bluuebunny/crossref_metadata_2025 huggingface dataset:
A scalable EHR-based approach for phenotype discovery and variant interpretation for hereditary cancer genes
Authors: Zeng Chenjie , Bastarache Lisa A. , Tao Ran , Venner Eric , Hebbring Scott , Andujar Justin D. , Bland Sarah T. , Crosslin David R. , Pratap Siddharth , Cooley Ayorinde , Pacheco Jennifer A. , Christensen Kurt D. , Perez Emma , Zawatsky Carrie L. Blout , Witkowski Leora , Zouk Hana , Weng Chunhua , Leppig Kathleen A. , Sleiman Patrick M. A. , Hakonarson Hakon , Williams Marc. S. , Luo Yuan , Jarvik Gail P. , Green Robert C. , Chung Wendy K. , Gharavi Ali G. , Lennon Niall J. , Rehm Heidi L. , Gibbs Richard A. , Peterson Josh F. , Roden Dan M. , Wiesner Georgia L. , Denny Joshua C.
Published: March 2021

Knowledge of the clinical spectrum of rare genetic disorders helps in disease management and variant pathogenicity interpretation. Leveraging electronic health record (EHR)-linked genetic testing data from the eMERGE network, we determined the associations between a set of 23 hereditary cancer genes and 3017 phenotypes in 23544 individuals. This phenome-wide association study replicated 45% (184/406) of known gene-phenotype associations (P = 5.1×10−125). Meta-analysis with an independent EHR-derived cohort of 3242 patients confirmed 14 novel associations with phenotypes in the neoplastic, genitourinary, digestive, congenital, metabolic, mental and neurologic categories. Phenotype risk scores (PheRS) based on weighted aggregations of EHR phenotypes accurately predicted variant pathogenicity for at least 50% of pathogenic variants for 8/23 genes. We generated a catalog of PheRS for 7800 variants, including 5217 variants of uncertain significance, to provide empirical evidence of potential pathogenicity. This study highlights the potential of EHR data in genomic medicine.
SARS-CoV-2 Seroprevalence in 12 Cities of India from July-December 2020
Authors: Velumani Arokiaswamy , Nikam Chaitali , Suraweera Wilson , Fu Sze Hang , Gelband Hellen , Brown Patrick , Bogoch Isaac , Nagelkerke Nico , Jha Prabhat
Published: March 2021

Objectives

We sought to understand the spread of SARS-CoV-2 infection in urban India, which has surprisingly low COVID-19 deaths.

Design

Cross-sectional and trend analyses of seroprevalence in self-referred test populations, and of reported cases and COVID mortality data.

Participants

448,518 self-referred individuals using a nationwide chain of private laboratories with central testing of SARS-CoV-2 antibodies and publicly available case and mortality data.

Setting

12 populous cities with nearly 92 million total population.

Main outcome measures

Seropositivity trends and predictors (using a Bayesian geospatial model) and prevalence derived from mortality data and infection fatality rates (IFR).

Results

For the whole of India, 31% of the self-referred individuals undergoing antibody testing were seropositive for SARS-CoV-2 antibodies. Seropositivity was higher in females (35%) than in males (30%) overall and in nearly every age group. In these 12 cities, seroprevalence rose from about 18% in July to 41% by December, with steeper increases at ages <20 and 20-44 years than at older ages. The “M-shaped” age pattern is consistent with intergenerational transmission. Areas of higher childhood measles vaccination in earlier years had lower seropositivity. The patterns of increase in seropositivity and in peak cases and deaths varied substantially across cities. In Delhi, death rates and cases first peaked in June and again in November; Chennai had a single peak in July. Based local IFRs and COVID deaths (adjusted for undercounts), we estimate that 43%-65% of adults above age 20 had been infected (range of mid-estimates of 12%-77%) corresponding 26 to 36 million infected adults in these cities, or an average of 9-12 infected adults per confirmed case.

Conclusion

Even with relatively low death rates, the large cities of India had remarkably high levels of SARS-CoV-2 infection. Vaccination strategies need to consider widespread intergenerational transmission.
Argentine Registry of neurological manifestations due to coronavirus-19 (COVID-19)
Authors: Alessandro Lucas , Appiani Franco , Bendersky Mariana , Borrego Guerrero Brenda , Bruera Guadalupe , Cairola Patricia , Calandri Ismael , Cardozo Oliver Juan Martín , Clément María Emilia , Di Egidio Marianna , Di Pace José Luis , Diaconchuk Melina , Esliman Celeste , Esnaola y Rojas Ma Martha , Fernández Boccazzi Julián , Franco Andrea Fabiana , Gargiulo Gisella , Giardino Daniela Laura , Gómez César , Guevara Ana Karina , Gutierrez Natalia , Hryb Javier , Viviana Ibarra , Janota Franco , Laserna Mabel , Larcher Luis Alfredo , Leone Fernando , Luetic Geraldine , Medina Claudia Andrea , Menichini María Laura , Nieto Gonzalo , Páez María Fernanda , Peñalver Francisco , Perassolo Mónica , Persi Gabriel , Pestchanker Claudia , Porta Oscar , Rey Roberto Daniel , Rodríguez Gabriel Eduardo , Romano Marina , Rugiero Marcelo , Saidón Patricia , Sica María Florencia , Stankievich Erica , Tarulla Adriana , Zalazar Guillermo
Published: March 2021

COVID-19 disease has spread around the world since December 2019. Neurological symptoms are part of its clinical spectrum.

Objective

To know the neurological manifestations in patients infected by COVID-19 in Argentina.

