bluuebunny/crossref_metadata_2025 huggingface dataset:
Mental Health Utilization in Children in the time of COVID-19
Authors: Coates Leah , Marshall Rebecca , Johnson Kyle , Foster Byron A.
Published: August 2021

Background

In early 2020, coronavirus disease 2019 (COVID-19) was declared a public health emergency and a combination of lockdown and social distancing measures were put in place across the globe. Many children, adolescents and adults have experienced adverse mental health effects related to the pandemic and its impact on daily life, although the long-term impact on individuals and health systems is not well understood.

Methods

This cross-sectional study was based on data from 2018-2021 collected via medical records from our hospital. Admissions were transformed into time-series data, and models were generated to analyze changes in admission rates for mental health emergencies in 2020 and 2021 compared to previous years.

Results

Of 1906 inpatient encounters among 1543 unique patients seen by the Child and Adolescent Psychiatry Consultation-Liaison service, there was a decrease in overall admissions beginning in March 2020, coinciding with statewide lock down due to the COVID-19 pandemic. In April 2020, admissions were reduced 36% compared to average admissions from 2018-2019. By 2021, overall admissions were significantly higher than for the previous three years. Similarly, the count of suicide attempts was significantly higher in 2021 compared to previous years. The rate of patients admitted to inpatient facilities upon discharge was significantly higher during the COVID-19 pandemic period.

Conclusion

Admissions for mental health emergencies fluctuated during the period associated with the COVID-19 pandemic across an array of diagnoses. Increases in admissions and severity of mental health emergencies during COVID-19 may reflect a detrimental impact of the pandemic on the mental health of children, as well as unmet needs during this time.
The role of incentives in deciding to receive the available COVID-19 vaccine
Authors: Shmueli Liora
Published: August 2021

Objective

To assess the public’s intention to get vaccinated immediately after COVID-19 vaccine became available, and to determine the role of incentives beyond socio-demographic, health-related and behavioral factors, in predicting this intention.

Methods

An online survey was conducted among adults in Israel (n=461), immediately after the first COVID-19 vaccine became available (22/12/2020 to 10/1/2021). Two regressions were performed to investigate determinants of intention and sense of urgency to receive the available COVID-19 vaccine.

Results

Although many adults intended to receive available COVID-19 vaccine, only 65% intended to immediately receive the vaccine; 16% preferred to wait 3 months and 18% preferred to wait a year. The sense of urgency to get vaccinated differed by age, periphery-level, perceived barriers, cues to action and availability. Monetary rewards or the “green pass” incentives didn’t increase the probability of getting vaccination immediately.

Conclusions

Providing data on the role of incentives in increasing the intention to immediately receive the available COVID-19 vaccine is important for health policy makers and healthcare providers. Our findings underscore the importance of COVID-19 vaccine accessibility.

Practice Implications

Health policy makers should consider allocating funds for making the vaccine accessible and encourage methods of persuasion, instead of investing funds in monetary incentives.
Changing Dynamics of COVID-19 in the U.S. with the Emergence of the Delta Variant: Projections of the COVID-19 Simulator
Authors: Chhatwal Jagpreet , Xiao Yingying , Mueller Peter , Adee Madeline , Dalgic Ozden O , Ladd Mary Ann , Ayer Turgay , Linas Benjamin P
Published: August 2021

With the recent emergence of the B.1.617.2 (Delta) variant of SARS-CoV-2 in the U.S., many states are seeing rising cases and hospitalizations after a period of steady decline. As We used theCOVID-19 Simulator, an interactive online tool that utilizes a validated mathematical model, to simulate the trajectory of COVID-19 at the state level in the U.S. COVID-19 Simulator’s forecasts are updated weekly and included in the Centers for Disease Control and Prevention (CDC) ensemble model. We employed our model to analyze scenarios where the Delta variant becomes dominant in every state.

The combination of high transmissibility of the Delta variant, low vaccination coverage in several regions, and more relaxed attitude towards social distancing is expected to result in as surge in COVID-19 deaths in at least 40 states. In several states – including Idaho, Maine, Montana, Nebraska, North Carolina, Oregon, Puerto Rico, Washington, and West Virginia – the projected daily deaths in 2021 could exceed the prior peak daily deaths under current social distancing behavior and vaccination rate. The number of COVID-19 deaths across the U.S. could exceed 1600 per day.

Between August 1, 2021, and December 31, 2021, there could be additional 157,000 COVID-19 deaths across the U.S. Of note, our model projected approximately 20,700 COVID-19 deaths in Texas, 16,000 in California, 12,400 in Florida, 12,000 in North Carolina, and 9,300 in Georgia during this period. In contrast, the projected number of COVID-19 deaths would remain below 200 in New Jersey, Massachusetts, Connecticut, Vermont, and Rhode Island.

We project COVID-19 deaths based on the current vaccination rates and social distancing behavior. Our hope is that the findings of this report serve a warning sign and people revert to wearing masks and maintain social distancing to reduce COVID-19 associated deaths in the U.S. Our projections are updated weekly by incorporating vaccination rates and social distancing measures in each state; the latest results can be found at theCOVID-19 Simulatorwebsite.
Epidemiological Study of COVID-19 Infections: Case of Ga East Municipal Hospital Treatment Centre - Kwabenya-Ghana
Authors: Oduro-Mensah Ebenezer , Asubonteng Delali , Crankson Shirley
Published: August 2021

Background

The COVID-19 pandemic still poses a considerable threat to global health, resulting in an unprecedented demand for regular research to continuously identify and update its risk profiles to ensure relevant interventions.

