bluuebunny/crossref_metadata_2025 huggingface dataset:
Pediatric surgical rib fixation: A collected case series of a rare entity
Authors: Polycarpou Andreas , Kim Brian D.
Published: August 2021

BACKGROUND

Rib fractures are uncommon in children and are markers of extreme traumatic force from high-energy or nonaccidental etiology. Traditional care includes nonoperative management, with analgesia, ventilator support, and pulmonary physiotherapy. Surgical stabilization of rib fractures (SSRFs) has been associated with improved outcomes in adults. In children, SSRF is performed and its role remains unclear, with data only available from case reports. We created a collected case series of published pediatric SSRF cases, with the aim to provide a descriptive summary of the existing data.

METHODS

Published cases of SSRF following thoracic trauma in patients younger than 18 years were identified. Collected data included demographics, injury mechanism, associated injuries, surgical indication(s), surgical technique, time to extubation, postoperative hospital stay, and postoperative follow-up.

RESULTS

Six cases were identified. All were boys, with age range 6 to 16 years. Injury mechanism was high-energy blunt force in all cases, and all patients suffered multiple associated injuries. Five of six cases were related to motor vehicles, and one was horse-related. Indication(s) for surgery included ventilator dependence in five, significant chest deformity in two, and poor pain control in one case. Plating systems were used for rib stabilization in five of six cases, while intramedullary splint was used in one. All patients were extubated within 7 days following SSRF, and all were discharged by postoperative Day 20. On postoperative follow-up, no SSRF-related major issues were reported. One patient underwent hardware removal at 2 months.

CONCLUSION

Surgical stabilization of rib fractures in children is safe and feasible, and should be considered as an alternative to nonoperative therapy in select pediatric thoracic trauma cases. Potential indications for SSRF in pediatric patients include poor pain control, chest wall deformity, or ventilator dependence. Further studies are needed to establish the role and possible benefits of SSRF in pediatric thoracic trauma.

LEVEL OF EVIDENCE

Collected case series, level V.
Screening of anti-Acinetobacter baumanniiphytochemicals, based on the potential inhibitory effect on OmpA and OmpW functions
Authors: Shahryari Shahab , Mohammadnejad Parvin , Noghabi Kambiz Akbari
Published: August 2021

Therapeutic options including last-line or combined antibiotic therapies for multi-drug-resistant strains ofAcinetobacter baumanniiare ineffective. The outer membrane protein A (OmpA) and outer membrane protein W (OmpW) are two porins known for their different cellular functions. Identification of natural compounds with the potentials to block these putative porins can attenuate the growth of the bacteria and control the relating diseases. The current work aimed to screen a library of 384 phytochemicals according to their potentials to be used as a drug, and potentials to inhibit the function of OmpA and OmpW inA. baumannii. The phytocompounds were initially screened based on their physico-chemical, absorption, distribution, metabolism, excretion and toxicity (ADMET) drug-like properties. Afterwards, the selected ligands were subjected to standard docking calculations against the predicted three-dimensional structure of OmpA and OmpW inA. baumannii. We identified three phytochemicals (isosakuranetin, aloe-emodin and pinocembrin) possessing appreciable binding affinity towards the selected binding pocket of OmpA and OmpW. Molecular dynamics simulation analysis confirmed the stability of the complexes. Among them, isosakuranetin was suggested as the best phytocompound for furtherin vitroandin vivostudy.
Sex, mating and repeatability ofDrosophila melanogasterlongevity
Authors: Hoffman Jessica M. , Dudeck Sophie K. , Patterson Heather K. , Austad Steven N.
Published: August 2021

Costs of reproduction are seemingly ubiquitous across the animal kingdom, and these reproductive costs are generally defined by increased reproduction leading to decreases in other fitness components, often longevity. However, some recent reports question whether reproductive costs exist in every species or population. To provide insight on this issue, we sought to determine the extent to which genetic variation might play a role in one type of reproductive cost—survival—usingDrosophila melanogaster. We found, surprisingly, no costs of reproduction nor sex differences in longevity across all 15 genetic backgrounds in two cohorts. We did find significant variation within some genotypes, though these were much smaller than expected. We also observed that small laboratory changes lead to significant changes in longevity within genotypes, suggesting that longevity repeatability in flies may be difficult. We finally compared our results to previously published longevities and found that reproducibility is similar to what we saw in our own laboratory, further suggesting that stochasticity is a strong component of fruit fly lifespan. Overall, our results suggest that there are still large gaps in our knowledge about the effects of sex and mating, as well as genetic background and laboratory conditions on lifespan reproducibility.
Relationship between rice farming and polygenic scores potentially linked to agriculture in China
Authors: Zhu Chen , Talhelm Thomas , Li Yingxiang , Chen Gang , Zhu Jiong , Wang Jun
Published: August 2021

Following domestication in the lower Yangtze River valley 9400 years ago, rice farming spread throughout China and changed lifestyle patterns among Neolithic populations. Here, we report evidence that the advent of rice domestication and cultivation may have shaped humans not only culturally but also genetically. Leveraging recent findings from molecular genetics, we construct a number of polygenic scores (PGSs) of behavioural traits and examine their associations with rice cultivation based on a sample of 4101 individuals recently collected from mainland China. A total of nine polygenic traits and genotypes are investigated in this study, including PGSs of height, body mass index, depression, time discounting, reproduction, educational attainment, risk preference,
ADH1B
rs1229984 and
ALDH2
rs671. Two-stage least-squares estimates of the county-level percentage of cultivated land devoted to paddy rice on the PGS of age at first birth (
b
= −0.029,
p
= 0.021) and
ALDH2
rs671 (
b
= 0.182,
p
< 0.001) are both statistically significant and robust to a wide range of potential confounds and alternative explanations. These findings imply that rice farming may influence human evolution in relatively recent human history.
On the utility of oddities: exceptional bee reproduction illuminates fundamental questions of recombination
Authors: Roy Scott William
Published: August 2021

