bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of the COVID-19 Pandemic on Patient Volumes, Acuity, and Outcomes in Pediatric Emergency Departments
Authors: Finkelstein Yaron , Maguire Bryan , Zemek Roger , Osmanlliu Esli , Kam April J. , Dixon Andrew , Desai Neil , Sawyer Scott , Emsley Jason , Lynch Tim , Mater Ahmed , Schuh Suzanne , Rumantir Maggie , Freedman Stephen B. ,   on behalf of Pediatric Emergency Research Canada (PERC)
Published: June 2021

Objectives

The aim of this study was to quantify the effect of the COVID-19 pandemic on pediatric emergency department (ED) utilization and outcomes.

Methods

This study is an interrupted-time-series observational study of children presenting to 11 Canadian tertiary-care pediatric EDs. Data were grouped into weeks in 3 study periods: prepandemic (January 1, 2018–January 27, 2020), peripandemic (January 28, 2020–March 10, 2020), and early pandemic (March 11, 2020–April 30, 2020). These periods were compared with the same time intervals in the 2 preceding calendar years. Primary outcomes were number of ED visits per week. The secondary outcomes were triage acuity, hospitalization, intensive care unit (ICU) admission, mortality, length of hospital stay, ED revisits, and visits for trauma and mental health concerns.

Results

There were 577,807 ED visits (median age, 4.5 years; 52.9% male). Relative to the prepandemic period, there was a reduction [−58%; 95% confidence interval (CI), −63% to −51%] in the number of ED visits during the early-pandemic period, with concomitant higher acuity. There was a concurrent increase in the proportion of ward [odds ratio (OR), 1.39; 95% CI, 1.32–1.45] and intensive care unit (OR, 1.20; 95% CI, 1.01–1.42) admissions, and trauma-related ED visits among children less than 10 years (OR, 1.51; 95% CI, 1.45–1.56). Mental health–related visits in children declined in the early-pandemic period (in <10 years, −60%; 95% CI, −67% to −51%; in children ≥10 years: −56%; 95% CI, −63% to −47%) relative to the pre–COVID-19 period. There were no differences in mortality or length of stay; however, ED revisits within 72 hours were reduced during the early-pandemic period (percent change: −55%; 95% CI, −61% to −49%;P< 0.001).

Conclusions

After the declaration of the COVID-19 pandemic, dramatic reductions in pediatric ED visits occurred across Canada. Children seeking ED care were sicker, and there was an increase in trauma-related visits among children more than 10 years of age, whereas mental health visits declined during the early-pandemic period. When faced with a future pandemic, public health officials must consider the impact of the illness and the measures implemented on children's health and acute care needs.
Determining the Independent Risk Factors for Worse SCAR-Q Scores and Future Scar Revision Surgery
Authors: Ziolkowski Natalia I. , Behman Ramy , Klassen Anne F. , Fish Joel S. , Mundy Lily R. , She Richard Wong , Forrest Christopher R. , Hollenbeck Scott , Arriagada Cristian , Greenhalgh David , Pusic Andrea L.
Published: June 2021

Background:

Scar revisions have been increasing in number. Patient-reported outcome measures are one tool to aid scar modulation decision-making. The aims of this study were to determine patient, scar, and clinical risk factors for (1) low SCAR-Q Appearance, Symptom, and Psychosocial Impact scores and how this differs for children; and (2) the potential need for future scar revision surgery to better identify such patients in a clinical setting.

Methods:

A multicenter international cross-sectional cohort study based on survey data of participants with traumatic, surgical, and burn scars attending plastic, hand, and burn clinics in four countries was conducted following the Strengthening the Reporting of Observational Studies in Epidemiology checklist. Univariate analysis to identify risk factors and multivariable logistic analysis to select risk factors were completed. Collinearity for nonindependent factors and C statistic for model discrimination were also calculated.

Results:

Seven hundred thirty-one participants completed the study booklet, and 546 participants (74.7 percent) had full data. Independent risk factors were determined to be a bothersome scar and perception of scarring badly for all three scales. Risk factors for self-reporting the need for future surgery included a health condition, scarring badly, scar diagnosis, prior scar revision, and low Psychosocial Impact scores. We did not identify evidence of multicollinearity. C statistics were high (0.81 to 0.84).