Objectives

This study aimed to examine the epidemiological characteristics of the COVID-19 outbreak in Ghana and identify risk factors for severe COVID-19 disease.

Method

This was a cross-sectional study involving the data of patients with COVID-19 clinically managed at the Ga-East Municipal Hospital, the main COVID-19 treatment centre in Ghana, from 21st March to 21st June 2020. The data were retrieved from the electronic medical records and folders of the patients. It included sociodemographic characteristics, COVID-19 disease severity, and treatment outcomes. Binomial logistic regression was used to identify risk factors of severe COVID-19 illness.

Result

Among the 360 COVID-19 cases in this study, 55.3% were males, and 44.7% were females. Their mean age was 39.9±16.7years. Most of them were Ghanaians (92.8%) and employed (72.5%). The majority (93%) presented with mild disease, and hypertension (19.2%) was the most common comorbidity. The average length of hospital admission was 10.6±6.4day. Many of the cases recovered (98.6%), resulting in a case fatality of 1.4%. Finally, the logistic regression showed that increasing age (OR=1.12, p= 0.002) and diabetes mellitus (OR=19.85, p=0.007) are risk factors for severe COVID-19 disease.

Conclusion

Findings from the study confirmed that increasing age and diabetes mellitus are risk factors for severe COVID-19 disease. Thus, Ghana could prioritise these identified populations when implementing interventions to reduce the COVID-19 disease burden.

Strength and limitations of this study

This study is one of the few studies exploring the risk factors for severe COVID-19 disease in Ghana; thus, it presents novel context-specific findings that could inform COVID-19 case management in Ghana.

The study was limited in drawing a causal association between the explanatory and outcome variables due to the cross-sectional design.

The study included only one COVID-19 treatment centre. Consequently, the findings may not be generalizable to the entire COVID-19 population in Ghana, even though the included centre is the main COVID-19 treatment centre.
Heterozygous PRKN mutations are common but do not increase the risk of Parkinson’s disease
Authors: Zhu William , Huang Xiaoping , Yoon Esther , Bandres-Ciga Sara , Blauwendraat Cornelis , Cade Joshua H. , Wu Beverly P. , Williams Victoria H. , Schindler Alice B. , Brooks Janet , Gibbs J Raphael , Hernandez Dena G , Ehrlich Debra , Singleton Andrew , Narendra Derek
Published: August 2021

PRKN mutations are the most common recessive cause of Parkinson’s disease (PD) and are a promising target for gene and cell replacement therapies. Identification of biallelic PRKN patients (PRKN-PD) at the population scale, however, remains a challenge, as roughly half are copy number variants (CNVs) and many single nucleotide polymorphisms (SNPs) are of unclear significance. Additionally, the true prevalence and disease risk associated with heterozygous PRKN mutations is unclear, as a comprehensive assessment of PRKN SNPs and CNVs has not been performed at a population scale. To address these challenges, we evaluated PRKN mutations in 2 cohorts analyzed with both a genotyping array and exome or genome sequencing: the NIH PD cohort, a deeply phenotyped cohort of PD patients, and the UK Biobank, a population scale cohort with nearly half a million participants. Genotyping array identified the majority of PRKN mutations and at least 1 mutation in most biallelic PRKN mutation carriers in both cohorts. Additionally, in the NIH-PD cohort, functional assays of patient fibroblasts resolved variants of unclear significance in biallelic carriers and ruled out cryptic loss of function variants in monoallelic carriers. In the UK Biobank, we identified 2,692 PRKN CNVs from genotyping array data from nearly half a million participants (the largest collection to date). Deletions or duplications involving exons 2 accounted for roughly half of all CNVs and the vast majority (88%) involved exons 2, 3, or 4. Combining estimates from whole exome sequencing (from ∼200,000 participants) and genotyping array data, we found a pathogenic PRKN mutation in 1.8% of participants and 2 mutations in ∼1/7,800 participants. Those with 1 PRKN pathogenic variant were as likely as non-carriers to have PD (OR = 0.91, CI= 0.58 – 1.38, p-value = 0.76) or a parent with PD (OR = 1.12, CI = 0.94 – 1.31, p-value = 0.19). Together our results demonstrate that heterozygous pathogenic PRKN mutations are common in the population but do not increase the risk of PD. Additionally, they suggest a cost-effective framework to screen for biallelic PRKN patients at the population scale for targeted studies.
Grandparent inference from genetic data: The potential for parentage-based tagging programs to identify offspring of hatchery strays
Authors: Delomas Thomas A. , Campbell Matthew
Published: August 2021

Fisheries managers routinely use hatcheries to increase angling opportunity. Many hatcheries operate as segregated programs where hatchery-origin fish are not intended to spawn with natural-origin conspecifics in order to prevent potential negative effects on the natural-origin population. Currently available techniques to monitor the frequency with which hatchery-origin strays successfully spawn in the wild rely on either genetic differentiation between the hatchery- and natural-origin fish or extensive sampling of fish on the spawning grounds. We present a method to infer grandparent-grandchild trios using only genotypes from two putative grandparents and one putative grandchild. We developed estimators of false positive and false negative error rates and showed that genetic panels containing 500 - 700 single nucleotide polymorphisms or 200 - 300 microhaplotypes are expected to allow application of this technique for monitoring segregated hatchery programs. We discuss the ease with which this technique can be implemented by pre-existing parentage-based tagging programs and provide an R package that applies the method.
The relationship between sleep disturbance and cognitive impairment in mood disorders: A systematic review
Authors: Pearson Oliver , Uglik-Marucha Nora , Miskowiak Kamilla W. , Cairney Scott A. , Rosenzweig Ivana , Young Allan H. , Stokes Paul R.A.
Published: August 2021