Methods

Multicenter study conducted in adults, from May 2020 to January 2021, with confirmed COVID-19 and neurological symptoms. Demographic variables, existence of systemic or neurological comorbidities, the form of onset of the infection, alteration in complementary studies and the degree of severity of neurological symptoms were recorded.

Results

817 patients from all over the country were included, 52% male, mean age 38 years, most of them without comorbidities or previous neurological pathology. The first symptom of the infection was neurological in 56.2% of the cases, predominantly headache (69%), then anosmia / ageusia (66%). Myalgias (52%), allodynia / hyperalgesia (18%), and asthenia (6%) were also reported. 3.2% showed diffuse CNS involvement such as encephalopathy or seizures. 1.7% had cerebrovascular complications. Sleep disorders were observed in 3.2%. 6 patients were reported with Guillain Barré (GBS), peripheral neuropathy (3.4%), tongue paresthesia (0.6%), hearing loss (0.4%), plexopathy (0.3%). The severity of neurological symptoms was correlated with age and the existence of comorbidities.

Conclusions

Our results, similar to those of other countries, show two types of neurological symptoms associated with COVID-19: some potentially disabling or fatal such as GBS or encephalitis, and others less devastating, but more frequent such as headache or anosmia that demand increasingly long-term care.
Determinants of anti-PD1 response and resistance in clear cell renal cell carcinoma
Authors: Au Lewis , Hatipoglu Emine , de Massy Marc Robert , Litchfield Kevin , Rowan Andrew , Thompson Rachael , Schnidrig Desiree , Byrne Fiona , Beattie Gordon , Horswell Stuart , Fotiadis Nicos , Hazell Steve , Nicol David , Shepherd Scott Thomas Colville , Fendler Annika , Mason Robert , Attig Jan , Joshi Kroopa , Uddin Imran , Becker Pablo , Sunderland Mariana Werner , Akarca Ayse , Puccio Ignazio , Yang William , Lund Tom , Dhillon Kim , Vasquez Marcos Duran , Ghorani Ehsan , Xu Hang , López José Ignacio , Green Anna , Mahadeva Ula , Borg Elaine , Mitchison Miriam , Moore David , Proctor Ian , Falzon Mary , Furness Andrew , Pickering Lisa , Reading James L. , Salgado Roberto , Marafioti Teresa , Jamal-Hanjani Mariam , Kassiotis George , Chain Benny , Larkin James , Swanton Charles , Quezada Sergio A , Turajlic Samra
Published: March 2021

Antigen recognition and T-cell mediated cytotoxicity in clear-cell renal cell carcinoma (ccRCC) remains incompletely understood. To address this knowledge gap, we analysed 115 multiregion tumour samples collected from 15 treatment-naïve patients pre- and post-nivolumab therapy, and at autopsy in three patients. We performed whole-exome sequencing, RNAseq, TCRseq, multiplex immunofluorescence and flow cytometry analyses and correlated with clinical response. We observed pre-treatment intratumoural TCR clonal expansions suggesting pre-existing immunity. Nivolumab maintained pre-treatment expanded, clustered TCR clones in responders, suggesting ongoing antigen-driven stimulation of T-cells. T-cells in responders were enriched for expanded TCF7+CD8+T-cells and upregulated GZMK/B upon nivolumab-binding. By contrast, nivolumab promoted accumulation of new TCR clones in non-responders, replacing pre-treatment expanded clonotypes. In this dataset, mutational features did not correlate with response to nivolumab and human endogenous retrovirus expression correlated indirectly. Our data suggests that nivolumab potentiates clinical responses in ccRCC by binding pre-existing expanded CD8+T-cells to enhance cytotoxicity.
Population homogeneity for the antibody response to COVID-19 BNT162b2 / Comirnaty vaccine is only reached after the second dose, across all adult age ranges
Authors: Viana João F. , Bergman Marie-Louise , Gonçalves Lígia A. , Duarte Nádia , Coutinho Teresa Penha , Borges Patrícia C. , Diwo Christian , Castro Rute , Matoso Paula , Malheiro Vanessa , Brennand Ana , Kosack Lindsay , Akpogheneta Onome , Figueira João M. , Cardoso Conceição , Casaca Ana M. , Alves Paula M. , Nunes Telmo , Penha-Gonçalves Carlos , Demengeot Jocelyne
Published: March 2021

BACKGROUND

While mRNA vaccines authorized for emergency use are administrated worldwide in an effort to contain the COVID-19 pandemic, little is known about the heterogeneity of the humoral immune response they induce at the population scale.

METHODS

We conducted a prospective observational longitudinal study in 1245 hospital care workers and 146 nursing home residents, together covering adult ages from 19 to 99 years. Blood samples were taken before vaccination, 3-5 weeks after the first vaccine dose, and 3 weeks after the second dose of BNT162b2 mRNA COVID-19 (Comirnaty, Pfizer/BioNTech). End points were seroconversion to SARS-CoV-2 spike protein and amount of spike-specific IgG, IgM and IgA following the first dose and the boosting effect of the second vaccination. We also addressed the effect of age, sex and pre-exposure to SARSCov-2 on these parameters.

RESULTS

Among 1067 baseline seronegative participants, seroconversion after the first vaccine dose varied from a maximum of 98,6% in the younger age strata [19-29 years] to a minimum of 25.4 % in the older age group [70-100 years], while sex had little effect. Large inter-individual variation in the amplitude of the antibody response were observed in all age strata. The second dose brought seroconversion to high frequency (100% and 94.9% in younger and older age strata, respectively) and homogenised IgG responses to high levels, while IgM and IgA levels remained low and heterogeneous. Previous exposure to SARS-Cov-2 boosted IgG level after a single injection. Seven non-responders were identified after the second dose.