Conclusions:

This study is the first multicenter international study to examine independent risk factors for low patient-reported outcome measure scores and the potential need for future scar revision surgery. Patients that perceive themselves as scarring badly and having a bothersome scar were at a higher risk of scar appearance concern, an increased symptom burden, and poorer psychosocial impact scores.

CLINICAL QUESTION/LEVEL OF EVIDENCE:

Risk, III.
Secondary Rhinoplasty for Unilateral Cleft Nasal Deformity
Authors: Rohrich Rod J. , Benkler Michal , Avashia Yash J. , Savetsky Ira L.
Published: June 2021

Background:

Secondary cleft rhinoplasty presents some of the most challenging cases of both cosmetic and functional nasal deformities. Understanding the anatomy and growth abnormality seen with the cleft nasal deformity helps to tailor surgical management. This article seeks to expand on the application of current concepts in secondary rhinoplasty for unilateral cleft lip nasal deformity.

Methods:

The authors review nasal analysis in the cleft rhinoplasty patient and provide the surgical management for each aspect in the secondary cleft rhinoplasty.

Results:

The secondary rhinoplasty was divided into seven areas: piriform hypoplasia, septal reconstruction, dorsal reshaping, tip reshaping, tip projection, alar reshaping, and alar repositioning. Surgical management for each is provided.

Conclusion:

Secondary cleft rhinoplasty requires an understanding of the structural dysmorphology, and the use of cosmetic, functional, and secondary rhinoplasty techniques for its successful management.
Soluble biomarkers associated with chronic lung disease in older children and adolescents with perinatal HIV infection
Authors: Hameiri-Bowen Dan , Sovershaeva Evgeniya , Flaegstad Trond , Gutteberg Tore Jarl , Ngwira Lucky Gift , Simms Victoria , Rehman Andrea M. , Mchugh Grace , Bandason Tsitsi , Ferrand Rashida Abbas , Rowland-Jones Sarah , Yindom Louis-Marie
Published: June 2021

Objective:

HIV-associated chronic lung disease (HCLD) is a common comorbidity in children and adolescents in sub-Saharan Africa (SSA). The pathogenesis of HCLD is unclear and may be driven by underlying dysregulated systemic immune activation and inflammation. We investigated the association between 26 plasma soluble biomarkers and HCLD.

Design:

Case--control analysis of baseline biomarker data from 336 children and adolescents (6–19 years old) with perinatal HIV infection (PHIV) and HCLD (cases) and 74 age-matched and sex-matched controls with PHIV but no CLD. HCLD was defined as having a forced expiratory volume in one second (FEV1) z score less than −1 with no reversibility.

Methods:

Cryopreserved plasma collected at recruitment was used in a multiplex bead assay (Luminex) to measure baseline levels of soluble biomarkers. Logistic regression alongside data-reduction and techniques quantifying the interconnectedness of biomarkers were used to identify biomarkers associated with odds of HCLD.

Results:

Biomarkers of general immune activation and inflammation (β2M, CRP, sCCL5, GCSF, IFN-γ, IP-10), T-cell activation (sCD25, sCD27), platelet activation (sCD40-L), monocyte activation (sCD14), coagulation (D-Dimer), cellular adhesion (E-selectin), and extracellular matrix degradation (MMP-1, MMP-7, MMP-10) were associated with increased odds of HCLD. Exploratory PCA and assessment of biomarker interconnectedness identified T-cell and platelet activation as centrally important to this association.

