bluuebunny/crossref_metadata_2025 huggingface dataset:
Verbalization, Categorization, and Evaluation of Fundamental Surgical Skills
Authors: Mitani Sohei , Nishio Naoki , Kitani Takashi , Ugumori Toru , Wakisaka Hiroyuki , Tanaka Keiko , Miao Beiping , Chan Jason Y. K. , Holsinger F. Christopher , Hato Naohito
Published: April 2021

Objective:

This study aimed to verbalize fundamental surgical skills required for open head and neck surgery (OHNS), to organize them by categorization, and to establish a consensus among surgeons regarding the importance and difficulty of each skill.

Summary Background Data:

Improvement of fundamental surgical skills is the core of surgical education; however, surgical skills are not yet organized, and consensus in any surgical field remains uncertain.

Methods:

Fundamental surgical skills during OHNS were collected from surgical textbooks, real surgeries, and expert interviews. The items were analyzed to calculate the frequency of words and were categorized by 2 expert surgeons. After consensus on the importance and difficulty of each item was established by 15 expert surgeons using a Delphi survey, principal component (PC) analysis was performed to integrate importance and difficulty into a single parameter.

Results:

Sixty skills were verbalized and categorized into 7 categories: “skin flap elevation (n = 6),” “vessel management (n = 9),” “nerve preservation (n = 8),” “instrument handling (n = 11),” “counter traction (n = 7),” “tissue exposure (n = 9),” and “flow and planning (n = 10).” In the Delphi survey, expert consensus was established after 2 voting rounds (Cronbach’s α ≥ 0.80). The “counter traction” and “flow and planning” categories had high PC scores, which indicate priority in surgical education.

Conclusion:

Fundamental OHNS skills were verbalized, categorized, and evaluated via expert consensus. Assessment of surgeons’ skills by the structured items hereby developed will help standardize the quality of OHNS and improve patient outcomes.
Administrative Data Are Unreliable for Ranking Hospital Performance Based on Serious Complications After Spine Fusion
Authors: Greenberg Jacob K. , Olsen Margaret A. , Poe John , Dibble Christopher F. , Yamaguchi Ken , Kelly Michael P. , Hall Bruce L. , Ray Wilson Z.
Published: April 2021

Study Design.

Retrospective analysis of administrative billing data.

Objective.

To evaluate the extent to which a metric of serious complications determined from administrative data can reliably profile hospital performance in spine fusion surgery.

Summary of Background Data.

While payers are increasingly focused on implementing pay-for-performance measures, quality metrics must reliably reflect true differences in performance among the hospitals profiled.

Methods.

We used State Inpatient Databases from nine states to characterize serious complications after elective cervical and thoracolumbar fusion. Hierarchical logistic regression was used to risk-adjust differences in case mix, along with variability from low case volumes. The reliability of this risk-stratified complication rate (RSCR) was assessed as the variation between hospitals that was not due to chance alone, calculated separately by fusion type and year. Finally, we estimated the proportion of hospitals that had sufficient case volumes to obtain reliable (>0.7) complication estimates.

Results.

From 2010 to 2017 we identified 154,078 cervical and 213,133 thoracolumbar fusion surgeries. 4.2% of cervical fusion patients had a serious complication, and the median RSCR increased from 4.2% in 2010 to 5.5% in 2017. The reliability of the RSCR for cervical fusion was poor and varied substantially by year (range 0.04–0.28). Overall, 7.7% of thoracolumbar fusion patients experienced a serious complication, and the RSCR varied from 6.8% to 8.0% during the study period. Although still modest, the RSCR reliability was higher for thoracolumbar fusion (range 0.16–0.43). Depending on the study year, 0% to 4.5% of hospitals had sufficient cervical fusion case volume to report reliable (>0.7) estimates, whereas 15% to 36% of hospitals reached this threshold for thoracolumbar fusion.

Conclusion.

A metric of serious complications was unreliable for benchmarking cervical fusion outcomes and only modestly reliable for thoracolumbar fusion. When assessed using administrative datasets, these measures appear inappropriate for high-stakes applications, such as public reporting or pay-for-performance.

Level of Evidence: 3
Text Messaging as a Means to Engage Patients in the Postpartum Period
Authors: GOMEZ HELEN B. , HOFFMAN MATTHEW K.
Published: April 2021

The use of electronic information and telecommunications technologies to support health systems has been increasingly recognized as an important tool in postpartum care. An emerging body of research has suggested that telehealth during the postpartum period may alleviate racial disparities and transportation barriers, while improving access to health resources. Thus, the purpose of this article is to describe current barriers to postpartum health, review prevalence and access to mobile devices, and current uses of text messaging in the postpartum period. We describe key areas of telemedicine utilization including lactation services, blood pressure monitoring, diabetes screening, mental health services, weight loss programs, and access to contraception in the postpartum period. Future research and clinical work should aim to further examine the use of telehealth among postpartum individuals.
How Telehealth Can be Used to Improve Maternal and Child Health Outcomes: A Population Approach
Authors: MADUBUONWU JOY , MEHTA POOJA
Published: April 2021

Mobile applications and telehealth services are being used to unprecedented degrees in maternal and child care, with uncertain impact on population health outcomes. In this article, we will review the role of the COVID-19 pandemic in accelerating large scale implementation of telehealth services, known and anticipated impacts on maternal and child health and related inequities, and potential strategies to optimize outcomes at the population level.
Microinvasive Glaucoma Surgery in US Ophthalmology Residency: Surgical Case Log Cross-sectional Analysis and Proposal for New Glaucoma Procedure Classification
Authors: Qiu Mary , Woreta Fasika A. , Boland Michael V.
Published: April 2021

Precis:

A cross-sectional sample of the US ophthalmology residency graduating class of 2018 revealed that 18.4% of residents logged <5 traditional glaucoma surgeries, and 63.4% logged at least 1 microinvasive glaucoma surgery (MIGS).