Despite its importance, the selective and mechanistic forces governing recombination remain obscure. A recent study of facultatively asexual honeybees suggests a clear case of adaptive adjustment of recombination rate. That these bees' atypical genetics were central to the experiment underscores the utility of genetic oddities as model organisms for studying fundamental questions.
Whole Genome Sequencing Analysis of Spike D614G Mutation Reveals Unique SARS-CoV-2 Lineages of B.1.524 and AU.2 in Malaysia
Authors: Zainulabid Ummu Afeera , Mat Yassim Aini Syahida , Soffian Sharmeen Nellisa , Mohd Ibrahim Mohamad Shafiq , Kamarudin Norhidayah , Kamarulzaman Mohd Nazli , Hin How Soon , Ahmad Hajar Fauzan
Published: August 2021

The SARS-CoV-2 has spread throughout the world since its discovery in China, and Malaysia is no exception. WGS has been a crucial approach in studying the evolution and genetic diversity of SARS-CoV-2 in the ongoing pandemic, and while an exceptional number of SARS-CoV-2 complete genomes have since been submitted to GISAID and NCBI, there is a scarcity of data from Malaysia. This study aims to report new Malaysian lineages responsible for the sustained spikes in COVID-19 cases during the third wave of the pandemic. Patients whose nasopharyngeal and oropharyngeal swabs were confirmed positive by real-time RT-PCR with Ct-value < 25 were chosen for WGS. The 10 SARS-CoV-2 isolates obtained were then sequenced, characterized and analyzed, including 1356 sequences of the dominant lineages of D614G variant currently circulating throughout Malaysia. The prevalence of clade GH and G formed strong ground of the discovery of two Malaysian lineages that caused sustained spikes of cases locally. Statistical analysis on the association of gender and age group with Malaysian lineages revealed a significant association (p < 0.05). Phylogenetic analysis revealed dispersion of 41 lineages, for which 22 lineages are still active. Mutational analysis observed unique G1223C missense mutation in Transmembrane Domain of Spike protein. Thus, calls for the large-scale WGS analysis of strains found around the world for greater understanding of viral evolution and genetic diversity especially in addressing the question of the effect of deleterious substitution mutation in transmembrane region of Spike protein.
Cardiac Inflammation after COVID-19 mRNA Vaccines: A Global Pharmacovigilance Analysis
Authors: Chouchana Laurent , Blet Alice , Al-Khalaf Mohammad , Kafil Tahir S. , Nair Girish , Robblee James , Drici Milou-Daniel , Valnet-Rabier Marie-Blanche , Micallef Joëlle , Salvo Francesco , Treluyer Jean-Marc , Liu Peter P.
Published: August 2021

Background

To counter the COVID-19 pandemic, mRNA vaccines, namely tozinameran and elasomeran, have been authorized in several countries. These next generation vaccines have shown high efficacy against COVID-19 and demonstrated a favorable safety profile. As widespread vaccinations efforts are taking place, incidents of myocarditis and pericarditis cases following vaccination have been reported. This safety signal has been recently confirmed by the European Medicine Agency and the U.S. Food and Drug Administration.

This study aimed to investigate and analyze this safety signal using a dual pharmacovigilance database analysis.

Methods

This is as an observational study of reports of inflammatory heart reactions associated with mRNA COVID-19 vaccines reported in the World Health Organization’s global individual case safety report database (up to June 30th2021), and in the U.S. Vaccine Adverse Event Reporting System (VAERS, up to May 21st2021). Cases were described, and disproportionality analyses using reporting odds-ratios (ROR) and their 95% confidence interval (95%CI) were performed to assess relative risk of reporting according to patient sex and age.

Results

At a global scale, the inflammatory heart reactions most frequently reported were myocarditis (1241, 55%) and pericarditis (851, 37%), the majority requiring hospitalization (n=796 (64%)). Overall, patients were young (median age 33 [21-54] years). The main age group was 18-29 years old (704, 31%), and mostly males (1555, 68%). Pericarditis onset was delayed compared to myocarditis with a median time to onset of 8 [3-21] vs. 3 [2-6] days, respectively (p=0.001). Regarding myocarditis, an important disproportionate reporting in males (ROR, 9.4 [8.3-10.6]) as well as in adolescents (ROR, 22.3 [19.2-25.9]) and 18-29 years old (ROR, 6.6 [5.9-7.5]) compared to older patients were observed.

Conclusions

The inflammatory heart reactions, namely myocarditis and pericarditis, have been reported world-wide shortly following COVID-19 mRNA vaccination. An important disproportionate reporting among adolescents and young adults, particularly in males, was observed especially for myocarditis. Guidelines must take this specific risk into account and to optimize vaccination protocols according to sex and age. While the substantial benefits of COVID-19 vaccination still prevail over risks, clinicians and the public should be aware of these reactions and seek appropriate medical attention.
Patient-centered care, advance care planning, and treatment preferences among home medical care patients in Japan: The ZEVIOUS study
Authors: Hayashi Shinu , Shirahige Yutaka , Tsugihashi Yukio , Iida Hidekazu , Hirose Misaki , Yasunaka Masakazu , Kurita Noriaki ,   the ZEVIOUS group
Published: August 2021

Background

It remains unclear how both the quality of patient-centered care and the patient’s illness affect advance care planning (ACP) in primary care settings. Identifying the facilitators and barriers to ACP in primary care settings has become a growing scientific and clinical challenge.