CONCLUSIONS

In this large study, covering all adult age ranges, BNT162b2 vaccination resulted in isotypic and heterogeneous antibody responses, advocating for the interval between the two doses not to be extended and for serological monitoring of elderly and immunosuppressed vaccinees.
A Quantitative Framework to Study Potential Benefits and Harms of Multi-cancer Early Detection Testing
Authors: Jiao Boshen , Gulati Roman , Katki Hormuzd A. , Castle Philip E. , Etzioni Ruth
Published: March 2021

Background

Multi-cancer tests permit identification of multiple cancers with one blood draw. The objective of this study was to quantify potential population impact of a multi-cancer test.

Methods

We formulate mathematical expressions for expected numbers of (1) individuals exposed to unnecessary confirmation tests (UCT), (2) cancers detected (CD), and (3) lives saved (LS) given disease prevalence and mortality and the test’s performance and expected mortality reduction. We consider additions of colorectal, liver, lung, ovary, and pancreatic cancer to a test for breast cancer using published performance characteristics of a multi-cancer test and prevalence of each cancer at ages 50, 60, or 70 based on 5-year incidence rates and corresponding 15-year probabilities of cancer death in the Surveillance, Epidemiology, and End Results registry, assuming 20% mortality reduction for each.

Results

UCT depends on screening age but is overwhelmingly determined by overall specificity of the test and is relatively insensitive to the types and number of cancers included. For a given overall specificity, UCT/CD is most favorable for higher-prevalence cancers (e.g., UCT/CD = 5.6 for breast+lung versus 6.5 for breast+liver at age 50). Under a common mortality reduction, UCT/LS is most favorable when the test includes higher-mortality cancers (e.g., UCT/LS = 48.5 for breast+lung versus 74.7 for breast+liver at age 50).

Conclusions

The harm-benefit tradeoffs of multi-cancer testing depend on the number and type of cancers included. Overall specificity is paramount for controlling unnecessary confirmation tests. For a given overall specificity, multi-cancer tests should prioritize prevalent and/or lethal cancers for which curative treatments exist.
Incidence of and factors associated with SARS-CoV-2 infection among people living with HIV in Southern Spain
Authors: Fernandez-Fuertes Marta , Corma-Gomez Anaïs , Torres Eva , Rodriguez-Pineda Elena , Fuentes-Lopez Ana , Rincon Pilar , Fernanddez Nieves , Garcia Federico , Bernal Samuel , Real Luis M , Macias Juan , Pineda Juan A
Published: March 2021

Background

Whether people living with HIV (PLWH) are at greater risk of acquiring SARS-CoV-2 infection is currently unknown. Prospective serologic studies may allow seroincidence analyses, where all infections are accurately identified. Because of this, we evaluated the incidence of and associated factors with SARS-CoV-2 infection in PLWH in Southern Spain.

Methods

This was a prospective cohort study including PLWH from a University Hospital in Southern Spain. Patients were enrolled if 1) they had attended as outpatients our Unit from August 1st, 2019 to February 8th, 2020; 2) had two subsequent evaluations from February 9th, 2020 to February 15th, 2021. Serum antibodies against SARS-CoV-2 were determined in baseline and intra-pandemic samples.

Results

710 PLWH were included in the study. Of them, 46 [6.5%, 95% confidence interval (95% CI): 4.8%-8.5%] patients developed SARS-CoV-2 infection. Between May 18th and November 29th, 2020, the rate of seroconversion was 5.3% (95% CI: 3.1%-9%) for the general population in the area of Seville and 2.3% (95% CI: 1.3%-3.6%) for PLWH in this study (p=0.001). After multivariate analysis, adjusted by age and sex, active tobacco smoking was the only factor independently associated with lower risk of SARS-Cov-2 infection (Incidence rate ratio 0.35, 95% CI: 0.18-0.68, p=0.002).

Conclusions

The incidence of SARS-CoV-2 infection among PLWH in Southern Spain during the ongoing pandemic was lower than that reported for the general population in the same area. Tobacco smoking was the only factor independently associated with a lower risk of incident SARS-CoV-2 infection.

The incidence of SARS-CoV-2 infection among people living with HIV is lower than that of general population in Southern Spain. Active tobacco smoking could be associated with a lower risk of developing COVID-19.
Functional and microstructural brain abnormalities, fatigue, and cognitive dysfunction after mild COVID-19
Authors: Silva Lucas Scardua , Joao Rafael Batista , Nogueira Mateus Henrique , Aventurato Italo Karmann , de Campos Brunno Machado , de Brito Mariana Rabelo , Alvim Marina Koutsodontis Machado , Ludwig Guilherme Vieira Nunes , Rocha Cristiane , Souza Thierry Kaue Alves Silva , da Costa Beatriz Amorim , Mendes Maria Julia , Waku Takeshi , de Oliveira Boldrini Vinicius , Brunetti Natália Silva , Baptista Sophia Nora , Schmitt Gabriel da Silva , de Sousa Jhulia Gabriela Duarte , de Oliveira Cardoso Tânia Aparecida Marchiori , Vieira André Schwambach , Santos Leonilda Maria Barbosa , Farias Alessandro dos Santos , Cendes Fernando , Yasuda Clarissa Lin
Published: March 2021

Although post-acute cognitive dysfunction and neuroimaging abnormalities have been reported after hospital discharge in patients recovered from COVID-19, little is known about persistent, long-term alterations in patients who did not require hospitalization. Therefore, we conducted a cross-sectional study of 87 consecutive, non-hospitalized recovered individuals, with a median of 54 days after the laboratory confirmation of COVID-19. We performed structured interviews, neurological examination, and 3T-MRI scans. The MRI study included white matter investigation with diffusion tensor images (DTI) and seed-based resting-state functional MRI (fMRI) connectivity analyses of the default mode network (DMN). In addition, we used validated instruments to examine fatigue, symptoms of anxiety and depression, somnolence, language, memory, and cognitive flexibility.