Purpose:

Describe the state of MIGS in US ophthalmology residency training and propose a glaucoma procedure classification system for residents’ surgical case logs.

Methods:

Deidentified case logs from residents graduating in 2018 were requested from US residency program directors.

Results:

Case logs were received for 152/488 (31%) residents from 36/115 (31%) programs. The mean number of traditional glaucoma surgeries per resident was 9.0±5.9 (range: 0 to 31). The mean number of MIGS per resident was 5.2±8.9 cases (range: 0 to 58). There were 28/152 (18.4%) residents from 16/36 (44.4%) programs who logged <5 traditional glaucoma surgeries as primary surgeon, and 3/152 (2.0%) residents from 3/36 (8.3%) programs who logged zero traditional glaucoma surgeries as primary surgeon. There were 98/152 (64.5%) residents from 32/36 (88.8%) programs who logged <5 MIGS as primary surgeon, and 48/152 (31.6%) residents from 25 of 36 (69.4%) programs who logged zero MIGS as primary surgeon. There were 104/152 (63.4%) residents from 33/36 (91.6%) programs who logged at least 1 MIGS as primary surgeon; there were 3/36 (8.3%) residency programs where no resident logged any MIGS as primary surgeon.

Conclusions:

US ophthalmology residents’ MIGS experience varies widely. Residents can satisfy glaucoma surgery requirements with some MIGS, even in the absence of adequate traditional glaucoma surgeries. We propose a residency case log classification system that better reflects the growing role of MIGS in clinical practice and helps ophthalmic educators more accurately track procedures requiring related skills.
Long-term all-cause mortality among asymptomatic individuals with 80th percentile of coronary calcium score based on age and gender in the St. Francis Heart Study
Authors: Chen Lu Q. , Weber Jonathan , Christian Timothy , Guerci Alan D. , Cao J. Jane
Published: April 2021

Objectives

High coronary artery calcium score (CAC) is a significant risk factor for cardiovascular morbidity and mortality. We investigated the long-term outcome of subjects with elevated CAC.

Methods

We studied 1005 participants of The St. Francis Heart Study who were asymptomatic and apparently healthy and had CAC scores at 80th percentile or higher for age and gender. They were randomized to receive atorvastatin 20 mg daily or placebo for up to 5 years. We used an as-treated study design accounting for cross-overs at the end of the original trial. All-cause mortality risk was assessed using adjusted hazard ratios.

Results

Mean age was 59 ± 6 years and 26% (N = 263) were female. After 17 ± 3 years follow-up 176 subjects died. High CAC at baseline was associated with increased mortality risk with adjusted hazard ratio for logarithmic transformed CAC at 1.33 and 95% confidence interval 1.06–1.68. The mortality risk associated with CAC was similar between the group with high-sensitivity CRP ≥2 and <2 mg/dL. Those with a family history of premature coronary artery disease exhibited a higher mortality risk in association with high CAC with an adjusted hazard ratio 1.51 (1.09, 2.09).

Conclusion

Elevated CAC is an independent risk for long-term all-cause mortality. The screening of CAC score in addition to identifying conventional risk factors can differentiate asymptomatic individuals with and without increased long-term mortality risk.
Initial optimal medical therapy with or without invasive strategy for stable coronary disease: a meta-analysis and systematic review
Authors: Barbarawi Mahmoud , Alabdouh Ahmad , Barbarawi Owais , Lakshman Harini , Alkasasbeh Mariam , Khallad Muad , Radaideh Qais
Published: April 2021

Introduction

There is a persistent controversy regarding the benefit and timing of angiography in patients with stable coronary artery disease (CAD). With this meta-analysis of randomized controlled trials (RCTs) the advantages of initial invasive strategy and medical therapy compared with only medical therapy.

Methods

We conducted a literature search of the following databases Pubmed/MEDLINE, Cochrane Library and Embase. Data was collected from all the RCTs that compared early invasive approach with medical therapy alone in treating stable CAD which was conducted by two independent authors. Primary outcomes were all-cause mortality and myocardial infarction (MI), while the secondary outcomes included major adverse cardiovascular events (MACE), cardiovascular mortality, cardiovascular hospitalization, hospitalization due to unstable angina and revascularization events. The Mantel–Haenszel random-effects model was used to estimate risk ratios (RRs) and 95% confidence intervals (CIs).

Results

We included 15 RCTs (13 916 patients, mean age 63.1, 78.9% men). The early invasive strategy, compared with medical therapy alone, did not reveal a significant reduction in the incidence of all-cause mortality (RR, 0.94; 95% CI, 0.84–1.05, P = 0.30) or MI (RR, 0.93; 95% CI, 0.79–1.10, P = 0.42). Furthermore, the early invasive strategy did not reduce the incidence of cardiovascular mortality, cardiovascular hospitalization or the revascularization rate compared with medical therapy alone (P > 0.05). However, the incidence of MACE and hospitalization due to unstable angina were lower in patients treated with early invasive strategy (RR, 0.79; 95% CI, 0.63–0.99, P = 0.04), and (RR, 0.46; 95% CI, 0.32–0.67, P < 0.0001), respectively.