Background

Cognitive impairment experienced by people with bipolar disorders (BD) or major depressive disorder (MDD) is associated with impaired psychosocial function and poorer quality of life. Sleep disturbance is another core symptom of mood disorders which may be associated with, and perhaps worsen, cognitive impairments. The aim of this systematic review was to critically assess the relationship between sleep disturbance and cognitive impairment in mood disorders.

Methods

In this systematic review, relevant studies were identified using electronic database searches of PsychINFO, MEDLINE, Embase and Web of Science.

Findings

Fourteen studies were included; eight investigated people with BD, five investigated people with MDD, and one included both people with MDD and people with BD. One study was an intervention for sleep disturbance and the remaining thirteen studies used either a longitudinal or cross-sectional observational design. Ten studies reported a significant association between subjectively measured sleep disturbance and cognitive impairment in people with MDD or BD after adjusting for demographic and clinical covariates, whereas no such association was found in healthy participants. Two studies reported a significant association between objectively measured sleep abnormalities and cognitive impairment in mood disorders. One study of cognitive behavioural therapy for insomnia modified for BD (CBTI-BD) found an association between improvements in sleep and cognitive performance in BD.

Interpretation

There is preliminary evidence to suggest a significant association between sleep disturbance and cognitive impairment in mood disorders. These findings suggest that identifying and treating sleep disturbance may be important when addressing cognitive impairment in mood disorders.
A causal association between schizophrenia and bipolar disorder on rheumatoid arthritis: A two-sample Mendelian randomization study
Authors: Koc Gonul Hazal , Ozel Fatih , Okay Kaan , Koc Dogukan , de Jong Pascal H.P.
Published: August 2021

Background

Schizophrenia (SCZ) and bipolar disorder (BD) are both associated with several autoimmune disorders including rheumatoid arthritis(RA). However, a causal association of SCZ and BD on RA is controversial and elusive. In the present study, we aimed to investigate the causal association of SCZ and BD with RA by using the Mendelian randomization (MR) approach.

Methods

A two-sample MR (2SMR) study including the inverse-variance weighted(IVW), weighted median, simple mode, weighted mode and MR-Egger methods were performed. We used summary-level genome-wide association study(GWAS) data in which BD and SCZ are the exposure and RA the outcome. We used data from the Psychiatric Genomics Consortium(PGC) for BD(n= 41,917) and SCZ(n= 33,426) and RA GWAS dataset(n= 2,843) from the European ancestry for RA.

Results

We found 48 and 52 independent single nucleotide polymorphisms (SNPs, r2 <0.001)) that were significant for respectively BD and SCZ (p <5×10-8). Subsequently, these SNPs were utilized as instrumental variables(IVs) in 2SMR analysis to explore the causality of BD and SCZ on RA. The two out of five MR methods showed a statistically significant inverse causal association between BD and RA: weighted median method(odds ratio (OR), 0.869, [95% CI, 0.764-0.989];P= 0.034) and inverse-variance weighted(IVW) method (OR, 0.810, [95% CI, 0.689-0.953];P= 0.011). However, we did not find any significant association of SCZ with RA (OR, 1.008, [95% CI, 0.931-1.092];P= 0.829, using the IVW method).

Conclusions

These results provide support for an inverse causal association between BD and RA. Further investigation is needed to explain the underlying protective mechanisms in the development of RA.

Key messages

Mendelian randomization can offer strong insight into the cause-effect relationships in rheumatology.

Bipolar disorder had a protective effect on rheumatoid arthritis.

There is no inverse causal association between schizophrenia and rheumatoid arthritis contrary to the findings from observational studies.
Efficacy of SARS-CoV-2 vaccine in thoracic cancer patients: a prospective study supporting a third dose in patients with minimal serologic response after two vaccine doses
Authors: Gounant Valérie , Ferré Valentine Marie , Soussi Ghassen , Charpentier Charlotte , Flament Héloïse , Fidouh Nadhira , Collin Gilles , Namour Céline , Assoun Sandra , Bizot Alexandra , Brouk Zohra , Vicaut Eric , Teixeira Luis , Descamps Diane , Zalcman Gérard
Published: August 2021

Hypothesis

Coronavirus disease 2019 (COVID-19) resulted in a 30% mortality rate in thoracic cancer patients. Given that cancer patients were excluded from serum anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) vaccine registration trials, it is still unknown whether they would develop a protective anti-spike antibody response following vaccination. This prospective vaccine monitoring study primarily aimed to assess humoral responses to SARS-CoV2 vaccine in thoracic cancer patients.

Methods

SARS-CoV2-spike antibodies were measured using Abbot ARCHITECT SARS-CoV-2 IgG immunoassay, prior to first injection of BNT162b2 mRNA vaccine, as well as at Week 4, and two-to-sixteen weeks after second vaccine dose. The factors associated with antibody response were analyzed.