Objective

To examine the association between the quality of primary care and ACP preparedness among patients. Additionally, to investigate whether ACP preparedness and the patient’s illness are associated with the expression of future treatment preferences.

Design

Multicenter cross-sectional study.

Participants

Adult Japanese patients receiving home medical care.

Main Measures

A survey was run to assess consideration of ACP by patients and expression of future treatment preferences. The quality of primary care, which reflects patient centeredness, was assessed with the Japanese version of the Primary Care Assessment Tool– Short Form. Information on the clinical conditions that required home medical care was collected from physicians.

Key Results

Of 194 patients using 29 home medical services, 62 patients (32%) showed signs of ACP preparedness, and 153 patients (78%) expressed their treatment preferences. In a multivariable-adjusted generalized estimating equation, primary care quality was associated with ACP preparedness (per 10-point increase, adjusted OR: 1.96, 95% CI: 1.51–2.56). However, we found insufficient evidence to support that ACP preparedness was associated with a lower incidence of non-expression of treatment preferences (adjusted OR: 1.02, 95% CI 0.49–2.12). In contrast, having cancer was associated with a lower incidence of non-expression of treatment preferences (adjusted OR: 0.12, 95% CI: 0.01–0.995).

Conclusions

At a minimum, patient centeredness in home medical care facilitates must ensure the initiation of ACP preparedness. To understand the association between ACP preparedness and expression of treatment preferences, further efforts are warranted to clarify the quality and content of ACP preparedness simultaneously with the patient’s illness.
Early Reduction of SARS-CoV-2 Replication in Bronchial Epithelium by Kinin B2 Receptor Antagonism
Authors: Jakwerth Constanze A. , Feuerherd Martin , Guerth Ferdinand M. , Oelsner Madlen , Schellhammer Linda , Giglberger Johanna , Pechtold Lisa , Jerin Claudia , Kugler Luisa , Mogler Carolin , Haller Bernhard , Erb Anna , Wollenberg Barbara , Spinner Christoph D. , Buch Thorsten , Protzer Ulrike , Schmidt-Weber Carsten B. , Zissler Ulrich M. , Chaker Adam M.
Published: August 2021

Background

SARS-CoV2 has evolved to enter the host via the ACE2 receptor which is part of the Kinin-kallirein pathway. This complex pathway is only poorly understood in context of immune regulation but critical to control infection. This study examines SARS-CoV2 infection and epithelial mechanisms of the kinin-kallikrein system at the kinin B2 receptor level in SARS-CoV-2 infection that is of direct translational relevance.

Methods

From acute SARS-CoV-2-positive patients and -negative controls, transcriptomes of nasal brushings were analyzed. Primary airway epithelial cells (NHBEs) were infected with SARS-CoV-2 and treated with the approved B2R antagonist icatibant. SARS-CoV-2 RNA RT-qPCR, cytotoxicity assays, plaque assays and transcriptome analyses were performed. The treatment effect was further studied in a murine airway inflammation model in vivo.

Results

Here, we report a broad and strong upregulation of kallikreins and the kinin B2 receptor (B2R) in the nasal mucosa of acutely symptomatic SARS-CoV-2-positive patients. A B2R antagonist impeded SARS-CoV-2 replication and spread in NHBEs, as determined in plaque assays on Vero E6 cells. B2R antagonism reduced the expression of SARS-CoV-2 entry receptor ACE2 in vitro and in a murine airway inflammation model in vivo. In addition, it suppressed gene expression broadly, particularly genes involved in G-protein-coupled-receptor signaling and ion transport.

Conclusions

In summary, this study provides evidence that treatment with B2R antagonists protects airway epithelial cells from SARS-CoV-2 by inhibiting its replication and spread, through the reduction of ACE2 levels and the interference with several cellular signaling processes. Future clinical studies need to shed light on the airway protection potential of approved B2R antagonists, like icatibant, in the treatment of early-stage COVID-19.
Gut microbiome activity predicts risk of type 2 diabetes and metformin control in a large human cohort
Authors: Shen Nan , Dimitrova Nevenka , Ho Cleo H. , Torres Pedro J. , Camacho Francine R , Cai Ying , Vuyisich Momchilo , Tanton Damon , Banavar Guruduth
Published: August 2021

Recognizing and treating the early stages of type 2 diabetes (T2D) is the most cost effective way to decrease prevalence, before heart disease, renal disease, blindness, and limb amputation become inevitable. In this study, we employ high resolution gut microbiome metatranscriptomic analysis of stool samples from 53,970 individuals to identify predictive biomarkers of type 2 diabetes progression and potential for diagnosis and treatment response. The richness of the metatranscriptomic data enabled us to develop a T2D risk model to delineate individuals with glycemic dysregulation from those within normal glucose levels, with ROC-AUC of 0.83+/-0.04. This risk score can predict the probability of having insulin dysregulation before detecting high glycated hemoglobin (HbA1c), the standard-of-care marker for prediabetes and diabetes. Additionally, a machine learning model was able to distinguish novel metatranscriptomic features that segregate patients who receive metformin and are able to control their HbA1c from those who do not. These discoveries set the stage for developing multiple therapeutic avenues for prevention and treatment of T2D.
Triaging and Referring In Adjacent General and Emergency Departments (the TRIAGE trial): a cluster randomised controlled trial
Authors: Morreel Stefan , Philips Hilde , De Graeve Diana , Monsieurs Koenraad G , Kampen Jarl K , Meysman Jasmine , Lefevre Eva , Verhoeven Veronique
Published: August 2021

Objectives

To determine the effectiveness and safety of a tool diverting low urgency patients eligible for primary care from an emergency department (ED) to the adjacent general practitioner cooperative (GPC).