Conclusions

Early invasive strategy with medical therapy did not reduce the incidence of all-cause mortality and MI when compared with medical therapy alone among patients with stable CAD with significant stenosis. However, there was a significant reduction in the incidence of MACE and hospitalization due to unstable angina in the early invasive group.
Systemic immune-inflammation index predicts the severity of coronary stenosis in patients with coronary heart disease
Authors: Liu Yehong , Ye Ting , Chen Liang , Jin Tianhui , Sheng Ying , Wu Gangyong , Zong Gangjun
Published: April 2021

Background

Coronary atherosclerosis is a systemic chronic inflammatory disease with variable occurrence and progression. Some laboratory parameters, such as the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and C-reactive protein (CRP) level, are used to evaluate the degree of inflammation and the severity of coronary artery disease (CAD). The neutrophil*platelet/lymphocyte is a novel systemic immune-inflammation index (SII), and its relationship with the development and severity of CAD is unclear.

Objective

To investigate the association between the SII and the severity of CAD.

Methods

Three-hundred and ninety-five patients who underwent coronary angiography were enrolled; among whom, 285 patients were included in the CAD group and 110 patients were included in the non-CAD group according to the WHO guidelines. Patients with CAD were further divided according to the Gensini score into the severe coronary stenosis group and the mild coronary stenosis group. The SII was calculated using the following formula: neutrophil*platelet/lymphocyte.

Results

When the cutoff value of the SII was set at 439.44, the predictive power of CAD was the highest, with a sensitivity and specificity of 64.6 and 68.2%, respectively. When the cutoff value of the SII was set at 652.83, the predictive power of severe coronary stenosis was the highest, with a sensitivity and specificity of 71.0 and 86.0%, respectively. The area under the curve of the SII in predicting severe coronary stenosis was greater than that of the NLR, PLR and CRP level.

Conclusion

The SII is an independent risk factor for the occurrence and severity of CAD.
Multiple nutritional phenotypes of fission yeast mutants defective in genes encoding essential mitochondrial proteins
Authors: Uehara Lisa , Saitoh Shigeaki , Mori Ayaka , Sajiki Kenichi , Toyoda Yusuke , Masuda Fumie , Soejima Saeko , Tahara Yuria , Yanagida Mitsuhiro
Published: April 2021

Mitochondria are essential for regulation of cellular respiration, energy production, small molecule metabolism, anti-oxidation and cell ageing, among other things. While the mitochondrial genome contains a small number of protein-coding genes, the great majority of mitochondrial proteins are encoded by chromosomal genes. In the fission yeast
Schizosaccharomyces pombe
, 770 proteins encoded by chromosomal genes are located in mitochondria. Of these, 195 proteins, many of which are implicated in translation and transport, are absolutely essential for viability. We isolated and characterized eight temperature-sensitive (
ts
) strains with mutations in essential mitochondrial proteins. Interestingly, they are also sensitive to limited nutrition (glucose and/or nitrogen), producing low-glucose-sensitive and ‘super-housekeeping' phenotypes. They fail to produce colonies under low-glucose conditions at the permissive temperature or lose cell viability under nitrogen starvation at the restrictive temperature. The majority of these
ts
mitochondrial mutations may cause defects of gene expression in the mitochondrial genome.
mrp4
and
mrp17
are defective in mitochondrial ribosomal proteins.
ppr3
is defective in rRNA expression, and
trz2
and
vrs2
are defective in tRNA maturation. This study promises potentially large dividends because mitochondrial quiescent functions are vital for human brain and muscle, and also for longevity.
Integrative omics identification, evolutionary and structural analysis of low affinity nitrate transporters in diatoms, diNPFs
Authors: Santin Anna , Caputi Luigi , Longo Antonella , Chiurazzi Maurizio , Ribera d'Alcalà Maurizio , Russo Monia Teresa , Ferrante Maria Immacolata , Rogato Alessandra
Published: April 2021

Diatoms are one of the major and most diverse groups of phytoplankton, with chimeric genomes harbouring a combination of genes of bacterial, animal and plant origin. They have developed sophisticated mechanisms to face environmental variations. In marine environments, nutrients concentration shows significant temporal and spatial variability, influencing phytoplankton growth. Among nutrients, nitrogen, present at micromolar levels, is often a limiting resource. Here, we report a comprehensive characterization of the Nitrate Transporter 1/Peptide Transporter Family (NPF) in diatoms, diNPFs. NPFs are well characterized in many organisms where they recognize a broad range of substrates, ranging from short-chained di- and tri-peptides in bacteria, fungi and mammals to a wide variety of molecules including nitrate in higher plants. Scarce information is available for diNPFs. We integrated-omics, phylogenetic, structural and expression analyses, to infer information on their role in diatoms.
diNPF
genes diverged to produce two distinct clades with strong sequence and structural homology with either bacterial or plant NPFs, with different predicted sub-cellular localization, suggesting that the divergence resulted in functional diversification. Moreover, transcription analysis of
diNPF
genes under different laboratory and environmental growth conditions suggests that diNPF diversification led to genetic adaptations that might contribute to diatoms ability to flourish in diverse environmental conditions.
A TOR (target of rapamycin) and nutritional phosphoproteome of fission yeast reveals novel targets in networks conserved in humans
Authors: Halova Lenka , Cobley David , Franz-Wachtel Mirita , Wang Tingting , Morrison Kaitlin R. , Krug Karsten , Nalpas Nicolas , Maček Boris , Hagan Iain M. , Humphrey Sean J. , Petersen Janni
Published: April 2021