Results

Overall, 306 patients, with a median age of 67.0 years (IQR=58-74), were vaccinated. Of these, 283 patients received two vaccine doses at 28-day intervals. After 4.7-month median follow-up, seven patients (2.3%) contracted proven symptomatic SARS-CoV-2 infection, with rapid favorable evolution. Of 269 serological results available beyond Day 14 post-second vaccine dose, 17 (6.3%) were still negative (<50 AU/mL) (arbitrary units/mL), while 34 (11%)were <300 AU/mL (12.5thpercentile). In multivariate analysis, only age and chronic corticosteroid treatment were significantly associated with a lack of immunization. Thirty patients received a third vaccine dose, with only three patients showing persistent negative serology thereafter, whereas the others demonstrated clear seroconversion.

Conclusion

SARS-CoV2 vaccines were shown to be efficient in thoracic cancer patients, most of them being immunized after two doses. A third shot given to 1% of patients with persistent low antibody titers resulted in a 88% immunization rate.
Pandemic excess mortality in Spain, Sweden, and Switzerland during the COVID-19 pandemic in 2020 was at its highest since 1918
Authors: Staub Kaspar , Panczak Radoslaw , Matthes Katarina L. , Floris Joël , Berlin Claudia , Junker Christoph , Weitkunat Rolf , Mamelund Svenn-Erik , Egger Matthias , Zwahlen Marcel , Riou Julien
Published: August 2021

Estimating excess mortality allows quantification of overall pandemic impact. For recent decades, mortality data are easily accessible for most industrialized countries, but only a few countries have continuous data available for longer periods. Since Spain, Sweden, and Switzerland were militarily neutral and not involved in combat during both world wars, these countries have monthly all-cause mortality statistics available for over 100 years with no interruptions. We show that during the COVID-19 pandemic in 2020, Spain, Sweden and Switzerland recorded the highest aggregated monthly excess mortality (17%, 9% and 14%) since the 1918 influenza pandemic (53%, 33% and 49%), when compared to respective expected values. For Sweden and Switzerland, the highest monthly spikes in 2020 almost reached those of January 1890. These findings emphasize the historical dimensions of the ongoing pandemic and support the notion of a pandemic disaster memory gap.

One-Sentence Summary

During the COVID-19 pandemic in 2020, Spain, Sweden, and Switzerland recorded their highest monthly excess and all-cause mortality levels since the 1918 influenza pandemic, emphasizing the historical dimension of the ongoing pandemic.
Clinical course impacts early kinetics and long-term magnitude and amplitude of SARS-CoV-2 neutralizing antibodies beyond one year after infection
Authors: Pradenas Edwards , Trinité Benjamin , Urrea Víctor , Marfil Silvia , Tarrés-Freixas Ferran , Ortiz Raquel , Rovirosa Carla , Rodon Jordi , Vergara-Alert Júlia , Segalés Joaquim , Guallar Victor , Valencia Alfonso , Izquierdo-Useros Nuria , Noguera-Julian Marc , Carrillo Jorge , Paredes Roger , Mateu Lourdes , Chamorro Anna , Toledo Ruth , Massanella Marta , Clotet Bonaventura , Blanco Julià
Published: August 2021

Background

Understanding the determinants of long-term immune responses to SARS-CoV-2 and the concurrent impact of vaccination and emerging variants of concern will guide optimal strategies to achieve global protection against the COVID-19 pandemic.

Methods

A prospective cohort of 332 COVID-19 patients was followed beyond one year. Plasma neutralizing activity was evaluated using HIV-based reporter pseudoviruses expressing different SARS-CoV-2 spikes and was longitudinally analyzed using mixed-effects models.

Findings

Long-term neutralizing activity was stable beyond one year after infection in mild/asymptomatic and hospitalized participants. However, longitudinal models suggest that hospitalized individuals generate both short- and long-lived memory B cells, while outpatient responses were dominated by long-lived B cells. In both groups, vaccination boosted responses to natural infection, although viral variants, mainly B.1.351, reduced the efficacy of neutralization. Importantly, despite showing higher neutralization titers, hospitalized patients showed lower cross-neutralization of B.1.351 variant compared to outpatients. Multivariate analysis identified severity of primary infection as the factor that independently determines both the magnitude and the inferior cross-neutralization activity of long-term neutralizing responses.

Conclusions

Neutralizing response induced by SARS-CoV-2 is heterogeneous in magnitude but stable beyond one year after infection. Vaccination boosts these long-lasting natural neutralizing responses, counteracting the significant resistance to neutralization of new viral variants. Severity of primary infection determines higher magnitude but poorer quality of long-term neutralizing responses.
Seroprevalence of anti-SARS-CoV-2 antibodies six months into the vaccination campaign in Geneva, Switzerland
Authors: Stringhini Silvia , Zaballa María-Eugenia , Pullen Nick , Perez-Saez Javier , de Mestral Carlos , Loizeau Andrea , Lamour Julien , Pennacchio Francesco , Wisniak Ania , Dumont Roxane , Baysson Hélène , Richard Viviane , Lorthe Elsa , Semaani Claire , Balavoine Jean-François , Pittet Didier , Vuilleumier Nicolas , Chappuis François , Kherad Omar , Azman Andrew S. , Posfay-Barbe Klara , Kaiser Laurent , Guessous Idris ,   the Specchio-COVID19 study group
Published: August 2021

Background

Up-to-date seroprevalence estimates are critical to describe the SARS-CoV-2 immune landscape in the population and guide public health measures. We aimed to estimate the seroprevalence of anti-SARS-CoV-2 antibodies 15 months into the COVID-19 pandemic and six months into the vaccination campaign.