Individuals self-reported a high frequency of headaches (40%) and memory difficulties (33%). The quantitative analyses confirmed symptoms of fatigue (68% of participants), excessive somnolence (35%), symptoms of anxiety (29%), impaired cognitive flexibility (40%) and language dysfunction (33%). In addition, we observed a correlation between DTI fractional anisotropy (FA) and abnormal attention and cognitive flexibility measured by the Trail Making Test part B. The resting-state fMRI study of the DMN showed an association between higher connectivity of the posterior cingulate cortex (PCC) and higher levels of fatigue and somnolence. While greater connectivity of the PCC with bilateral angular gyri was associated with higher fatigue levels, the elevated levels of somnolence correlated with higher connectivity between the PCC and both the left thalamus and putamen.
Willingness to Vaccinate against COVID-19 among Healthcare Workers: An Online Survey in 10 Countries in the Eastern Mediterranean Region
Authors: Elhadi Yasir Ahmed Mohammed , Mehanna Azza , Adebisi Yusuff Adebayo , El Saeh Haider M. , Alnahari Saddam Abdulhakem , Alenezi Omar Hassan , Chbib Diala El , Yahya Zahraa , Ahmed Eiman , Ahmad Shoaib , Uakkas Saad , Sabahelzain Majdi Mohammed , Alyamani Bushra Ahmed , Nemat Arash , Lucero-Prisno Don Eliseo , Zaghloul Ashraf
Published: March 2021

Background

Willingness of healthcare workers to be vaccinated is an important factor to be consider for successful COVID-19 vaccination programme. Our study aimed to understand the willingness of health workers to receive COVID-19 vaccine and associated concerns across 10 countries in the Eastern Mediterranean Region (EMRO).

Method

A cross-sectional study was conducted in January 2021 among healthcare workers using an online survey. A total of 2806 health workers (Physicians, Nurses and Pharmacists) completed and returned the informed consent along with the questionnaire electronically. Data were analyzed using IBM SPSS software package version 20.0. S

Results

More than half of the respondents (58.0%) were willing to receive COVID-19 vaccine, even if the vaccination is not mandatory for them. On the other hand, 25.7% of respondents were not willing to undertake COVID-19 vaccination while 16.3 % answered undecided. The top three reasons for not intending to be vaccinated were unreliability of COVID-19 vaccine clinical trials (62.0%), fear of the side effects of the vaccine (45.3%), and that COVID-19 vaccine will not give immunity for a long period of time (23.1%).

Conclusion

Overall, our study revealed suboptimal acceptance of COVID-19 vaccine among our respondents in the EMRO region. Significant refusal of COVID-19 vaccine among healthcare professionals can reverse hard-won progress in building public trust in COVID-19 vaccination program. Our findings suggest the need to develop tailored strategies to address concerns identified in the study in order to ensure optimal vaccine acceptance among healthcare workers in the EMRO.
Economic Crisis and Mental Health during the COVID-19 Pandemic in Japan
Authors: Matsubayashi Tetsuya , Ishikawa Yumi , Ueda Michiko
Published: March 2021

Background

The economic crisis induced by the COVID-19 pandemic can have a serious impact on population mental health. This study seeks to understand whether the economic shocks associated with the pandemic have a differential impact by sex because the current pandemic may have disproportionally affected women compared to men.

Methods

We analyzed data from original online monthly surveys of the general population in Japan conducted between April 2020 and February 2021 (N=9000). We investigate whether individuals who had experienced a major job-related were more likely to have experienced depressive symptoms (PHQ-9) and anxiety disorders (GAD-7) during the pandemic and also if its effect varied by sex.

Results

The results of logistic regression suggest that depressive and anxiety symptoms were more prevalent among those who had recently experienced drastic changes in employment and working conditions, as well as among individuals with low income and those without college education. We also found that female respondents who had experienced a major employment-related change were more likely to have experienced both depression and anxiety disorders, but its effect on male workers was limited to depressive symptoms.

Limitations

We do not have data on the pre-COVID mental health conditions of our respondents, and our findings are descriptive. Some segments of the population may not be represented in our sample because our surveys were conducted online.

Conclusions

COVID-induced economic shocks can have a differential detrimental effect on mental health depending on the sex of workers. The mental health of female workers can be particularly vulnerable.
P1 variants and key amino acid mutations at the Spike gene identified using Sanger protocols
Authors: Cabral Gabriela Bastos , Ahagon Cintia Mayumi , Lopez-Lopes Giselle Ibette Silva , Hussein Igor Mohamed , Guimaraes Paula Morena , Cilli Audrey , Silva Valeria Oliveira , Timenetsky Maria do Carmo CT , de Jesus Alves Ivy , Bombonatte Andrea GC , dos Santos Fabiana C Pereira , Brígido Luís Fernando de Macedo
Published: March 2021