Fluctuations in TOR, AMPK and MAP-kinase signalling maintain cellular homeostasis and coordinate growth and division with environmental context. We have applied quantitative, SILAC mass spectrometry to map TOR and nutrient-controlled signalling in the fission yeast
Schizosaccharomyces pombe
. Phosphorylation levels at more than 1000 sites were altered following nitrogen stress or Torin1 inhibition of the TORC1 and TORC2 networks that comprise TOR signalling. One hundred and thirty of these sites were regulated by both perturbations, and the majority of these (119) new targets have not previously been linked to either nutritional or TOR control in either yeasts or humans. Elimination of AMPK inhibition of TORC1, by removal of AMPK
α
(

ssp2::ura4
+

), identified phosphosites where nitrogen stress-induced changes were independent of TOR control. Using a yeast strain with an ATP analogue-sensitized Cdc2 kinase, we excluded sites that were changed as an indirect consequence of mitotic control modulation by nitrogen stress or TOR signalling. Nutritional control of gene expression was reflected in multiple targets in RNA metabolism, while significant modulation of actin cytoskeletal components points to adaptations in morphogenesis and cell integrity networks. Reduced phosphorylation of the MAPKK Byr1, at a site whose human equivalent controls docking between MEK and ERK, prevented sexual differentiation when resources were sparse but not eliminated.
Structural and biophysical characterization of the tandem substrate-binding domains of the ABC importer GlnPQ
Authors: Ploetz Evelyn , Schuurman-Wolters Gea K. , Zijlstra Niels , Jager Amarins W. , Griffith Douglas A. , Guskov Albert , Gouridis Giorgos , Poolman Bert , Cordes Thorben
Published: April 2021

The ATP-binding cassette transporter GlnPQ is an essential uptake system that transports glutamine, glutamic acid and asparagine in Gram-positive bacteria. It features two extra-cytoplasmic substrate-binding domains (SBDs) that are linked in tandem to the transmembrane domain of the transporter. The two SBDs differ in their ligand specificities, binding affinities and their distance to the transmembrane domain. Here, we elucidate the effects of the tandem arrangement of the domains on the biochemical, biophysical and structural properties of the protein. For this, we determined the crystal structure of the ligand-free tandem SBD1-2 protein from
Lactococcus lactis
in the absence of the transporter and compared the tandem to the isolated SBDs. We also used isothermal titration calorimetry to determine the ligand-binding affinity of the SBDs and single-molecule Förster resonance energy transfer (smFRET) to relate ligand binding to conformational changes in each of the domains of the tandem. We show that substrate binding and conformational changes are not notably affected by the presence of the adjoining domain in the wild-type protein, and changes only occur when the linker between the domains is shortened. In a proof-of-concept experiment, we combine smFRET with protein-induced fluorescence enhancement (PIFE–FRET) and show that a decrease in SBD linker length is observed as a linear increase in donor-brightness for SBD2 while we can still monitor the conformational states (open/closed) of SBD1. These results demonstrate the feasibility of PIFE–FRET to monitor protein–protein interactions and conformational states simultaneously.
Free moment induced by oblique transverse tarsal joint: investigation by constructive approach
Authors: Chen Tsung-Yuan , Kawakami Takahiro , Ogihara Naomichi , Hosoda Koh
Published: April 2021

The human foot provides numerous functions that let humans deal with various environments. Recently, study of the structure of the human foot and adjustment of an appropriate reaction force and vertical free moment during bipedal locomotion has gained attention. However, little is known about the mechanical (morphological) contribution of the foot structure to the reaction force and free moment. It is difficult to conduct a comparative experiment to investigate the contribution systematically by using conventional methods with human and cadaver foot experiments. This study focuses on the oblique transverse tarsal joint (TTJ) of the human foot, whose mechanical structure can generate appropriate free moments. We conduct comparative experiments with a rigid foot, a non-oblique joint foot (i.e. mimicking only the flexion/extension of the midfoot), and an oblique joint foot. Axial loading and walking experiments were conducted with these feet. The axial loading experiment demonstrated that the oblique foot generated free moment in the direction of internal rotation, as observed in the human foot. The walking experiment showed that the magnitude of the free moment generated with the oblique foot is significantly lower than that with the rigid foot during the stance phase. Using this constructive approach, the present study demonstrated that the oblique axis of the TTJ can mechanically generate free moments. This capacity might affect the transverse motion of bipedal walking.
Evidence for natural hybridization and novel
Wolbachia
strain superinfections in the
Anopheles gambiae
complex from Guinea
Authors: Jeffries Claire L. , Cansado-Utrilla Cintia , Beavogui Abdoul H. , Stica Caleb , Lama Eugene K. , Kristan Mojca , Irish Seth R. , Walker Thomas
Published: April 2021