Methods

We conducted a population-based cross-sectional serosurvey between June 1 and July 7, 2021, recruiting participants from age- and sex-stratified random samples of the general population. We tested participants for anti-SARS-CoV-2 antibodies targeting the spike (S) or nucleocapsid (N) proteins (Roche Elecsys immunoassays). We estimated the anti-SARS-CoV-2 antibodies seroprevalence following vaccination and/or infection (anti-S antibodies), or infection only (anti-N antibodies).

Results

We included 3355 individuals, of which 1814 (54.1%) were women, 697 (20.8%) were aged <18 years and 449 (13.4%) were aged ≥65 years, 2161 (64.4%) tested positive for anti-S antibodies, and 906 (27.0%) tested positive for anti-N antibodies. The total seroprevalence of anti-SARS-CoV-2 antibodies was 66.1% (95% credible interval, 64.1-68.0). We estimated that 29.9% (28.0-31.9) of the population developed antibodies after infection; the rest having developed antibodies only via vaccination. Seroprevalence estimates were similar across sexes, but differed markedly across age groups, being lowest among children aged 0-5 years (20.8% [15.5-26.7]) and highest among older adults aged ≥75 years (93.1% [89.6-96.0]). Seroprevalence of antibodies developed via infection and/or vaccination was higher among participants with a higher educational level.

Conclusions

Most adults have developed anti-SARS-CoV-2 antibodies, while most teenagers and children remain vulnerable to infection. As the SARS-CoV-2 Delta variant spreads and vaccination rates stagnate, efforts are needed to address vaccine hesitancy, particularly among younger individuals and socioeconomically disadvantaged groups, and to minimize spread among children.
Learning to Automatically Diagnose Multiple Diseases in Pediatric Chest Radiographs Using Deep Convolutional Neural Networks
Authors: Tran Thanh T. , Pham Hieu H. , Nguyen Thang V. , Le Tung T. , Nguyen Hieu T. , Nguyen Ha Q.
Published: August 2021

Chest radiograph (CXR) interpretation is critical for the diagnosis of various thoracic diseases in pediatric patients. This task, however, is error-prone and requires a high level of understanding of radiologic expertise. Recently, deep convolutional neural networks (D-CNNs) have shown remarkable performance in interpreting CXR in adults. However, there is a lack of evidence indicating that D-CNNs can recognize accurately multiple lung pathologies from pediatric CXR scans. In particular, the development of diagnostic models for the detection of pediatric chest diseases faces significant challenges such as (i) lack of physician-annotated datasets and (ii) class imbalance problems. In this paper, we retrospectively collect a large dataset of 5,017 pediatric CXR scans, for which each is manually labeled by an experienced radiologist for the presence of 10 common pathologies. A D-CNN model is then trained on 3,550 annotated scans to classify multiple pediatric lung pathologies automatically. To address the highclass imbalance issue, we propose to modify and apply “Distribution-Balanced loss” for training D-CNNs which reshapes the standard Binary-Cross Entropy loss (BCE) to efficiently learn harder samples by down-weighting the loss assigned to the majority classes. On an independent test set of 777 studies, the proposed approach yields an area under the receiver operating characteristic (AUC) of 0.709 (95% CI, 0.690–0.729). The sensitivity, specificity, and F1-score at the cutoff value are 0.722 (0.694–0.750), 0.579 (0.563–0.595), and 0.389 (0.373–0.405), respectively. These results significantly outperform previous state-of-the-art methods on most of the target diseases. Moreover, our ablation studies validate the effectiveness of the proposed loss function compared to other standard losses, e.g., BCE and Focal Loss, for this learning task. Overall, we demonstrate the potential of D-CNNs in interpreting pediatric CXRs.
Genetic variants link lower segregation of brain networks to higher blood pressure and worse cognition within the general aging population
Authors: Neitzel Julia , Malik Rainer , Muetzel Ryan , Knol Maria J , Zonneveld Hazel , Georgakis Marios K , Franzmeier Nicolai , Rubinski Anna , Dichgans Martin , Ikram M Arfan , Vernooij Meike W , Ewers Michael
Published: August 2021

The functional architecture of the brain is composed of distinct networks, where higher system segregation, i.e. greater differentiation of such functional networks, is associated with better cognitive performance. Aging and many neurological diseases have been associated with reduced system segregation and thus cognitive impairment. The genetic basis and risk factors of system segregation are largely unknown. Here, we present the first genome-wide association study of fMRI-assessed system segregation in 16,635 UK Biobank participants, identifying nine independent genomic loci. The 66 implicated genes were significantly downregulated in brain tissue and upregulated in vascular tissue. Of major vascular risk factors (Life’s Simple 7), blood pressure showed a robust genetic correlation with system segregation. Observational and Mendelian randomization analyses confirmed a unfavourable effect of higher blood pressure on system segregation and of lower system segregation on cognition. Replication analyses in 2,414 Rotterdam Study participants supported these conclusions.
Transmission dynamics and epidemiological characteristics of Delta variant infections in China
Authors: Kang Min , Xin Hualei , Yuan Jun , Ali Sheikh Taslim , Liang Zimian , Zhang Jiayi , Hu Ting , Lau Eric H. Y. , Zhang Yingtao , Zhang Meng , Cowling Benjamin J. , Li Yan , Wu Peng
Published: August 2021

Background

The Delta variant of SARS-CoV-2 has become predominant globally. We evaluated the transmission dynamics and epidemiological characteristics of the Delta variant in an outbreak in southern China.