SARS-CoV-2 variants, along with vaccination, mark the second year of the pandemic. The spike region is a focal point in COVID-19 pathogenesis, with different amino acid changes potentially modulating vaccine response and some being part of variant signatures. NGS is the standard tool to sequence the virus but limitations of different sources hinders expansion of genomic surveillance in many places. To improve surveillance capability we developed a Sanger based sequencing protocol to obtain coverage of most (>95%) spike gene. Eleven nasopharyngeal swabs collections had RNA extracted for real time PCR diagnosis and leftover RNA had up to 3785 bp sequenced at an ABI3500 using dye termination chemistry of nested PCR products of two reactions of one-step RT-PCR. P1 amino acid mutations signatures were present in 18% (2/11), with 82% (9/11) with three or more additional amino acid changes (GISAID CoVsurver list). Most sequences (86%, 6/7) from 2021 have the E484K, whereas the mutation was not present in samples collected in 2020 (0/4, p=0.015).The swiftness that favorable mutations to the virus may prevail and their potential impact in vaccines and other current interventions need broader surveillance and more public health attention.
Prediction of COVID-19 Mortality to Support Patient Prognosis and Triage and Limits of Current Open-Source Data
Authors: Doyle Riccardo
Published: March 2021

This study examines the accuracy and applicability of machine learning methods in early prediction of mortality in COVID-19 patients. Patient symptoms, pre-existing conditions, age and sex were employed as predictive attributes from data spanning 17 countries. Performance on a semi-evenly balanced class sample of 212 patients resulted in high detection accuracy of 92.5%, with strong specificity and sensitivity. Performance on a larger sample of 5,121 patients with only age and mortality information was added as a measure of baseline discriminatory ability. Stratifying - Random Forest - and linear - Logistic Regression - methods were applied, both achieving modestly strong performance, with 77.4%-79.3% sensitivity and 71.4%-72.6% accuracy, highlighting predictive power even on the basis of a single attribute. Mutual information was employed as a dimensionality reduction technique, greatly improving performance and showing how a small number of easily retrievable attributes can provide timely and accurate predictions, with applications for datasets with slowly available variables - such as laboratory results.

Unlike existing studies making use of the same dataset, limitations of the data were extensively explored and detailed, as each results section outlines the main shortcomings of relevant analysis. Future use of this dataset should be cautious and always accompanied by disclaimers on issues of real-life reproducibility. While its open-source nature is a credit to the wider research community and more such datasets should be published, in its current state it can produce valid conclusions only for a limited set of applications, some of which were explored in this study.
The PKN1- TRAF1 signaling axis as a potential new target for chronic lymphocytic leukemia
Authors: Edilova Maria I. , Law Jaclyn C. , Zangiabadi Safoura , Ting Kenneth , Mbanwi Achire N. , Arruda Andrea , Uehling David , Isaac Methvin , Prakesch Michael , Al-awar Rima , Minden Mark D. , Abdul-Sater Ali A. , Watts Tania H.
Published: March 2021

TRAF1 is a pro-survival adaptor molecule in TNFR superfamily (TNFRSF) signaling. TRAF1 is overexpressed in many B cell cancers including refractory chronic lymphocytic leukemia (CLL). Little has been done to assess the role of TRAF1 in human cancer. Here we show that the protein kinase C related kinase Protein Kinase N1 (PKN1) is required to protect TRAF1 from cIAP-mediated degradation during constitutive CD40 signaling in lymphoma. We show that the active phospho-Thr774 form of PKN1 is constitutively expressed in CLL but minimally detected in unstimulated healthy donor B cells. Through a screen of 700 kinase inhibitors, we identified two inhibitors, OTSSP167 and XL-228, that inhibited PKN1 in the nanomolar range and induced dose-dependent loss of TRAF1 in RAJI cells. OTSSP167 and XL-228 treatment of primary patient CLL samples led to a reduction in TRAF1, pNF-κB p65, pS6, pERK, Mcl-1 and Bcl-2 proteins, and induction of activated caspase-3. OTSSP167 synergized with venetoclax in inducing CLL death, correlating with loss of TRAF1, Mcl-1 and Bcl-2. Although correlative, these findings suggest the PKN1-TRAF1 signaling axis as a potential new target for CLL. These findings also suggest OTSSP167 and venetoclax as a combination treatment for TRAF1 high CLL.
Physical, cognitive and mental health impacts of COVID-19 following hospitalisation – a multi-centre prospective cohort study
Authors:   PHOSP-COVID Collaborative Group, Evans Rachael Andrea , McAuley Hamish , Harrison Ewen M , Shikotra Aarti , Singapuri Amisha , Sereno Marco , Elneima Omer , Docherty Annemarie B , Lone Nazir I , Leavy Olivia C , Daines Luke , Baillie J Kenneth , Brown Jeremy S , Chalder Trudie , De Soyza Anthony , Diar Bakerly Nawar , Easom Nicholas , Geddes John R , Greening Neil J , Hart Nick , Heaney Liam G , Heller Simon , Howard Luke , Jacob Joseph , Jenkins R Gisli , Jolley Caroline , Kerr Steven , Kon Onn M , Lewis Keir , Lord Janet M , McCann Gerry P , Neubauer Stefan , Openshaw Peter JM , Pfeffer Paul , Rowland Matthew , Semple Malcolm G , Singh Sally J , Sheikh Aziz , Thomas David , Toshner Mark , Chalmers James D , Ho Ling-Pei , Horsley Alex , Marks Michael , Poinasamy Krisnah , Wain Louise V , Brightling Christopher E
Published: March 2021

Background

The impact of COVID-19 on physical and mental health, and employment following hospitalisation is poorly understood.

Methods

PHOSP-COVID is a multi-centre, UK, observational study of adults discharged from hospital with a clinical diagnosis of COVID-19 involving an assessment between two- and seven-months later including detailed symptom, physiological and biochemical testing. Multivariable logistic regression was performed for patient-perceived recovery with age, sex, ethnicity, body mass index (BMI), co-morbidities, and severity of acute illness as co-variates. Cluster analysis was performed using outcomes for breathlessness, fatigue, mental health, cognition and physical function.