Wolbachia
, a widespread bacterium which can influence mosquito-borne pathogen transmission, has recently been detected within
Anopheles
(
An
.) species that are malaria vectors in Sub-Saharan Africa. Although studies have reported
Wolbachia
strains in the
An. gambiae
complex, apparent low density and prevalence rates require confirmation. In this study, wild
Anopheles
mosquitoes collected from two regions of Guinea were investigated. In contrast with previous studies, RNA was extracted from adult females (
n
= 516) to increase the chances for the detection of actively expressed
Wolbachia
genes, determine
Wolbachia
prevalence rates and estimate relative strain densities. Molecular confirmation of mosquito species and
Wolbachia
multilocus sequence typing (MLST) were carried out to analyse phylogenetic relationships of mosquito hosts and newly discovered
Wolbachia
strains. Strains were detected in
An. melas
(prevalence rate of 11.6%–16/138) and hybrids between
An. melas
and
An. gambiae
sensu stricto (prevalence rate of 40.0%–6/15) from Senguelen in the Maferinyah region. Furthermore, a novel high-density strain, termed
w
AnsX, was found in an unclassified
Anopheles
species. The discovery of novel
Wolbachia
strains (particularly in members, and hybrids, of the
An. gambiae
complex) provides further candidate strains that could be used for future
Wolbachia
-based malaria biocontrol strategies.
A renewal equation model to assess roles and limitations of contact tracing for disease outbreak control
Authors: Scarabel Francesca , Pellis Lorenzo , Ogden Nicholas H. , Wu Jianhong
Published: April 2021

We propose a deterministic model capturing essential features of contact tracing as part of public health non-pharmaceutical interventions to mitigate an outbreak of an infectious disease. By incorporating a mechanistic formulation of the processes at the individual level, we obtain an integral equation (delayed in calendar time and advanced in time since infection) for the probability that an infected individual is detected and isolated at any point in time. This is then coupled with a renewal equation for the total incidence to form a closed system describing the transmission dynamics involving contact tracing. We define and calculate basic and effective reproduction numbers in terms of pathogen characteristics and contact tracing implementation constraints. When applied to the case of SARS-CoV-2, our results show that only combinations of diagnosis of symptomatic infections and contact tracing that are almost perfect in terms of speed and coverage can attain control, unless additional measures to reduce overall community transmission are in place. Under constraints on the testing or tracing capacity, a temporary interruption of contact tracing may, depending on the overall growth rate and prevalence of the infection, lead to an irreversible loss of control even when the epidemic was previously contained.
Social rank and not physiological capacity determines competitive success in zebrafish (Danio rerio)
Authors: Miln Clare , Ward Ashley J. W. , Seebacher Frank
Published: April 2021

Competition for resources shapes ecological and evolutionary relationships. Physiological capacities such as in locomotor performance can influence the fitness of individuals by increasing competitive success. Social hierarchy too can affect outcomes of competition by altering locomotor behaviour or because higher ranking individuals monopolize resources. Here, we tested the hypotheses that competitive success is determined by sprint performance or by social status. We show that sprint performance of individuals measured during escape responses (fast start) or in an accelerated sprint test did not correlate with realized sprint speed while competing for food within a social group of five fish; fast start and accelerated sprint speed were higher than realized speed. Social status within the group was the best predictor of competitive success, followed by realized speed. Social hierarchies in zebrafish are established within 7 days of their first encounter, and interestingly, there was a positive correlation between social status and realized speed 1 and 4 days after fish were placed in a group, but not after 7 days. These data indicate that physiological performance decreases in importance as social relationships are established. Also, maximal physiological capacities were not important for competitive success, but swimming speed changed with social context.
Application of a strain-level shotgun metagenomics approach on food samples: resolution of the source of a Salmonella food-borne outbreak
Authors: Buytaers Florence E. , Saltykova Assia , Mattheus Wesley , Verhaegen Bavo , Roosens Nancy H. C. , Vanneste Kevin , Laisnez Valeska , Hammami Naïma , Pochet Brigitte , Cantaert Vera , Marchal Kathleen , Denayer Sarah , De Keersmaecker Sigrid C.J.
Published: April 2021

Food-borne outbreak investigation currently relies on the time-consuming and challenging bacterial isolation from food, to be able to link food-derived strains to more easily obtained isolates from infected people. When no food isolate can be obtained, the source of the outbreak cannot be unambiguously determined. Shotgun metagenomics approaches applied to the food samples could circumvent this need for isolation from the suspected source, but require downstream strain-level data analysis to be able to accurately link to the human isolate. Until now, this approach has not yet been applied outside research settings to analyse real food-borne outbreak samples. In September 2019, a

Salmonella

outbreak occurred in a hotel school in Bruges, Belgium, affecting over 200 students and teachers. Following standard procedures, the Belgian National Reference Center for human salmonellosis and the National Reference Laboratory for

Salmonella

in food and feed used conventional analysis based on isolation, serotyping and MLVA (multilocus variable number tandem repeat analysis) comparison, followed by whole-genome sequencing, to confirm the source of the contamination over 2 weeks after receipt of the sample, which was freshly prepared tartar sauce in a meal cooked at the school. Our team used this outbreak as a case study to deliver a proof of concept for a short-read strain-level shotgun metagenomics approach for source tracking. We received two suspect food samples: the full meal and some freshly made tartar sauce served with this meal, requiring the use of raw eggs. After analysis, we could prove, without isolation, that