Methods

Data on confirmed cases and their close contacts were retrospectively collected from the outbreak that occurred in Guangdong, China in May-June 2021. Key epidemiological parameters, temporal trend of viral loads and secondary attack rates were estimated and compared between the Delta variant and the wild-type SARS-CoV-2 virus. We also evaluated the association of vaccination with viral load and transmission.

Results

We identified 167 patients infected with the Delta variant in the Guangdong outbreak. The mean estimates of the latent period and the incubation period were 4.0 days and 5.8 days, respectively. A relatively higher viral load was observed in Delta cases than in wild-type infections. The secondary attack rate among close contacts of Delta cases was 1.4%, and 73.9% (95% confidence interval: 67.2%, 81.3%) of the transmissions occurred before onset. Index cases without vaccination (OR: 2.84, 95% confidence interval: 1.19, 8.45) or with one dose of vaccination (OR: 6.02, 95% confidence interval: 2.45, 18.16) were more likely to transmit infection to their contacts than those who had received 2 doses of vaccination.

Discussion

Patients infected with the Delta variant had more rapid symptom onset. The shorter and time-varying serial interval should be accounted in estimation of reproductive numbers. The higher viral load and higher risk of pre-symptomatic transmission indicated the challenges in control of infections with the Delta variant.
Overexpression of the SETD2 WW domain inhibits the phosphor-IWS1/SETD2 interaction and the oncogenic AKT/IWS1 RNA splicing program
Authors: Laliotis Georgios I. , Chavdoul Evangelia , Anastas Vollter , Singh Satishkumar , Kenney Adam D. , Acharya Samir , Yount Jacob S. , Sehgal Lalit , Tsichlis Philip N.
Published: August 2021

The authors have withdrawn their manuscript. While attempting to reproduce the data on the alternative splicing of exon 2 of U2AF2, they observed that the proposed splicing mechanism could not give rise to a functional U2AF2 protein. In addition, they observed evidence of manipulation in the electropherogram of the splicing junction between exons 1 and 3 and in the primary data on which this electropherogram was based, which were deposited in Mendeley by the first author. These observations raise questions on the integrity of the reported results. In light of this information, the authors have no confidence in the key findings of the paper, and therefore, do not wish it to be cited. If you have any questions, please contact the corresponding author.
The longitudinal dynamics and natural history of clonal haematopoiesis
Authors: Fabre Margarete A. , Almeida José Guilherme de , Fiorillo Edoardo , Mitchell Emily , Damaskou Aristi , Rak Justyna , Orrù Valeria , Marongiu Michele , Vijayabaskar MS , Baxter Joanna , Hardy Claire , Abascal Federico , Chapman Michael Spencer , Williams Nicholas , Nangalia Jyoti , Martincorena Iñigo , Campbell Peter J. , McKinney Eoin F. , Cucca Francesco , Gerstung Moritz , Vassiliou. George S.
Published: August 2021

Human cells acquire somatic mutations throughout life, some of which can drive clonal expansion. Such expansions are frequent in the haematopoietic system of healthy individuals and have been termed clonal haematopoiesis (CH). While CH predisposes to myeloid neoplasia and other diseases, we have limited understanding of how and when CH develops, what factors govern its behaviour, how it interacts with ageing and how these variables relate to malignant progression. Here, we track 697 CH clones from 385 individuals aged 55 or older over a median of 13 years. We find that 92.4% of clones expanded at a stable exponential rate over the study period, with different mutations driving substantially different growth rates, ranging from 5% (DNMT3A,TP53) to over 50%/yr (SRSF2-P95H). Growth rates of clones with the same mutation differed by approximately +/−5%/yr, proportionately impacting “slow” drivers more substantially. By combining our time-series data with phylogenetic analysis of 1,731 whole genome-sequenced haematopoietic colonies from 7 older individuals, we reveal distinct patterns of lifelong clonal behaviour.DNMT3A-mutant clones preferentially expanded early in life and displayed slower growth in old age, in the context of an increasingly competitive oligoclonal landscape. By contrast, splicing gene mutations only drove expansion later in life, while growth ofTET2-mutant clones showed minimal age-dependency. Finally, we show that mutations driving faster clonal growth carry a higher risk of malignant progression. Our findings characterise the lifelong natural history of CH and give fundamental insights into the interactions between somatic mutation, ageing and clonal selection.
An efficient method to identify, date and describe admixture events using haplotype information
Authors: Wangkumhang Pongsakorn , Greenfield Matthew , Hellenthal Garrett
Published: August 2021

We present fastGLOBETROTTER, an efficient new haplotype-based technique to identify, date and describe admixture events using genome-wide autosomal data. With simulations, we demonstrate how fastGLOBETROTTER reduces computation time by 4-20 fold relative to the haplotype-based technique GLOBETROTTER without suffering loss of accuracy. We apply fastGLOBETROTTER to a cohort of >6000 Europeans from ten countries, revealing previously unreported admixture signals. In particular we infer multiple periods of admixture related to East Asian or Siberian-like sources, starting >2000 years ago, in people living in countries north of the Baltic Sea. In contrast, we infer admixture related to West Asian, North African and/or Southern European sources in populations south of the Baltic Sea, including admixture dated to ≈300-700CE, overlapping the fall of the Roman Empire, in people from Belgium, France and parts of Germany. Our new approach scales to analysing hundreds to thousands of individuals from a putatively admixed populations and hence is applicable to emerging large-scale cohorts of genetically homogeneous populations.
Large-scale integration of DNA methylation and gene expression array platforms
Authors: Lancaster Eva E. , Vladimirov Vladimir I. , Riley Brien P. , Landry Joseph W. , Roberson-Nay Roxann , York Timothy P.
Published: August 2021