Conclusion:

HCLD was associated with a large number of soluble biomarkers representing a range of different pathways. Our findings suggest a prominent role for T-cell and platelet activation in HCLD.
Generic Health-Related Quality of Life in Patients Seeking Care for Pelvic Organ Prolapse
Authors: Bradley Catherine S. , Brown Heidi W. , Shippey Stuart S. , Gutman Robert E. , Andy Uduak U. , Yurteri-Kaplan Ladin A. , Kudish Bela , Mehr Allen , O’Boyle Amy , Foster Raymond T. , Anger Jennifer T. , Ten Eyck Patrick , Moalli Pamela A.
Published: June 2021

Objective

Using the American Urogynecologic Society multicenter Pelvic Floor Disorder Registry for Research, we (1) compared generic quality of life (QOL) in women planning pelvic organ prolapse (POP) treatment (surgery vs pessary), (2) correlated generic and condition-specific QOL scores, and (3) identified associations between generic QOL and other factors.

Methods

This cross-sectional analysis assessed generic physical and mental QOL using the Patient-Reported Outcomes Measurement Information System Global Health Scale at baseline. Global Physical and Mental T-scores center on a representative US population sample (mean [SD], 50 [10]; higher scores, better health). Condition-specific QOL was assessed with Pelvic Floor Distress Inventory, Pelvic Floor Impact Questionnaire, and POP/Urinary Incontinence Sexual Function Questionnaire. Linear regression models identified associations between clinical factors and Global Physical/Mental scores.

Results

Five hundred sixty-eight women (419 surgery, 149 pessary) were included. Surgery patients were younger, heavier, and more often sexually active (all P’s ≤ 0.01). Global Physical scores were lower in the surgery versus pessary group, but not likely clinically meaningful (mean [SD], 48.8 [8.1] vs 50.4 [8.5]; P = 0.035); Global Mental scores were similar (51.4 [8.4] vs 51.9 [9.5], P = 0.56). Global Health scores correlated with Pelvic Floor Distress Inventory, Pelvic Floor Impact Questionnaire, and POP/Urinary Incontinence Sexual Function Questionnaire scores (all P’s < 0.0001). In multivariable models, menopause was associated with better physical QOL, and constipation, coronary artery disease, pelvic pain, and increased body mass index with worse physical QOL. Age was associated with better mental QOL, and constipation, fecal incontinence, pelvic pain, and coronary artery disease with worse mental QOL.

Conclusions

Women choosing POP surgery versus pessary had similar physical and mental generic QOL.
Impact of COVID-19 on Lung Allograft and Clinical Outcomes in Lung Transplant Recipients: A Case-control Study
Authors: Permpalung Nitipong , Bazemore Katrina , Chiang Teresa Po-Yu , Mathew Joby , Barker Lindsay , Nematollahi Saman , Cochran Willa , Sait Afrah S. , Avery Robin K. , Shah Pali D.
Published: June 2021

Background.

The impacts of COVID-19 on lung allograft function, rejection, secondary infection, and clinical outcomes in lung transplant recipients (LTRs) remain unknown.

Methods.

A 1:2 matched case–control study was performed to evaluate rehospitalization, lung allograft function, and secondary infections up to 90 d after COVID-19 diagnosis (or index dates for controls).

Results.

Twenty-four LTRs with COVID-19 (cases) and 48 controls were identified. Cases and controls had similar baseline characteristics and lung allograft function. LTRs with COVID-19 had higher incidence of secondary bacterial infection (29.2% versus 6.3%, P = 0.008), readmission (29.2% versus 10.4%, P = 0.04), and for-cause bronchoscopy (33.3% versus 12.5%, P = 0.04) compared with controls. At d 90, mortality in cases versus controls was 8.3% versus 2.1% (P = 0.21), incidence of invasive fungal infections in cases versus controls was 20.8% versus 8.3% (P = 0.13) and forced expiratory volume in 1 s (FEV1) decline ≥10% from baseline occurred in 19% of cases versus 12.2% of controls (P = 0.46). No acute cellular rejection, acute antibody-mediated rejection, or new donor-specific anti-HLA antibodies were observed among cases or controls within 90 d post index date.

Conclusions.