Salmonella

was present in both samples, and we obtained an inferred genome of a

Salmonella enterica

subsp.

enterica

serovar Enteritidis that could be linked back to the human isolates of the outbreak in a phylogenetic tree. These metagenomics-derived outbreak strains were separated from sporadic cases as well as from another outbreak circulating in Europe at the same time period. This is, to our knowledge, the first

Salmonella

food-borne outbreak investigation uniquely linking the food source using a metagenomics approach and this in a fast time frame.
In (deficit) schizophrenia, a general cognitive decline (G-CoDe) partly mediates the effects of neuro-immune and neuro-oxidative toxicity on the symptomatome and quality of life
Authors: Maes Michael , Kanchanatawan Buranee
Published: April 2021

Objective

Schizophrenia and deficit schizophrenia are accompanied by neurocognitive impairments. The aim of this study was to examine whether a general factor underpins impairments in key Cambridge Neuropsychological Test Automated Battery (CANTAB) probes, verbal fluency (VFT), world list memory (WLM), true recall, and Mini Mental State Examination (MMSE).

Methods

We recruited 80 patients with schizophrenia and 40 healthy controls. All patients were assessed using CANTAB tests, namely paired-association learning (PAL), rapid visual information (RVP), spatial working memory (SWM), one touch stocking (OTS), intra/extradimensional set shifting (IED), and emotional recognition test (ERT).

Results

We found that a general factor, which is essentially unidimensional, underlies those CANTAB, VFT, WLM, True Recall, and MMSE scores. This common factor shows excellent psychometric properties and fits a reflective model and, therefore, reflects a general cognitive decline (G-CoDe) comprising deficits in semantic and episodic memory, recall, executive functions, strategy use, rule acquisition, visual sustained attention, attention set-shifting, and emotional recognition. Partial least Square analysis showed that 40.5% of the variance in G-Code is explained by CCL11, IgA to tryptophan catabolites, and increased oxidative toxicity; and that G-CoDe explains 44.8% of the variance in a general factor extracted from psychosis, hostility, excitation, mannerism, negative symptoms, formal thought disorders, and psychomotor retardation; and 40.9% in quality of life scores. The G-CoDe is significantly greater in deficit than in nondeficit schizophrenia.

Conclusions

A common core shared by a multitude of neurocognitive impairments (G-CoDe) mediates the effects of neurotoxic pathways on the phenome of (deficit) schizophrenia.
Leveraging Health Systems Data to Characterize a Large Effect Variant Conferring Risk for Liver Disease in Puerto Ricans
Authors: Belbin Gillian M. , Rutledge Stephanie , Dodatko Tetyana , Cullina Sinead , Turchin Michael C. , Kohli Sumita , Torre Denis , Yee Muh-Ching , Gignoux Christopher R. , Abul-Husn Noura S. , Houten Sander M. , Kenny Eimear E.
Published: April 2021

Broad-scale adoption of genomic data in health systems offers opportunities for extending methods for the discovery of variation linked to underlying genomic disease risk. We applied a population-scale linkage mapping approach in a large multi-ethnic biobank to a spectrum of disease outcomes derived from Electronic Health Records (EHRs) and uncovered a risk locus for liver disease. We used genome sequencing and in silico approaches to fine-map the signal to a non-coding variant (c.2784-12T>C) in the gene ABCB4. In vitro analysis confirmed the variant disrupted splicing of the ABCB4 pre-mRNA. Four of five homozygotes had evidence of advanced liver disease, and there was a significant association with liver disease among heterozygotes, suggesting the variant is linked to increased risk of liver disease in an allele dose-dependent manner. Population-level screening revealed the variant to be at a carrier rate of 1.95% in Puerto Rican individuals, likely as the result of a Puerto Rican founder effect. This work demonstrates that integrating EHR and genomic data at a population-scale can facilitate novel strategies for understanding the continuum of genomic risk for common diseases, particularly in populations underrepresented in genomic medicine.
Novel prognostic determinants of COVID-19-related mortality: a pilot study on severely-ill patients in Russia
Authors: Rubina K. , Shmakova A. , Shabanov A. , Andreev Yu. , Borovkova N. , Kulabukhov V. , Evseev A. , Popugaev K. , Petrikov S. , Semina E.
Published: April 2021

COVID-19 pandemic has posed a severe healthcare challenge calling for an integrated approach in determining the clues for early non-invasive diagnostics of the potentially severe cases and efficient patient stratification.

Here we analyze the clinical, laboratory and CT scan characteristics associated with high risk of COVID-19-related death outcome in the cohort of severely-ill patients in Russia. The data obtained reveal that elevated dead lymphocyte counts, decreased early apoptotic lymphocytes, decreased CD14+/HLA-Dr+ monocytes, increased expression of JNK in PBMCs, elevated IL-17 and decreased PAI-1 serum levels are associated with a high risk of COVID-19-related mortality thus suggesting them to be new prognostic factors. This set of determinants could be used as early predictors of potentially severe course of COVID-19 for trials of prevention or timely treatment.

