-RBD IgG assay: comparison with neutralization titers
Authors: Padoan Andrea , Bonfante Francesco , Cosma Chiara , Chiara Costanza Di , Sciacovelli Laura , Pagliari Matteo , Bortolami Alessio , Costenaro Paola , Musso Giulia , Basso Daniela , Giaquinto Carlo , Plebani Mario
Published: March 2021

Background

SARS-CoV-2 serology presents an important role in understanding the virus epidemiology, in vaccine prioritization strategies and in convalescent plasma therapy. Immunoassays performances have to be accurately evaluated and correlated with neutralizing antibodies to be used as a surrogate measure of neutralizing activity. We investigate the analytical and clinical performance of a SARS-CoV-2 RBD IgG assay, automated on a high throughput platform, and the correlation of the antibodies (Ab) levels with the plaque reduction neutralization (PRNT50) Ab titers.

Methods

A series of 546 samples were evaluated by SARS-CoV-2 RBD IgG assay (Snibe diagnostics), including 171 negative and 168 positive SARS-CoV-2 subjects and a further group of 207 subjects of the COVID-19 family clusters follow-up cohort.

Results

Assay precision was acceptable at low and medium levels; linearity was excellent in all the measurement range. Considering specimens collected after 14 days post symptoms onset, overall sensitivity and specificity were 99.0% and 92.5%, respectively. A total of 281 leftover samples results of the PRNT50 test were available. An elevated correlation was obtained between the SARS-CoV-2 RBD IgG assay and the PRNT50 titer at univariate (rho = 0.689) and multivariate (rho = 0.712) analyses.

Conclusions

SARS-CoV-2 S-RBD IgG assay achieves elevated analytical and clinical performances, and a strong correlation with sera neutralization activity.
The impact of headache disorders on COVID-19 survival: a world population-based analysis
Authors: Shapiro Robert E. , Gallardo Víctor J. , Caronna Edoardo , Pozo-Rosich Patricia
Published: March 2021

Importance

COVID-19 has not impacted people or countries uniformly. This disparity has prompted investigations to identify clinical and genetic predictors of COVID-19 mortality. Headache, a COVID-19 symptom, has been associated with positive disease prognosis. It is logical to consider whether primary headache disorders, among the most prevalent and disabling diseases globally, may also be associated with reduced viral mortality and thereby may have arisen as adaptive host defences

Objective

To study the relationship between COVID-19 mortality and primary headache disorders.

Main outcome measure

Using a generalized additive model regression (GAM), we analysed data across 171 nations to identify variables which impact COVID-19 mortality rates (demographics, national wealth and government effectiveness, pandemic management indexes, latitude of the country’s capital, prevalence of headache disorders and other diseases). We performed similar analyses of seasonal influenza mortality. Separately, we meta-analysed studies of COVID-19 inpatient survival reporting headache, using PRISMA guidelines.

Results

In the global population-level analysis, we observed that a higher prevalence of headache disorders was associated with a higher COVID-19 mortality rate, and represented the main variable contributing to differences in COVID-19 mortality rates between countries (37.8%; F value=10.68). By contrast, we observed a negative trend between the prevalence of headache disorders and influenza death rates. Controversially, when considering headache as a symptom of COVID-19, in the 48 meta-analysed studies we observed a significantly higher risk ratio of survival (RR:2.178 [1.882-2.520], p<0.0001) among COVID-19 inpatients with headache.

Conclusions and Relevance

Headache as a primary disorder is more prevalent in nations with higher COVID-19 mortality, whereas headache as a COVID-19 symptom is associated with enhanced survival. Further studies should clarify whether primary headache disorders represent a risk factor for mortality for COVID-19 or, rather, whether this association reflects evolutionary adaptive processes to enhance survival that, in the case of COVID-19, are insufficiently protective.
Specific allelic discrimination of N501Y and other SARS-CoV-2 mutations by ddPCR detects B.1.1.7 lineage in Washington State
Authors: Perchetti Garrett A. , Zhu Haiying , Mills Margaret G. , Shrestha Lasata , Wagner Cassia , Bakhash Shah Mohamed , Lin Michelle , Xie Hong , Huang Meei-Li , Mathias Patrick , Bedford Trevor , Jerome Keith R. , Greninger Alexander L. , Roychoudhury Pavitra
Published: March 2021

Real-time epidemiological tracking of variants of interest can help limit the spread of more contagious forms of SARS-CoV-2, such as those containing the N501Y mutation. Typically, genetic sequencing is required to be able to track variants of interest in real-time. However, sequencing can take time and may not be accessible in all laboratories. Genotyping by RT-ddPCR offers an alternative to sequencing to rapidly detect variants of concern through discrimination of specific mutations such as N501Y that is associated with increased transmissibility. Here we describe the first cases of the B.1.1.7 lineage of SARS-CoV-2 detected in Washington State by using a combination of RT-PCR, RT-ddPCR, and next-generation sequencing. We screened 1,035 samples positive for SARS-CoV-2 by our CDC-based laboratory developed assay using ThermoFisher’s multiplex RT-PCR COVID-19 assay over four weeks from late December 2020 to early January 2021. S gene dropout candidates were subsequently assayed by RT-ddPCR to confirm four mutations within the S gene associated with the B.1.1.7 lineage: a deletion at amino acid (AA) 69-70 (ACATGT), deletion at AA 145, (TTA), N501Y mutation (TAT), and S982A mutation (GCA). All four targets were detected in two specimens, and follow-up sequencing revealed a total of 10 mutations in the S gene and phylogenetic clustering within the B.1.1.7 lineage. As variants of concern become increasingly prevalent, molecular diagnostic tools like RT-ddPCR can be utilized to quickly, accurately, and sensitively distinguish more contagious lineages of SARS-CoV-2.