Abstract

Epigenome-wide association studies (EWAS) aim to provide evidence that marks of DNA methylation (DNAm) have downstream consequences that can result in the development of human diseases. Although these methods have been successful in identifying DNAm patterns associated with disease states, any further characterization of etiologic mechanisms underlying disease remains elusive. This knowledge gap does not originate from a lack of DNAm-trait associations, but rather stems from study design issues that affect the interpretability of EWAS results. Despite known limitations in predicting the function of a particular CpG site, most EWAS maintain the broad assumption that altered DNAm results in a concomitant change of transcription at the most proximal gene. This study integrated DNAm and gene expression (GE) measurements in two cohorts, the Adolescent and Young Adult Twin Study (AYATS) and the Pregnancy, Race, Environment, Genes (PREG) study, to improve the understanding of epigenomic regulatory mechanisms. CpG sites associated with GE inciswere enriched in areas of transcription factor binding and areas of intermediate-to-low CpG density. CpG sites associated withtransGE were also enriched in areas of known regulatory significance, including enhancer regions. These results highlight issues with restricting DNAm-transcript annotations to small genomic intervals and question the validity of assuming a canonicalcisDNAm-GE pathway. Based on these findings, the interpretation of EWAS results is limited in studies without multi-omic support and further research should identify genomic regions in which GE-associated DNAm is overrepresented.
Phase transition specified by a binary code patterns the vertebrate eye cup
Authors: Balasubramanian Revathi , Min Xuanyu , Quinn Peter M.J. , Giudice Quentin Lo , Tao Chenqi , Polanco Karina , Makrides Neoklis , Peregrin John , Bouaziz Michael , Mao Yingyu , Wang Qian , Costa Bruna L , Buenaventura Diego , Wang Fen , Ma Liang , Tsang Stephen H , Fabre Pierre J. , Zhang Xin
Published: August 2021

The developing vertebrate eye cup is partitioned into the neural retina (NR), the retinal pigmented epithelium (RPE) and the ciliary margin (CM). By single cell analysis, we showed that a gradient of FGF signaling regulates demarcation and subdivision of the CM and controls its stem cell-like property of self-renewal, differentiation and survival. This regulation by FGF is balanced by an evolutionarily conserved Wnt signaling gradient induced by the lens ectoderm and the periocular mesenchyme, which specifies the CM and the distal RPE. These two morphogen gradients converge in the CM where FGF signaling promotes Wnt signaling by stabilizing β-catenin in a GSK3β-independent manner. We further showed that activation of Wnt signaling converts the NR to either the CM or the RPE depending on the level of FGF signaling. Conversely, activation of FGF transforms the RPE to the NR or CM dependent on Wnt activity. We demonstrated that the default fate of the eye cup is the NR, but synergistic FGF and Wnt signaling promotes CM formation both in vivo and in retinal organoid culture of human iPS cells. Our study reveals that the vertebrate eye develops through phase transition determined by a combinatorial code of FGF and Wnt signaling.
Cancer cell hyper-proliferation disrupts the topological invariance of epithelial monolayers
Authors: Roshal Daria S. , Martin Marianne , Fedorenko Kirill , Molle Virginie , Baghdiguian Stephen , Rochal Sergei B.
Published: August 2021

Although the polygonal shape of epithelial cells has drawn the attention of scientists for several centuries, only recently, it has been demonstrated that distributions of polygon types (DOPTs) are similar in proliferative epithelia of many different plant and animal species. In this study we show that hyper-proliferation of cancer cells disrupts this universality paradigm and results in random epithelial structures. Examining non-synchronized and synchronized HeLa cervix cells, we suppose that the cell size spread is the single parameter controlling the DOPT in these monolayers. We test this hypothesis by considering morphologically similar random polygonal packings. By analyzing the differences between tumoral and non-tumoral epithelial monolayers, we uncover that the latter have more ordered structures and argue that the relaxation of mechanical stresses associated with cell division induces more effective ordering in the epithelia with lower proliferation rates. The proposed theory also explains the specific highly ordered structures of some post-mitotic unconventional epithelia.
Mapping the peptide binding groove of MHC class I
Authors: Kopicki Janine-Denise , Saikia Ankur , Niebling Stephan , Günther Christian , Garcia-Alai Maria , Springer Sebastian , Uetrecht Charlotte
Published: August 2021