Funding

The reported study was funded by RFBR according to the research project № 20-24-60029.
Neutrophil-mediated Oxidative Stress and Albumin Structural Damage Predict COVID-19-associated Mortality
Authors: Badawy Mohamed A. , Yasseen Basma A. , El-Messiery Riem M. , Abdel-Rahman Engy A. , Elkhodiry Aya A. , Kamel Azza G. , Shedra Asmaa M. , Hamdy Rehab , Zidan Mona , Al-Raawi Diaa , Hammad Mahmoud , Elsharkawy Nahla , Ansary Mohamed El , Al-Halfawy Ahmed , Elhadad Alaa , Hatem Ashraf , Abouelnaga Sherif , Dugan Laura L. , Ali Sameh S.
Published: April 2021

Human serum albumin (HSA) is the frontline antioxidant protein in blood with established anti-inflammatory and anticoagulation functions. Here we report that COVID-19-induced oxidative stress inflicts structural damages to HSA and is linked with mortality outcome in critically ill patients. We recruited 25 patients who were followed up for a median of 12.5 days (1-35 days), among them 14 had died. Analyzing blood samples from patients and healthy individuals (n=10), we provide evidence that neutrophils are major sources of oxidative stress in blood and that hydrogen peroxide is highly accumulated in plasmas of non-survivors. We then analyzed electron paramagnetic resonance (EPR) spectra of spin labelled fatty acids (SLFA) bound with HSA in whole blood of control, survivor, and non-survivor subjects (n=10-11). Non-survivors’ HSA showed dramatically reduced protein packing order parameter, faster SLFA correlational rotational time, and smaller S/W ratio (strong-binding/weak-binding sites within HSA), all reflecting remarkably fluid protein microenvironments. Stratified at the means, Kaplan–Meier survival analysis indicated that lower values of S/W ratio and accumulated H2O2 in plasma significantly predicted in-hospital mortality (S/W<0.16, 80% (9/12) vs. S/W>0.16, 20% (2/10), p=0.008; plasma [H2O2]>7.1 μM, 83.3% (5/6) vs. 16.7% (1/6), p=0.049). When we combined these two parameters as the ratio ((S/W)/[H2O2]) to derive a risk score, the resultant risk score lower than the mean (< 0.0253) predicted mortality with 100% accuracy (100% (6/6) vs. 0% (0/6), logrank χ2 = 12.01, p = 5×10−4). The derived parameters may provide a surrogate marker to assess new candidates for COVID-19 treatments targeting HSA replacements.
Trust boosts recovery of countries from COVID-19
Authors: Lenton Timothy M. , Boulton Chris A. , Scheffer Marten
Published: April 2021

Why have some countries suppressed waves of the COVID-19 pandemic much more effectively than others? We find that the decay rate of daily cases or deaths from peak levels varies by a factor of ∼40 between countries. This measure of country-level resilience to COVID-19 is positively correlated with trust within society, and with the adaptive increase in stringency of government interventions when epidemic waves occur. All countries where >40% agree “most people can be trusted” achieve a near complete reduction of new cases and deaths. In contrast, countries where governments maintain greater background stringency tend to be less trusting and less resilient. Building trust is therefore critical to resilience, both to epidemics and other unexpected disruptions, of which COVID-19 is unlikely to be the last.
Mendelian randomisation identifies alternative splicing of the FAS death receptor as a mediator of severe COVID-19
Authors: Klaric Lucija , Gisby Jack S. , Papadaki Artemis , Muckian Marisa D. , Macdonald-Dunlop Erin , Zhao Jing Hua , Tokolyi Alex , Persyn Elodie , Pairo-Castineira Erola , Morris Andrew P , Kalnapenkis Anette , Richmond Anne , Landini Arianna , Hedman Åsa K. , Prins Bram , Zanetti Daniela , Wheeler Eleanor , Kooperberg Charles , Yao Chen , Petrie John R. , Fu Jingyuan , Folkersen Lasse , Walker Mark , Magnusson Martin , Eriksson Niclas , Mattsson-Carlgren Niklas , Timmers Paul R.H.J. , Hwang Shih-Jen , Enroth Stefan , Gustafsson Stefan , Vosa Urmo , Chen Yan , Siegbahn Agneta , Reiner Alexander , Johansson Åsa , Thorand Barbara , Gigante Bruna , Hayward Caroline , Herder Christian , Gieger Christian , Langenberg Claudia , Levy Daniel , Zhernakova Daria V. , Smith J. Gustav , Campbell Harry , Sundstrom Johan , Danesh John , Michaëlsson Karl , Suhre Karsten , Lind Lars , Wallentin Lars , Padyukov Leonid , Landén Mikael , Wareham Nicholas J. , Göteson Andreas , Hansson Oskar , Eriksson Per , Strawbridge Rona J. , Assimes Themistocles L. , Esko Tonu , Gyllensten Ulf , Baillie J. Kenneth , Paul Dirk S. , Joshi Peter K. , Butterworth Adam S. , Mälarstig Anders , Pirastu Nicola , Wilson James F. , Peters James E.
Published: April 2021