Findings

We report findings of 1077 patients discharged in 2020, from the assessment undertaken a median 5 [IQR4 to 6] months later: 36% female, mean age 58 [SD 13] years, 69% white ethnicity, 27% mechanical ventilation, and 50% had at least two co-morbidities. At follow-up only 29% felt fully recovered, 20% had a new disability, and 19% experienced a health-related change in occupation. Factors associated with failure to recover were female, middle-age, white ethnicity, two or more co-morbidities, and more severe acute illness. The magnitude of the persistent health burden was substantial and weakly related to acute severity. Four clusters were identified with different severities of mental and physical health impairment: 1) Very severe (17%), 2) Severe (21%), 3) Moderate with cognitive impairment (17%), 4) Mild (46%), with 3%, 7%, 36% and 43% feeling fully recovered, respectively. Persistent systemic inflammation determined by C-reactive protein was related to cluster severity, but not acute illness severity.

Interpretation

We identified factors related to recovery from a hospital admission with COVID-19 and four different phenotypes relating to the severity of physical, mental, and cognitive health five months later. The implications for clinical care include the potential to stratify care and the need for a pro-active approach with wide-access to COVID-19 holistic clinical services.

Funding: UKRI and NIHR
Is attachment style in early childhood associated with mental health difficulties in late adolescence?
Authors: Clery Philippa , Rowe Angela , Munafò Marcus R. , Mahedy Liam
Published: March 2021

Background

Although existing research has suggested an association between insecure attachment styles and mental health difficulties, these studies often have small sample sizes, use cross-sectional designs, and measure attachment as a discrete variable at a single point. It is also unclear whether these associations persist into late adolescence. In this prospective study we aimed to determine whether insecure attachment style in early childhood is associated with depression and self-harm at 18 years.

Methods

We used data from the Avon Longitudinal Study of Parents and Children cohort. Mothers completed attachment related questionnaires when their child was 18, 30, and 42 months old. Offspring depression and lifetime self-harm was assessed at 18 years using the Clinical Interview Schedule-Revised. Attachment was derived as a latent variable in a structural equation modelling framework. Logistic regression was performed on participants with complete attachment data (n=7032) to examine the association between attachment style and depression and self-harm, with adjustment for potential confounders. Differential dropout was accounted for using multiple imputation.

Results

We found some evidence for an association between attachment quality and depression and self-harm. In the fully adjusted imputed model, a one standard deviation increase in insecure attachment was associated with a 13% increase in the odds of depression at age 18 (OR=1.13; 95%CI=1.00 to 1.27) and a 14% increase in the odds of self-harm at age 18 (OR=1.14; 95%CI=1.02 to 1.25).

Conclusions

Our findings strengthen the evidence suggesting that an insecure attachment style assessed in early childhood is associated with mental health difficulties in late adolescence. If this association is causal, policies to support parenting or attachment-based interventions to improve attachment quality could help reduce mental health difficulties in adolescence/young adulthood.
Efficient masking of plant genomes by combining kmer counting and curated repeats
Authors: Contreras-Moreira Bruno , Filippi Carla V , Naamati Guy , Girón Carlos García , Allen James E , Flicek Paul
Published: March 2021

Ii.

Summary/Abstract

The annotation of repetitive sequences within plant genomes can help in the interpretation of observed phenotypes. Moreover, repeat masking is required for tasks such as whole-genome alignment, promoter analysis or pangenome exploration. While homology-based annotation methods are computationally expensive, k-mer strategies for masking are orders of magnitude faster. Here we benchmark a two-step approach, where repeats are first called by k-mer counting and then annotated by comparison to curated libraries. This hybrid protocol was tested on 20 plant genomes from Ensembl, using the kmer-based Repeat Detector (Red) and two repeat libraries (REdat and nrTEplants, curated for this work). We obtained repeated genome fractions that match those reported in the literature, but with shorter repeated elements than those produced with conventional annotators. Inspection of masked regions overlapping genes revealed no preference for specific protein domains. Half of Red masked sequences can be successfully classified with nrTEplants, with the complete protocol taking less than 2h on a desktop Linux box. The repeat library and the scripts to mask and annotate plant genomes can be obtained athttps://github.com/Ensembl/plant-scripts.
Revisiting the role ofToxoplasma gondiiERK7 in the maintenance and stability of the apical complex
Authors: Dos Santos Pacheco Nicolas , Tosetti Nicolò , Krishnan Aarti , Haase Romuald , Soldati-Favre Dominique
Published: March 2021

Toxoplasma gondiiERK7 is known to contribute to the integrity of the apical complex and to be involved only in the final step of the conoid biogenesis. In the absence of ERK7, mature parasites lose their conoid complex and are unable to glide, invade or egress from host cells. In contrast to a previous report, we show here that depletion of ERK7 phenocopies the depletion of the apical cap proteins AC9 or AC10. The absence of ERK7 leads to the loss of the apical polar ring, the disorganization of the basket of subpellicular microtubules and an impairment in micronemes secretion. Ultra-expansion microscopy (U-ExM) coupled to NHS-Ester staining on intracellular parasites offers an unprecedented level of resolution and highlights the disorganization of the rhoptries as well as the dilated plasma membrane at the apical pole in the absence of ERK7. Comparative proteomics analysis of wild-type and ERK7 or AC9 depleted parasites led to the disappearance of known, predicted, as well as putative novel components of the apical complex. In contrast, the absence of ERK7 led to an accumulation of microneme proteins, resulting from the defect in exocytosis of the organelles.