Methods

Unblinded, randomised controlled trial with weekends serving as clusters (three intervention clusters for each control). The intervention was nurse-led triage using a new tool assigning patients to either ED or GPC. During intervention weekends, patients were encouraged to follow this assignment while it was not communicated to the patients during control weekends (they remained at the ED). The primary outcome was the proportion of patients assigned to and handled by the GPC during intervention weekends. The trial was randomised for the secondary outcome: the proportion of patients assigned to the GPC during intervention and control weekends. Additional outcomes were association of these outcomes with possible confounders (study tool parameters, nurse, and patient characteristics), proportion of patients referred back to the ED by the GPC, hospitalisations, and performance of the study tool to detect primary care eligible patients (with the opinion of the treating physician as the gold standard).

Results

In the intervention group, 838/6374 patients (13.3%, 95% CI 12.5 to 14.2) were assigned to the GPC (secondary outcome), in the control group 431/1744 (24.7%, 95% CI 22.7 to 26.8). In the intervention group, 599/6374 patients (9.5%, 95% CI 8.8 to 10.3) experienced the primary outcome which was influenced by the chosen MTS presentational flowchart, patient’s age, and the nurse. 24/599 patients (4.0%, 95% CI 2.7 to 5.9) patients were referred back to the ED of which three were hospitalised. Positive and negative predictive values of the studied tool during intervention weekends were 0.96 (95%CI 0.94 to 0.97) and 0.60 (95% CI 0.58 to 0.62). Out of the patients assigned to the GPC, 2.4% (95% CI 1.7 to 3.4) were hospitalised.

Conclusions

ED nurses using a new tool safely diverted 9.5% of the included patients to primary care.

ClinicalTrials.gov Identifier

NCT03793972

Funding

Research Foundation – Flanders (FWO)
Comparison of Demographic and Diagnostic Markers in New Onset Pediatric Type 1 and Type 2 Diabetes
Authors: Nieto Teresa , Castillo Beatriz , Nieto Jacobo , Redondo Maria J.
Published: August 2021

Purpose

Type 1 diabetes (T1D) is the most common type of diabetes in children, but the frequency of type 2 diabetes (T2D) is increasing rapidly. Classification of diabetes is based on a constellation of features that are typical of each type. We aimed to compare demographic, clinical and laboratory characteristics at diabetes diagnosis in pediatric T1D and T2D.

Methods

We studied children who attended a large academic hospital in Houston, Texas (USA) with a new diagnosis of T2D (n=753) or T1D (n=758). We compared age, sex, race/ethnicity, presence of obesity, glucose, hemoglobin A1c, islet autoantibody positivity, C-peptide, and presence of diabetic ketoacidosis (DKA) at diabetes diagnosis.

Results

At diagnosis of diabetes, children with T2D, compared with those with T1D, were older (13.6 vs 9.7% years old), more likely females (63.2% vs 47.8%), of racial/ethnic minority (91.1%% versus 42.3%) and obese (90.9% vs 19.4%), and were less likely to have DKA (7.8% vs 35.0%) and diabetes autoantibodies (5.5% vs 95.4%). Children with T2D also had significantly less marked elevation of glucose and hemoglobin A1c, and lower C-peptide levels (all comparisons, p<0.0001). In multiple logistic regression analysis, older age, racial/ethnic minority, obesity, higher C-peptide and negative islet autoantibodies were independently associated with T2D (all, p<0.05) while sex, glucose, hemoglobin A1c and DKA were not (model p<0.0001).

Conclusions

There are important demographic, clinical and laboratory differences between T1D and T2D in children. However, none of the characteristics was unique to either diabetes type, which poses challenges to diabetes classification at diagnosis.
Public opinion on global distribution of COVID-19 vaccines: evidence from two nationally representative surveys in Germany and the United States
Authors: Klumpp Matthias , Monfared Ida G. , Vollmer Sebastian
Published: August 2021

Background

Despite ongoing calls for more equity in the global distribution of COVID-19 vaccines, there remains a great disparity between high- and low- or middle-income countries. Based on the principles of distributive justice, we assessed the public opinion on this issue in the United States and Germany as examples for high-income countries with a high potential for redistribution.

Methods

We conducted representative surveys among the adult population in the United States (N=1,000) and Germany (N=1,003) in June 2021 using two instances of an analytic hierarchy process (AHP) to elicit how the public weighs different principles and criteria according to which the vaccines should be allocated as well as discrete choice experiments to split a limited supply of vaccine doses between a hypothetical high-income and low-income country.