We found LTRs with COVID-19 were at risk to develop secondary infections and rehospitalization post COVID-19, compared with controls. While we did not observe post viral acute cellular rejection or antibody-mediated rejection, further studies are needed to understand if LTRs with COVID-19 who did not recover baseline lung function within 90 d have developed chronic lung allograft dysfunction stage progression.
COVID-19 patient accounts of illness severity, treatments and lasting symptoms
Authors: Thomason Moriah E. , Werchan Denise , Hendrix Cassandra L.
Published: June 2021

First-person accounts of COVID-19 illness and treatment complement and enrich data derived from electronic medical or public health records. With patient-reported data, it is uniquely possible to ascertain in-depth contextual information as well as behavioral and emotional responses to illness. The Novel Coronavirus Illness Patient Report (NCIPR) dataset includes complete survey responses from 1,592 confirmed COVID-19 patients ages 18 to 98. NCIPR survey questions address symptoms, medical complications, home and hospital treatments, lasting effects, anxiety about illness, employment impacts, quarantine behaviors, vaccine-related behaviors and effects, and illness of other family/household members. Additional questions address financial security, perceived discrimination, pandemic impacts (relationship, social, stress, sleep), health history, and coping strategies. Detailed patient reports of illness, environment, and psychosocial impact, proximal to timing of infection and considerate of demographic variation, is meaningful for understanding pandemic-related public health from the perspective of those that contracted the disease.
Drug interactions in hospital prescriptions in Denmark: Prevalence and associations with adverse outcomes
Authors: Rodríguez Cristina Leal , Kaas-Hansen Benjamin Skov , Eriksson Robert , Biel Jorge Hernansanz , Belling Kirstine G. , Andersen Stig Ejdrup , Brunak Søren
Published: June 2021

Importance

While the beneficial effects of medications are numerous, drug-drug interactions may lead to adverse drug reactions that are preventable causes of morbidity and mortality.

Objective

To quantify the prevalence of potential drug-drug interactions in drug prescriptions at Danish hospitals, estimate the risk of adverse outcomes associated with discouraged drug combinations, and highlight the patient types (defined by the primary diagnosis of the admission) that appear to be more affected.

Design

Cross-sectional (descriptive part) and cohort study (adverse outcomes part).

Setting

Hospital electronic health records from two Danish regions (approx. 2.5 million people) from January 2008 through June 2016.

Participants

Inpatients receiving two or more medications during their admission.

Exposure

Concomitant prescriptions of potentially interacting drugs as per the Danish Drug Interaction Database.

Main outcome and measure

Descriptive part: prevalence of potential drug-drug interactions in general and discouraged drug pairs in particular during admissions. Adverse outcomes part: post-discharge all-cause mortality rate, readmission rate and length-of-stay.

Results

Among 2,886,227 hospital admissions (945,475 patients; median age 62 years [IQR: 41-74]; 54% female; median number of drugs 7 [IQR: 4-11]), patients in 1,836,170 admissions were exposed to at least one potential drug-drug interaction (659,525 patients; median age 65 years [IQR: 49-77]; 54% female; median number of drugs 9 [IQR: 6-13]), and in 27,605 admissions to a discouraged drug pair (18,192 patients; median age 68 years [IQR: 58-77]; female 46%; median number of drugs 16 [IQR: 11-22]). Meropenem-valproic acid (HR: 1.5, 95% CI: 1.1–1.9), domperidone-fluconazole (HR: 2.5, 95% CI: 2.1–3.1), imipramine-terbinafine (HR: 3.8, 95% CI: 1.2–12), agomelatine-ciprofloxacin (HR: 2.6, 95% CI: 1.3–5.5), clarithromycin-quetiapine (HR: 1.7, 95% CI: 1.1–2.7), and piroxicam-warfarin (HR: 3.4, 95% CI: 1–11.4) were associated with elevated mortality. Confidence interval bounds of pairs associated with readmission were close to 1; length-of-stay results were inconclusive.