Importance

The conoid is an enigmatic, dynamic organelle positioned at the apical tip of the coccidian subgroup of the Apicomplexa, close to the apical polar ring (APR) from which the subpellicular microtubules (SPTMs) emerge and at the site of microneme and rhoptry secretory organelles exocytosis. InToxoplasma gondii, the conoid protrudes concomitantly to microneme secretion, during egress, motility and invasion. The conditional depletion of the apical cap structural protein AC9 or AC10 leads to a disorganization of SPTMs as well as the loss of APR and conoid that result in microneme secretion defect and block in motility, invasion and egress. We show here that depletion of the kinase ERK7 phenocopies completely AC9 and AC10 mutants. Moreover, the combination of ultrastructure expansion microscopy with an NHS ester staining revealed that ERK7 depleted parasites exhibit a dilated apical plasma membrane and a mis-positioning of the rhoptry organelles.
Identification and characterization of novel infection associated transcripts in macrophages
Authors: Prabhakar A , Singla Mohit , Lodha Rakesh , Rao Vivek
Published: March 2021

Regulated expression of genes in response to internal and external stimuli is primarily responsible for the enormous plasticity and robustness of biological systems. Recent studies have elucidated complex regulatory non protein coding transcript (lncRNA) circuits in coordinated response of immune cells. By analysis of lncRNA expression profiles of macrophages in response to Mtb infection, we identified novel highly expressed transcripts, unique in encompassing one functional protein coding transcript- CMPK2 and a previously identified type I IFN responsive lncRNA- NRIR. While these RNA are induced by virulent Mtb early, the complete absence of expression in non-viable Mtb infected cells coupled to a more protracted expression profile in the case of BCG suggest an important role in macrophage response to mycobacteria. Moreover, enhanced expression was observed in macrophages from TB patients. The elevated expression by 1h in response to fast growing bacteria further emphasizes the importance of these RNAs in the macrophage infection response. These transcripts (TILT1, 2,3 -TLR4 andInfection inducedLongTranscript) are triggered exclusively by TLR4 stimulation (LPS) with faster and stronger kinetics in comparison to the lncRNA – NRIR. Overall, we provide evidence for the presence of numerous transcripts that is a part of the early infection response program of macrophages.
Prevalence of short interpregnancy interval and its associated factors among pregnant women in Debre Berhan town, Ethiopia
Authors: Mamo Hana , Dagnaw Abinet , Tadesse Nigussie , Berhane Kalayu , Shiferaw Kehabtimer
Published: March 2021

Background

Short inter-pregnancy interval is when the time elapsed between the dates of birth of the preceding child and the conception date of the current pregnancy is < 24 months. Despite its direct effects on the perinatal and maternal outcomes, there is a paucity of evidence on its prevalence and determinant factors, particularly in Ethiopia. Therefore, this study assessed the prevalence and associated factors of short inter-pregnancy interval among pregnant women in Debre Berhan town, Northern Ethiopia.

Methods

A community based cross sectional study was conducted among a randomly selected 496 pregnant women in Debre Berhan town from February 9 to March 9, 2020. The data was collected by using interviewer administered questionnaire and analyzed using STATA (14.2) statistical software. To identify the predictors of short inter-pregnancy interval, multivariable binary logistic regression was fitted and findings are presented using adjusted odds ratio (AOR) with 95% confidence interval (CI).

Result

The overall prevalence of short inter-pregnancy interval (<24 months) among pregnant women was 205 (40.9%). Being over 30 years of age at first birth (AOR=3.50; 95% CI: 2.12-6.01), non-use of modern contraceptive (AOR=2.51; 95% CI: 1.23-3.71), duration of breast feeding for less than 12 months (AOR= 2.62; 95% CI: 1.32-5.23), parity above four (AOR=0.31; 95% CI: 0.05-0.81), and unintended pregnancy (AOR= 5.42; 95% CI: 3.34-9.22) were independently associated factors with short inter-pregnancy interval.

Conclusion

Despite the family planning and other public health intervention tried in the country, the prevalence of short inter-pregnancy interval in this study was high. Therefore, it implies that increasing contraceptive use and encouraging optimal breast feeding might help in the efforts made to avert the problem.
Where to learn to flatten the curve: a modelling study
Authors: Silk Matthew J , Carrignon Simon , Bentley R. Alexander , Fefferman Nina H
Published: March 2021

Background

Individual behavioural decisions are responses to both a person’s perceived social norms and could be driven by both their physical and social environment. In the context of the COVID-19 pandemic, these environments correspond to epidemiological risk from contacts and the social construction of risk by communication within networks of friends. Understanding when, and under which circumstances, each modality of influence can foster the widespread adoption of protective behaviours is critical for shaping useful, practical public health messaging that will best enhance the public response.

Methods

We use a multiplex network approach to explore how information from both physical contact and social communication networks is driving a mitigating behavioural response to disease risk.

Findings

We show that maintaining focus on awareness of risk in each individual’s physical layer contacts promotes the greatest reduction in disease spread, but only when an individual is aware of the symptoms of a non-trivial proportion of their physical contacts (approximately 20% or more). Information from the communication layer was less useful when these connections matched less well with physical contacts and contributed little in combination with accurate information from the physical layer.