Findings

In the first AHP, respondents in the United States and Germany gave weight to “medical urgency” by 37·4% (37·2-37·5) and 49·4% (49·2-49·5), “equal access for all” 32·7% (32·6-32·8) and 25·4% (25·2-25·5), “production contribution” 13·7% (13·6-13·8) and 13·3% (13·2-13·4), and “free market rules” 16·3% (16·2-16·4) and 12·0% (11·9-12·1), respectively. In the discrete choice experiment responds in the United States split available vaccine doses such that the low-income country on average received 53·9 percent (95% CI: 52·6-55·1). For Germany this number was 57·5 percent (95% CI: 56·3-58·7). The low-income country had three times as many inhabitants as the high-income country. When facing the dilemma where a vulnerable family member was waiting for a vaccine as opposed to when there was no clear self-interest, 20·7% (18·2-23·3) of respondents in the United States and 18·2% (15·8-20·6) in Germany reduced the amount they allocated to the low-income country

Interpretations

The public in the United States and Germany favours utilitarian and egalitarian distribution principles of vaccines for COVID-19 over the currently prevailing libertarian or meritocratic principles. This implies that political approaches and decision favouring higher levels of redistribution would be supported by the public opinion in these two countries.

Funding

German Research Foundation DFG RTG 1723.
Serological survey of SARS-CoV-2 incidence conducted at a rural West Virginia hospital
Authors: Horspool Alexander M. , Russ Brynnan P. , Wolf M. Allison , Kang Jason , Blackwood Catherine B. , Hall Jesse M. , Wong Ting Y. , DeJong Megan A. , Bitzer Graham , Bevere Justin R. , Eggleston Robert , Stewart Anita , Costello Lisa , Welch Shelley , Kieffer Theodore , Hodder Sally , Damron F. Heath
Published: August 2021

The SARS-CoV-2 pandemic has affected all types of global communities. Differences in urban and rural environments have led to varying levels of transmission within these subsets of the population. To fully understand the prevalence and impact of SARS-CoV-2 it is critical to survey both types of community. This study establishes the prevalence of SARS-CoV-2 in a rural community: Montgomery, West Virginia. Approximately 10% of participants exhibited serological or PCR-based results indicating exposure to SARS-CoV-2 within 6 months of the sampling date. Quantitative analysis of IgG levels against SARS-CoV-2 receptor binding domain (RBD) was used to stratify individuals based on antibody response to SARS-CoV-2. A significant negative correlation between date of exposure and degree of anti-SARS-CoV-2 RBD IgG (R2 = 0.9006) was discovered in addition to a correlation between neutralizing anti-SARS-CoV-2 antibodies (R2 = 0.8880) and days post exposure. Participants were confirmed to have normal immunogenic profiles by determining serum reactivity B. pertussis antigens commonly used in standardized vaccines. No significant associations were determined between anti-SARS-CoV-2 RBD IgG and age or biological sex. Reporting of viral-like illness symptoms was similar in SARS-CoV-2 exposed participants greater than 30 years old (100% reporting symptoms 30-60 years old, 75% reporting symptoms >60 years old) in contrast to participants under 30 years old (25% reporting symptoms). Overall, this axnalysis of a rural population provides important information about the SARS-CoV-2 pandemic in small rural communities. The study also underscores the fact that prior infection with SARS-CoV-2 results in antibody responses that wane over time which highlights the need for vaccine mediated protection in the absence of lasting protection.
COVID-19 Infection, Admission and Death Amongst People with Rare Autoimmune Rheumatic Disease in England. Results from the RECORDER Project
Authors: Rutter Megan , Lanyon Peter C. , Grainge Matthew J. , Hubbard Richard , Peach Emily , Bythell Mary , Stilwell Peter , Aston Jeanette , Stevens Sarah , Pearce Fiona A.
Published: August 2021

Objectives

To calculate the rates of COVID-19 infection and COVID-19-related death among people with rare autoimmune rheumatic diseases (RAIRD) during the first wave of the COVID-19 pandemic in England compared to the general population.

Methods

We used Hospital Episode Statistics to identify all people alive 01 March 2020 with ICD-10 codes for RAIRD from the whole population of England. We used linked national health records (demographic, death certificate, admissions and PCR testing data) to calculate rates of COVID-19 infection and death up to 31 July 2020. Our primary definition of COVID-19-related death was mention of COVID-19 on the death certificate. General population data from Public Health England and the Office for National Statistics were used for comparison. We also describe COVID-19-related hospital admissions and all-cause deaths.

Results

We identified a cohort of 168,680 people with RAIRD, of whom 1874 (1.11%) had a positive COVID-19 PCR test. The age-standardised infection rate was 1.54 (95% CI 1.50-1.59) times higher than in the general population. 713 (0.42%) people with RAIRD died with COVID-19 on their death certificate and the age-sex-standardised mortality rate for COVID-19-related death was 2.41 (2.30 – 2.53) times higher than in the general population. There was no evidence of an increase in deaths from other causes in the RAIRD population.

Conclusions

During the first wave of COVID-19 in England, people with RAIRD had a 54% increased risk of COVID-19 infection and more than twice the risk of COVID-19-related death compared to the general population. These increases were seen despite shielding policies.

Key Messages

People with RAIRD were at increased risk of COVID-19 infection during the first wave.

Compared to the general population, they had over twice the risk of COVID-19-related death.