An essential element of adaptive immunity is the selective binding of peptide antigens by major histocompatibility complex (MHC) class I proteins and their presentation to cytotoxic T lymphocytes on the cell surface. Using native mass spectrometry, we here analyze the binding of peptides to an empty disulfide-stabilized HLA-A*02:01 molecule. This novel approach allows us to examine the binding properties of diverse peptides. The unique stability of our MHC class I even enables us to determine the binding affinity of complexes, which are suboptimally loaded with truncated or charge-reduced peptides. Notably, a unique erucamide adduct decouples affinity analysis from peptide identity alleviating issues usually attributed to clustering during electrospray ionization. We discovered that two anchor positions at the binding surface between MHC and peptide can be stabilized independently and further identify the contribution of other peptidic amino acids on the binding. We propose this as an alternative, likely universally applicable method to artificial prediction tools to estimate the binding strength of peptides to MHC class I complexes quickly and efficiently. This newly described MHC class I-peptide binding affinity quantitation represents a much needed orthogonal, independent approach to existing computational affinity predictions and has the potential to eliminate binding affinity biases and thus accelerate drug discovery in infectious diseases, autoimmunity, vaccine design, and cancer immunotherapy.
Simultaneous infection with porcine reproductive and respiratory syndrome and influenza viruses abrogates clinical protection induced by live attenuated porcine reproductive and respiratory syndrome vaccination
Authors: Chrun Tiphany , Maze Emmanuel A. , Vatzia Eleni , Martini Veronica , Paudyal Basu , Edmans Matthew , McNee Adam , Manjegowda Tanuja , Salguero Francisco J. , Wanasen Nanchaya , Koonpaew Surapong , Graham Simon P. , Tchilian Elma
Published: August 2021

The porcine respiratory disease complex (PRDC) is responsible for significant economic losses in the pig industry worldwide. Porcine reproductive and respiratory syndrome virus (PRRSV) and swine influenza virus are major viral contributors to PRDC. Vaccines are cost-effective measures for controlling PRRS, however, their efficacy in the context of co-infections has been poorly investigated. In this study, we aimed to determine the effect of PRRSV-2 and swine influenza H3N2 virus co-infection on the efficacy of PRRSV modified live virus (MLV) vaccination, which is widely used in the field. Following simultaneous challenge with contemporary PRRSV-2 and H3N2 field isolates, we found that the protective effect of PRRS MLV vaccination on clinical disease and pathology was abrogated, although viral load was unaffected and antibody responses were enhanced. In contrast, co-infection in non-immunized animals reduced PRRSV-2 viremia and H3N2 virus load in the upper respiratory tract and potentiated T cell responses against both PRRSV-2 and H3N2 in the lung. Further analysis suggested that an upregulation of inhibitory cytokines gene expression in the lungs of vaccinated pigs may have influenced responses to H3N2 and PRRSV-2. These findings provide important insights into the effect of viral co-infections on PRRS vaccine efficacy that may help identity more effective vaccination strategies against PRDC in the field.
Immunoglobulin heavy constant gamma gene evolution is modulated by both the divergent and birth-and-death evolutionary models
Authors: Garzón-Ospina Diego , Buitrago Sindy P.
Published: August 2021

Immunoglobulin G (IgG) is one of the five antibody classes produced in mammals as part of the humoral responses. This high-affinity antibody produced late in a primary immune response is responsible for protecting the organisms from infection. This protein’s heavy chain constant region is encoded by the Ig gamma gene (Igγ). In Humans, IgG has evolved into four subclasses with specialized effector functions. However, in Platyrrhini, IgG has been reported to be encoded by a single-copy gene. Here, we analyzed data from 38 primate genome sequences to identify Igγ genes and describe the evolution of this immunoglobulin in this group. Igγ belongs to a multigene family that evolves by the birth-death evolutionary model in primates. Whereas Strepsirrhini and Platyrrhini have a single-copy gene, in Catarrhini species it has expanded to having several paralogs in their genomes; some have been deleted or have become pseudogenes. Furthermore, episodic positive selection might promote a specialized species-specific IgG effector function. A hypothesis for the Igγ evolution has been proposed, suggesting that IgG has evolved to reach an optimal number of copies per genome to adapt their humoral immune responses to different environmental conditions.

Graphical abstract
Long reads and Hi-C sequencing illuminate the two compartment genome of the model arbuscular mycorrhizal symbiont Rhizophagus irregularis
Authors: Yildirir Gokalp , Sperschneider Jana , Mathu Malar C , Chen Eric CH , Iwasaki Wataru , Cornell Calvin , Corradi Nicolas
Published: August 2021

Chromosome folding links genome structure with gene function by generating distinct nuclear compartments and topologically associating domains (TADs). In mammals, these undergo preferential interactions and regulate gene expression. However, their role in fungal genome biology is unclear. Here, we combine Nanopore (ONT) sequencing with chromatin conformation capture sequencing (Hi-C) to reveal chromosome and epigenetic diversity in a group of obligate plant symbionts; the arbuscular mycorrhizal fungi (AMF). We find that five phylogenetically distinct strains of the model AMF Rhizophagus irregularis carry 33 chromosomes with substantial within species variability in size, as well as in gene and repeat content. Strain-specific Hi-C contact maps all reveal a ‘checkerboard’ pattern that underline two dominant euchromatin (A) and heterochromatin (B) compartments. Each compartment differs in the level of gene transcription, regulation of candidate effectors and methylation frequencies. The A-compartment is more gene-dense and contains most core genes, while the B-compartment is more repeat-rich and has higher rates of chromosomal rearrangement. While the B-compartment is transcriptionally repressed, it has significantly more secreted proteins and in planta up-regulated candidate effectors, suggesting a possible host-induced change in chromosome conformation. Overall, this study provides a fine-scale view into the genome biology and evolution of prominent plant symbionts, and opens avenues to study the epigenetic mechanisms that modify chromosome folding during host-microbe interactions.