Severe COVID-19 is characterised by immunopathology and epithelial injury. Proteomic studies have identified circulating proteins that are biomarkers of severe COVID-19, but cannot distinguish correlation from causation. To address this, we performed Mendelian randomisation (MR) to identify proteins that mediate severe COVID-19. Using protein quantitative trait loci (pQTL) data from the SCALLOP consortium, involving meta-analysis of up to 26,494 individuals, and COVID-19 genome-wide association data from the Host Genetics Initiative, we performed MR for 157 COVID-19 severity protein biomarkers. We identified significant MR results for five proteins: FAS, TNFRSF10A, CCL2, EPHB4 and LGALS9. Further evaluation of these candidates using sensitivity analyses and colocalization testing provided strong evidence to implicate the apoptosis-associated cytokine receptor FAS as a causal mediator of severe COVID-19. This effect was specific to severe disease. Using RNA-seq data from 4,778 individuals, we demonstrate that the pQTL at theFASlocus results from genetically influenced alternate splicing causing skipping of exon 6. We show that the risk allele for very severe COVID-19 increases the proportion of transcripts lacking exon 6, and thereby increases soluble FAS. Soluble FAS acts as a decoy receptor for FAS-ligand, inhibiting apoptosis induced through membrane-bound FAS. In summary, we demonstrate a novel genetic mechanism that contributes to risk of severe of COVID-19, highlighting a pathway that may be a promising therapeutic target.
Female-male differences in COVID vaccine adverse events have precedence in seasonal flu shots: a potential link to sex-associated baseline gene expression patterns
Authors: Venkatakrishnan AJ , Kumar-M Praveen , Silvert Eli , Garcia-Rivera Enrique , Szenk Mariola , Suratekar Rohit , Lenehan Patrick , Lindemer Emily , O’Horo John C. , Williams Amy W. , Badley Andrew D. , Virk Abinash , Swift Melanie D. , Gores Gregory J. , Soundararajan Venky
Published: April 2021

Nearly 150 million doses of FDA-authorized COVID vaccines have been administered in the United States. Sex-based differences of adverse events remain poorly understood, mandating the need for real-world investigation from Electronic Health Records (EHRs) and broader epidemiological data sets. Based on an augmented curation of EHR clinical notes of 31,064 COVID-vaccinated individuals (19,321 females and 11,743 males) in the Mayo Clinic, we find that nausea and vomiting were documented significantly more frequently in females than males after both vaccine doses (nausea: RRDose 1= 1.67, pDose 1<0.001, RRDose 2= 2.2, pDose 1< 0.001; vomiting: RRDose 1= 1.58, pDose 1< 0.001, RRDose 2= 1.88, pDose 1= 3.4×10−2). Conversely, fever, fatigue, and lymphadenopathy were more common in males after the first dose vaccination (fever RR = 0.62; p = 8.65×10−3; fatigue RR = 0.86, p = 2.89×10−2; lymphadenopathy RR = 0.61, p = 3.45×10−3). Analysis of the Vaccine Adverse Events Reporting System (VAERS) database further confirms that nausea comprises a larger fraction of total reports among females than males (RR: 1.58; p<0.001), while fever comprises a larger fraction of total reports among males than females (RR: 0.84; p<0.001). Importantly, increased reporting of nausea and fever among females and males, respectively, is also observed for prior influenza vaccines in the VAERS database, establishing that these differences are not unique to the recently developed COVID-19 vaccines. Investigating the mechanistic basis underlying these clinical findings, an analysis of bulk RNA-sequencing data from 12,158 human blood samples (8626 female, 3532 male) reveals 85 genes that are not only significantly different in their gene expression between females and males at baseline, but also have established literature-based associations to COVID-19 as well as the vaccine-related adverse events of clinical consequence. The NLRP3 inflammasome and the NR3C1 glucocorticoid receptor emerge as particularly promising baseline links to sex-associated vaccine adverse events, warranting targeted investigation of these signaling pathways and associated cell types. From a public health standpoint, our clinical findings shall aid in educating patients on the sex-associated risks they should expect for COVID-19 vaccines and also promote better clinical management of vaccine-associated adverse events.
Prospective analytical performance evaluation of the QuickNavi™-COVID19 Ag for asymptomatic individuals
Authors: Kiyasu Yoshihiko , Takeuchi Yuto , Akashi Yusaku , Kato Daisuke , Kuwahara Miwa , Muramatsu Shino , Notake Shigeyuki , Ueda Atsuo , Nakamura Koji , Ishikawa Hiroichi , Suzuki Hiromichi
Published: April 2021

Introduction

Antigen testing may help screen for and detect severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections in asymptomatic individuals. However, limited data regarding the diagnostic performance of antigen tests for this group are available.

Methods

We used clinical samples to prospectively evaluate the analytical and clinical performance of the antigen test QuickNavi™-COVID19 Ag. This study was conducted at a PCR center between October 7, 2020 and January 9, 2021. Two nasopharyngeal samples per patient were obtained with flocked swabs; one was used for the antigen test, and the other for real-time reverse transcription PCR (RT-PCR). The diagnostic performance of the antigen test was compared between asymptomatic and symptomatic patients, and the RT-PCR results were used as a reference.

Results

Among the 1,934 collected samples, SARS-CoV-2 was detected by real-time RT-PCR in 188 (9.7%); 76 (40.4%) of these samples were from asymptomatic individuals. Over half of the total samples (1,073; 55.5%) were obtained from asymptomatic volunteers. The sensitivity of the antigen test was significantly lower for asymptomatic group than for symptomatic patients (67.1% vs 89.3%, p < 0.001). The specificity was 100% for both groups, and no false positives were observed among all 1,934 samples. The median Ct value for the asymptomatic group was significantly higher than that of the symptomatic group (24 vs 20, p < 0.001).

Conclusions

The QuickNavi™-COVID19 Ag showed a lower sensitivity for asymptomatic group than for symptomatic patients. However, its specificity was consistently high, and no false positives were found in this study.