These increased risks were seen despite shielding policies in place in England.
Expression Atlas of Avian Neural Crest Proteins: Neurulation to Migration
Authors: Monroy Brigette Y. , Adamson Carly J. , Camacho-Avila Alexis , Guerzon Christian N. , Echeverria Camilo V. , Rogers Crystal D.
Published: August 2021

Neural crest (NC) cells are a dynamic population of embryonic stem cells that create various adult tissues in vertebrate species including craniofacial bone and cartilage and the peripheral and enteric nervous systems. NC development is a conserved and complex process that is controlled by a tightly regulated gene regulatory network (GRN) of morphogens, transcription factors, and cell adhesion proteins. While multiple studies have characterized the expression of several GRN factors in single species, a comprehensive protein analysis that directly compares expression across development is lacking. To address this, we used three closely related avian models, Gallus gallus (chicken), Coturnix japonica (Japanese quail), and Pavo cristatus (Indian peafowl), to compare the localization and timing of four GRN transcription factors, PAX7, SOX9, SNAI2, and SOX10 from the onset of neurulation to migration. While the spatial expression of these factors is largely conserved, we find that quail NC cells express SOX9, SNAI2, and SOX10 proteins at the equivalent of earlier developmental stages than chick and peafowl. In addition, quail NC cells migrate farther and more rapidly than the larger organisms. These data suggest that despite a conservation of NC GRN players, differences in the timing of NC development between species remain a significant frontier to be explored with functional studies.

Graphical abstract

Comparative analysis of neural crest (NC) protein spatiotemporal localization in quail, chick, and peafowl embryos.

Avian embryos were incubated for different lengths of time to achieve the same developmental stage marked by somite number (somite stage, SS) as described by Hamburger and Hamilton (HH) in 1951. (A) Quail, (B) chick, and (C) peafowl embryos were collected for immunohistochemistry (IHC) to define and quantify the timeline of NC protein expression. We specifically focused on the expression of PAX7, SNAI2, SOX9, and SOX10 proteins. We determined that neural crest development as marked by common NC-specific proteins differs between species. Rather than similar, but scaled development, each organism has its own NC developmental timeline. Quail embryos develop much more rapidly than their counterparts, chick and peafowl. Further, chick and peafowl amino acid sequences are more similar to each other than they are to quail.
Evidence of multiple genome duplication events inMytilusevolution
Authors: Corrochano-Fraile Ana , Davie Andrew , Carboni Stefano , Bekaert Michaël
Published: August 2021

Molluscs remain one significantly under-represented taxa amongst available genomic resources, despite being the second-largest animal phylum and the recent advances in genomes sequencing technologies and genome assembly techniques. With the present work, we want to contribute to the growing efforts by filling this gap, presenting a new high-quality reference genome forMytilus edulisand investigating the evolutionary history within the Mytilidae family, in relation to other species in the class Bivalvia.

Here we present, for the first time, the discovery of multiple whole genome duplication events in the Mytilidae family and, more generally, in the class Bivalvia. In addition, the calculation of evolution rates for three species of the Mytilinae subfamily sheds new light onto the taxa evolution and highlights key orthologs of interest for the study ofMytilusspecies divergences.

The reference genome presented here will enable the correct identification of molecular markers for evolutionary, population genetics, and conservation studies. Mytilidae have the capability to become a model shellfish for climate change adaptation using genome-enabled systems biology and multi-disciplinary studies of interactions between abiotic stressors, pathogen attacks, and aquaculture practises.
Characterisation of the Ubiquitin-ESCRT pathway in Asgard archaea sheds new light on origins of membrane trafficking in eukaryotes
Authors: Hatano Tomoyuki , Palani Saravanan , Papatziamou Dimitra , Souza Diorge P. , Salzer Ralf , Tamarit Daniel , Makwana Mehul , Potter Antonia , Haig Alexandra , Xu Wenjue , Townsend David , Rochester David , Bellini Dom , Hussain Hamdi M. A. , Ettema Thijs , Löwe Jan , Baum Buzz , Robinson Nicholas P. , Balasubramanian Mohan
Published: August 2021

The ESCRT machinery performs a critical role in membrane remodelling events in all eukaryotic cells, including in membrane trafficking, membrane repair, cytokinetic abscission, in viral egress, and in the generation of extracellular vesicles. While the machinery is complex in modern day eukaryotes, where it comprises dozens of proteins, the system has simpler and more ancient origins. Indeed, homologues of ESCRT-III and the Vps4 ATPase, the proteins that execute the final membrane scission reaction, play analogous roles in cytokinesis and potentially in extracellular vesicle formation in TACK archaea where ESCRT-I and II homologues seem to be absent. Here, we explore the phylogeny, structure, and biochemistry of homologues of the ESCRT machinery and the associated ubiquitylation system found in genome assemblies of the recently discovered Asgard archaea. In these closest living prokaryotic relatives of eukaryotes, we provide evidence for the ESCRT-I and II sub-complexes being involved in the ubiquitin-directed recruitment of ESCRT-III,_as it is in eukaryotes. This analysis suggests a pre-eukaryotic origin for the Ub-coupled ESCRT system and a likely path of ESCRT evolution via a series of gene duplication and diversification events.
Nicotinate degradation in a microbial eukaryote: a novel, complete pathway extant in Aspergillus nidulans
Authors: Bokor Eszter , Ámon Judit , Varga Mónika , Szekeres András , Hegedűs Zsófia , Jakusch Tamás , Flipphi Michel , Vágvölgyi Csaba , Gácser Attila , Scazzocchio Claudio , Hamari Zsuzsanna
Published: August 2021