Conclusions and Relevance

Well-described potential drug-drug interactions are still missed and alerts at point of prescription may reduce the risk of harming patients; prescribing clinicians should be alert when using strong inhibitor/inducer drugs (i.e. clarithromycin, valproic acid, terbinafine) and prevalent anticoagulants (i.e. warfarin and NSAIDs) due to their great potential for dangerous interactions. The most prominent CYP isoenzyme involved in mortality and readmission rates was 3A4.
Single cell sequencing reveals expanded cytotoxic CD4+ T cells and two states of peripheral helper T cells in synovial fluid of ACPA+ RA patients
Authors: Argyriou Alexandra , Wadsworth Marc H. , Lendvai Adrian , Christensen Stephen M. , Hensvold Aase H. , Gerstner Christina , Kravarik Kellie , Winkler Aaron , Malmström Vivianne , Chemin Karine
Published: June 2021

Rheumatoid arthritis is an autoimmune disease affecting the synovial joints where different subsets of CD4+ T cells are suspected to play a pathogenic role. So far, our understanding of the contribution of cytotoxic CD4+ T cells is incomplete, particularly in the context of the recently described peripheral helper T-cell subset (TPH). Here, using single cell sequencing and multi-parameter flow cytometry, we show that cytotoxic CD4+ T cells are enriched in synovial fluid of anti-citrullinated peptides antibody (ACPA)-positive RA patients. We identify two distinct TPH states differentially characterized by the expression of CXCL13 and PRDM1, respectively. Our data reveal that the adhesion G-Protein Coupled Receptor 56 (GPR56), a marker of circulating cytotoxic cells, delineates the synovial TPH CD4+ T-cell subset. At the site of inflammation, GPR56+CD4+ T cells expressed the tissue-resident memory markers LAG-3, CXCR6 and CD69. Further, TCR clonality analysis revealed that most expanded clones in SF are contained within the cytotoxic and the CXCL13+ TPH CD4+ T-cell populations. Finally, the detection of common TCRs between the two TPH and cytotoxic CD4+ T-cell clusters suggest a shared differentiation. Our study provides comprehensive immunoprofiling of the heterogenous T-cell subsets at the site of inflammation in ACPA+ RA and suggests GPR56 as a therapeutic target to modulate TPH cells and cytotoxic CD4+ T cell function.
The Immunogenetic Basis of Idiopathic Bone Marrow Failure Syndromes: A Paradox of Similarity and Self-Presentation
Authors: Pagliuca Simona , Gurnari Carmelo , Awada Hassan , Kishtagari Ashwin , Kongkiatkamon Sunisa , Terkawi Laila , Zawit Misam , Guan Yihong , LaFramboise Thomas , Jha Babal K. , Patel Bhumika J. , Hamilton Betty K. , Majhail Navneet S. , Lundgren Sofie , Mustjoki Satu , Saunthararajah Yogen , Visconte Valeria , Chan Timothy , Yang Chao-Yie , Lenz Tobias L. , Maciejewski Jaroslaw P.
Published: June 2021

Idiopathic aplastic anemia (IAA) is a rare autoimmune bone marrow failure disorder initiated by a human leukocyte antigen (HLA)-restricted T-cell response to unknown antigens. Immunogenetic patterns associated with self-antigenic presentation remain unclear. Herein we analyzed the molecular landscape of HLA complexes and T-cell receptor (TCR) repertoires of a large cohort of IAA patients and controls. We show that antigen binding sites of class II HLA molecules in IAA are characterized by a high level of structural homology, only partially explained by specific risk allele profiles, implying reduced binding capabilities compared to controls. Few amino acids within the synapsis HLA-DRB1-antigen-TCR, are identified as strongly associated with IAA phenotype. Those structural patterns may affect TCR repertoires, promoting immunological cross-reactivity and autoimmunity. These findings inform on the immunogenetic risk associated with IAA and on general pathophysiological mechanisms potentially involved in autoimmunity.

Key points

Class II human leukocyte antigen (HLA) loci in idiopathic bone marrow failure (BMF) syndromes are characterized by low functional divergence and decreased peptide binding capabilities, only partially explained by enrichment in risk alleles.

A superstructure at the interface with the peptide binding site of DRB1 locus, potentially involved in the presentation of self-antigenic specificities, can be identified in BMF patients.