Interpretation

We conclude that maintaining social focus on local outbreak status will allow individuals to structure their perceived social norms appropriately and respond more rapidly when risk increases. Finding ways to relay accurate local information from trusted community leaders could improve mitigation even where more intrusive/costly strategies, such as contact-tracing, are not possible.
The SARS-CoV-2 receptor angiotensin-converting enzyme 2 (ACE2) in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: analysis of high-throughput epigenetic and gene expression studies
Authors: Malato João , Sotzny Franziska , Bauer Sandra , Freitag Helma , Fonseca André , Grabowska Anna D , Graça Luís , Cordeiro Clara , Nacul Luís , Lacerda Eliana M , Castro-Marrero Jesus , Scheibenbogen Carmen , Westermeier Francisco , Sepúlveda Nuno
Published: March 2021

Patients affected by Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) show specific epigenetic and gene expression signatures of the disease. However, it is unknown whether these signatures include abnormal levels of the human angiotensin-converting enzymes, ACE and ACE2, the latter being the main receptor described for the host-cell invasion by SARS-CoV-2. To investigate that, we first re-analyzed available case-control epigenome-wide association studies based on DNA methylation data, and case-control gene expression studies based on microarray data. From these published studies, we found an association between ME/CFS and 4 potentially hypomethylated probes located in theACElocus. We also found another disease association with one hypomethylated probe located in the transcription start site of ACE2. The same disease associations were obtained for women but not for men after performing sex-specific analyses. In contrast, a meta-analysis of gene expression levels could not provide evidence for a differentially expression ofACEandACE2in affected patients when compared to healthy controls. In line with this negative finding, the analysis of a new data set on the gene expression ofACEandACE2in peripheral blood mononuclear cells did not find any differences between a female cohort of 37 patients and 34 age-matched healthy controls. Future studies should be conducted to extend this investigation to other potential receptors used by SARS-CoV-2. These studies will help researchers and clinicians to improve the understanding of the health risk imposed by this virus when infecting patients affected by this debilitating disease.
Salted roads lead to edema and reduced locomotor function in wood frogs
Authors: Frymus Lauren E. , Goedert Debora , Zamora-Camacho Francisco Javier , Smith Peter C. , Zeiss Caroline J. , Comas Mar , Abbott Timothy A. , Basu Silvia P. , DeAndressi Jason C. , Forgione Mia E. , Maloney Michael J. , Priester Joseph L. , Senturk Faruk , Szeligowski Richard V. , Tucker Alina S. , Zhang Mason , Calsbeek Ryan , Brady Steven P.
Published: March 2021

Human activities have caused massive losses of natural populations across the globe. Like many groups, amphibians have experienced substantial declines worldwide, driven by environmental changes such as habitat conversion, pollution, and disease emergence. Each of these drivers is often found in close association with the presence of roads. Here we report a novel consequence of roads affecting an amphibian native to much of North America, the wood frog (Rana sylvatica). Across 38 populations distributed from southern to central New England, we found that adult wood frogs living adjacent to roads had higher incidence and severity of edema (bloating caused by fluid accumulation) during the breeding season than frogs living away from the influence of roads. This effect was best explained by increased conductivity of breeding ponds, caused by runoff pollution from road salt used for de-icing. Edema severity was negatively correlated with locomotor performance in more northerly populations. Interestingly, northern populations experience more intense winters, which tends to result in more de-icing salt runoff and increased energetic demands associated with overwintering cryoprotection needs. Thus, this emerging consequence of roads appears to impose potential fitness costs associated with locomotion, and these effects might be most impactful on populations living in regions where de-icing is most intense.
Mycenaspecies can be opportunist-generalist plant root invaders
Authors: Harder Christoffer Bugge , Hesling Emily , Botnen Synnøve S. , Dima Bálint , von Bonsdorff-Salminen Tea , Niskanen Tuula , Jarvis Susan G. , Lorberau Kelsey E. , Ouimette Andrew , Hester Alison , Hobbie Erik A. , Taylor Andy F.S. , Kauserud Håvard
Published: March 2021

Recently, several saprotrophic genera have been found to invade/interact with plant roots in laboratory growth experiments, and this coincides with reports of abundant saprotrophic fungal sequences in plant roots. However, it is uncertain if this reflects field phenomena, and if reports on coincidentally amplified saprotrophs are simply coincidental.

We investigated root invasion by presumed saprotrophic fungi by focusing on the large genusMycenain1)a systematic analysis of the occurrence of saprotrophic fungi in new and previously published ITS1/ITS2 datasets generated from roots of 10 mycorrhizal plant species, and2)we analysed natural abundances of13C/15N stable isotope signatures of fungal/plant communities from five comparable field locations to examine the trophic status ofMycenaspecies.

Mycenawas the only saprotrophic genus consistently found in 9 of 10 plant host roots, with high within-host variation inMycenasequence proportions (0-80%) recovered.Mycenacarpophores displayed isotopic signatures consistent with published13C/15N profiles of both saprotrophic or mutualistic lifestyles, with considerable intraspecific variation, resembling the patterns seen in growth experiments. These results indicate that multipleMycenaspecies opportunistically invade the roots of a range of plant species, possibly forming a spectrum of interactions. This potentially challenges our general understanding of fungal ecology.

Originality significance statement

This is the first study to apply a dual approach of systematic metabarcoding of plant roots and stable isotope signatures on dried field material to the large and common saprotrophic fungal genusMycena. This is significant as it shows that members of this genus, normally not expected to be found inside plant roots at all, are in fact associated eith multiple plant hosts. The study furthermore shows that species in this genus may occupy different ecological roles in the field besides being saprotrophic. That a large and common fungal genus known to be a quantitatively important litter decayer can be an opportunistic root invader and interact with host plants is of interest to all mycologists and ecologists working on plant-fungus/microb symbiosis.