Several strikingly different aerobic and anaerobic pathways of nicotinate utilization had been described in bacteria. No similar work is extant in any eukaryote. Here we elucidate a complete eukaryotic nicotinate utilization pathway, by constructing single or multiple gene deleted strains and identifying metabolic intermediates by ultra-high performance liquid chromatography – high-resolution mass spectrometry. Enzymes catalyzing each step and all intermediate metabolites were identified. We previously established that the cognate eleven genes organized in three clusters constitute a regulon, strictly dependent on HxnR, a pathway-specific transcription factor. The first step, hydroxylation of nicotinic acid to 6-hydroxynicotinic acid is analogous to that occurring in bacterial pathways and is catalyzed by an independently evolved molybdenum-containing hydroxylase. The following enzymatic steps have no prokaryotic equivalents: 6-hydroxynicotinic acid is converted to 2,3,6-trihydroxypyridine through 2,5-dihydroxypiridine and the trihydroxylated pyridine ring is then saturated to 5,6-dihydroxypiperidine-2-one followed by the oxidation of the C6 hydroxyl group resulting in 3-hydroxypiperidine-2,6-dione. The latter two heterocyclic compounds are newly identified cellular metabolites, while 5,6-dihydroxypiperidine-2-one is a completely new chemical compound. Ring opening between C and N results in α-hydroxyglutaramate, an unprecedented compound in prokaryotic nicotinate catabolic routes. The pathway extant in A. nidulans, and in many other ascomycetes, is different from any other previously analyzed in bacteria. Our earlier phylogenetic analysis of Hxn proteins together with the complete novel biochemical pathway we now describe further illustrates the convergent evolution of catabolic pathways between fungi and bacteria.

Significance Statement

This eukaryotic nicotinate catabolic pathway illustrates the convergent evolution of prokaryotic and microbial eukaryotic metabolism. It brings to light newly identified metabolites and step processing enzymes. The identification of hitherto undescribed metabolites - which could serve as precursor biosynthetic molecules - is potentially relevant to both pharmaceutical and agrochemical industries.
Lack of authentic atrial fibrillation in commonly used murine atrial fibrillation models
Authors: Fu Fumin , Pietropaolo Michael , Cui Lei , Pandit Shilpa , Li Weiyan , Tarnavski Oleg , Shetty Suraj S. , Liu Jing , Lussier Jennifer M. , Murakami Yutaka , Grewal Prabhjit K. , Deyneko Galina , Turner Gordon M. , Taggart Andrew K.P. , Waters M. Gerard , Coughlin Shaun , Adachi Yuichiro
Published: August 2021

The mouse is a useful preclinical species for evaluating disease etiology due to the availability of a wide variety of genetically modified strains and the ability to perform disease-modifying manipulations. In order to better characterize atrial fibrillation (AF), we profiled several commonly used murine AF models. We initially evaluated a pharmacological model of acute carbachol (CCh) treatment plus atrial burst pacing in C57BL/6 mice. In an effort to observe micro-reentrant circuits indicative of authentic AF, we employed optical mapping imaging in isolated mouse hearts. While CCh reduced atrial refractoriness and increased atrial tachyarrhythmia vulnerability, the left atrial (LA) excitation patterns were rather regular without reentrant circuits or wavelets. Therefore, the atrial tachyarrhythmia resembled high frequency atrial flutter, not typical AF per se. We next examined both a chronic angiotensin II (Ang II) infusion model and the surgical model of transverse aortic constriction (TAC), which have both been reported to induce atrial and ventricular structural changes that serve as a substrates for micro-reentrant AF. Although we observed some extent of atrial remodeling such as fibrosis or enlarged LA diameter, burst pacing-induced atrial tachyarrhythmia vulnerability did not differ from control mice in either model. This again suggested that an AF-like pathophysiology is difficult to demonstrate in the mouse. To continue searching for a valid murine AF model, we studied mice with a cardiac-specific deficiency (KO) in liver kinase B1 (Cardiac-LKB1), which has been reported to exhibit spontaneous AF. Indeed, the electrocardiograms (ECG) of conscious Cardiac-LKB1 KO mice exhibited no P waves and had irregular RR intervals, which are characteristics of AF. Histological evaluation of Cardiac-LKB1 KO mice revealed dilated and fibrotic atria, again consistent with AF. However, atrial electrograms and optical mapping revealed that electrical activity was limited to the sino-atrial node area with no electrical conduction into the atrial myocardium beyond. Thus, Cardiac-LKB KO mice have severe atrial myopathy or atrial standstill, but not AF. In summary, the atrial tachyarrhythmias we observed in the four murine models were distinct from typical human AF, which often exhibits micro- or macro-reentrant atrial circuits. Our results suggest that the four murine AF models we examined are poor representations of human AF, and raise a cautionary note about the use of any murine model to study AF.
The effect of 0.01% atropine on ocular axial elongation for myopia children: a meta-analysis
Authors: Yu Yan , Liu Jiasu
Published: August 2021

Objectives

This meta-analysis aimed to identify the therapeutic effect of 0.01% atropine with on ocular axial elongation for myopia children.

Methods

We searched PubMed, Cochrane Library, and CBM databases from inception to July 2021. Meta-analysis was conducted using STATA version 14.0 and Review Manager version 5.3 softwares. We calculated the weighted mean differences(WMD) to analyze the change of ocular axial length (AL) between orthokeratology combined with 0.01% atropine (OKA) and orthokeratology (OA) alone. The Cochran’ s Q-statistic and I2 test were used to evaluate potential heterogeneity between studies. To evaluate the influence of single studies on the overall estimate, a sensitivity analysis was performed. We also performed sub group and meta-regression analyses to investigate potential sources of heterogeneity. We conducted Begger’ s funnel plots and Egger’ s linear regression tests to investigate publication bias.

Results

Nine studies that met all inclusion criteria were included in this meta-analysis. A total of 191 children in OKA group and 196 children in OK group were assessed. The pooled summary WMD of AL change was -0.90(95%CI=-1.25∼-0.55) with statistical significance(t=-5.03, p<0.01), which indicated there was obvious difference between OKA and OK in myopic children. Subgroup analysis also showed that OKA treatment resulted in significantly less axial elongation compared to OK treatment alone according to SER. We found no evidence for publication bias.

Conclusions

Our meta-analysis indicates 0.01% atropine atropine is effective in slowing axial elongation in myopia children with orthokeratology.
Transcriptomic analysis of astaxanthin hyper-producing Coelastrum sp. mutant obtained by chemical mutagenesis
Authors: Tharek Ameerah , Mohamad Shaza Eva , Suzuki Iwane , Iwamoto Koji , Hara Hirofumi , Yoshizaki Shinji , Jamaluddin Haryati , Salleh Madihah Md , Yahya Adibah
Published: August 2021

A newly isolated green microalga, Coelastrum sp. has the capability to produce and accumulate astaxanthin under various stress conditions. At present, a mutant G1-C1 of Coelastrum sp. obtained through chemical mutagenesis using ethyl methane sulfonate displayed an improvement in astaxanthin accumulation, which was 2-fold higher than that of the wild-type. However, lack of genomic information limits the understanding of the molecular mechanism that leads to a high level of astaxanthin in the mutant G1-C1. In this study, transcriptome sequencing was performed to compare the transcriptome of astaxanthin hyper-producing mutant G1-C1 and wild-type of Coelastrum sp. with respect to astaxanthin biosynthesis. This is to clarify why the mutant produced higher astaxanthin yield compared to the wild-type strain. Based on the transcriptomic analysis, the differentially expressed genes involved in astaxanthin biosynthesis were significantly upregulated in the mutant G1-C1 of Coelastrum sp. Genes coding phytoene synthase, phytoene desaturase, ζ-carotene desaturase, and lycopene β-cyclase involved in β-carotene biosynthesis in the mutant cells were upregulated by 10-, 9.2-, 8.4-, and 8.7-fold, respectively. Genes coding beta-carotene ketolase and beta-carotene 3-hydroxylase involved in converting β-carotene into astaxanthin were upregulated by 7.8- and 8.0-fold, respectively. In contrast, the lycopene ε-cyclase gene was downregulated by 9.7-fold in mutant G1-C1. Together, these results contribute to higher astaxanthin accumulation in mutant G1-C1. Overall, the data in this study provided molecular insight for a better understanding of the differences in astaxanthin biosynthesis between the wild-type and mutant G1-C1 strains.
Membrane fusion and immune evasion by the spike protein of SARS-CoV-2 Delta variant
Authors: Zhang Jun , Xiao Tianshu , Cai Yongfei , Lavine Christy L. , Peng Hanqin , Zhu Haisun , Anand Krishna , Tong Pei , Gautam Avneesh , Mayer Megan L. , Walsh Richard M. , Rits-Volloch Sophia , Wesemann Duane R. , Yang Wei , Seaman Michael S. , Lu Jianming , Chen Bing
Published: August 2021

The Delta variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has outcompeted previously prevalent variants and become a dominant strain worldwide. We report here structure, function and antigenicity of its full-length spike (S) trimer in comparison with those of other variants, including Gamma, Kappa, and previously characterized Alpha and Beta. Delta S can fuse membranes more efficiently at low levels of cellular receptor ACE2 and its pseudotyped viruses infect target cells substantially faster than all other variants tested, possibly accounting for its heightened transmissibility. Mutations of each variant rearrange the antigenic surface of the N-terminal domain of the S protein in a unique way, but only cause local changes in the receptor-binding domain, consistent with greater resistance particular to neutralizing antibodies. These results advance our molecular understanding of distinct properties of these viruses and may guide intervention strategies.
Branched ubiquitin chain binding and deubiquitination by UCH37 facilitate proteasome clearance of stress-induced inclusions
Authors: Song Aixin , Hazlett Zachary , Abeykoon Dulith , Dortch Jeremy , Dillon Andrew , Curtiss Justin , Martinez Sarah Bollinger , Hill Christopher P. , Yu Clinton , Huang Lan , Fushman David , Cohen Robert E. , Yao Tingting
Published: August 2021

UCH37, also known as UCHL5, is a highly conserved deubiquitinating enzyme (DUB) that associates with the 26S proteasome. Recently it was reported that UCH37 activity is stimulated by branched ubiquitin chain architectures. To understand how UCH37 achieves its unique debranching specificity, we performed biochemical and NMR structural analyses and found that UCH37 is activated by contacts with the hydrophobic patches of both distal ubiquitins that emanate from a branched ubiquitin. In addition, RPN13, which recruits UCH37 to the proteasome, further enhances branched-chain specificity by restricting linear ubiquitin chains from having access to the UCH37 active site. In cultured human cells under conditions of proteolytic stress, we show that substrate clearance by the proteasome is promoted by both binding and deubiquitination of branched polyubiquitin by UCH37. Proteasomes containing UCH37(C88A), which is catalytically inactive, aberrantly retain polyubiquitinated species as well as the RAD23B substrate shuttle factor, suggesting a defect in recycling of the proteasome. These findings provide a foundation to understand how proteasome degradation of substrates modified by a unique ubiquitin chain architecture is aided by a DUB.