This immunogenetic pattern may contribute to decrease T-cell receptor repertoire diversity, expand autoreactive T-cell clones and increase autoimmune propensity in BMF.
Prevention and Attenuation of COVID-19 by BNT162b2 and mRNA-1273 Vaccines
Authors: Thompson Mark G. , Burgess Jefferey L. , Naleway Allison L. , Tyner Harmony , Yoon Sarang K. , Meece Jennifer , Olsho Lauren E.W. , Caban-Martinez Alberto J. , Fowlkes Ashley L. , Lutrick Karen , Groom Holly C. , Dunnigan Kayan , Odean Marilyn J , Hegmann Kurt , Stefanski Elisha , Edwards Laura J. , Schaefer-Solle Natasha , Grant Lauren , Ellingson Katherine , Kuntz Jennifer L. , Zunie Tnelda , Thiese Matthew S. , Ivacic Lynn , Wesley Meredith G. , Lamberte Julie Mayo , Sun Xiaoxiao , Smith Michael E. , Phillips Andrew L. , Groover Kimberly D. , Yoo Young M. , Gerald Joe K. , Brown Rachel T. , Herring Meghan K. , Joseph Gregory , Beitel Shawn , Morrill Tyler C. , Mak Josephine , Rivers Patrick , Poe Brandon P. , Lynch Brian , Zhou Ying Tao , Zhang Jing , Kelleher Anna , Li Yan , Dickerson Monica , Hanson Erika , Guenther Kyley , Tong Suxiang , Bateman Allen , Reisdorf Erik , Barnes John , Azziz-Baumgartner Eduardo , Hunt Danielle R. , Arvay Melissa L. , Kutty Preeta , Fry Alicia M. , Gaglani Manjusha
Published: June 2021

BACKGROUND

Information is limited on messenger RNA (mRNA) BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna) COVID-19 vaccine effectiveness (VE) in preventing SARS-CoV-2 infection or attenuating disease when administered in real-world conditions.

METHODS

Prospective cohorts of 3,975 healthcare personnel, first responders, and other essential and frontline workers completed weekly SARS-CoV-2 testing during December 14 2020—April 10 2021. Self-collected mid-turbinate nasal swabs were tested by qualitative and quantitative reverse-transcription–polymerase-chain-reaction (RT-PCR). VE was calculated as 100%×(1−hazard ratio); adjusted VE was calculated using vaccination propensity weights and adjustments for site, occupation, and local virus circulation.

RESULTS

SARS-CoV-2 was detected in 204 (5.1%) participants; 16 were partially (≥14 days post-dose-1 to 13 days after dose-2) or fully (≥14 days post-dose-2) vaccinated, and 156 were unvaccinated; 32 with indeterminate status (<14 days after dose-1) were excluded. Adjusted mRNA VE of full vaccination was 91% (95% confidence interval [CI]=76%–97%) against symptomatic or asymptomatic SARS-CoV-2 infection; VE of partial vaccination was 81% (95% CI=64%-90%). Among partially or fully vaccinated participants with SARS-CoV-2 infection, mean viral RNA load (Log10 copies/mL) was 40% lower (95% CI=16%-57%), the risk of self-reported febrile COVID-19 was 58% lower (Risk Ratio=0.42, 95% CI=0.18-0.98), and 2.3 fewer days (95% CI=0.8-3.7) were spent sick in bed compared to unvaccinated infected participants.

CONCLUSIONS

Authorized mRNA vaccines were highly effective among working-age adults in preventing SARS-CoV-2 infections when administered in real-world conditions and attenuated viral RNA load, febrile symptoms, and illness duration among those with breakthrough infection despite vaccination.
Projections of human papillomavirus (HPV) vaccination impact in Ethiopia, India, Nigeria, and Pakistan: a comparative modelling study
Authors: Portnoy Allison , Abbas Kaja , Sweet Steven , Kim Jane J. , Jit Mark
Published: June 2021

Background

Cervical cancer is the second most common cancer among women in Ethiopia, India, Nigeria, and Pakistan. However, of these four countries, only Ethiopia has introduced human papillomavirus (HPV) vaccination at the national level in 2018 and India in a few states in 2016. Our study objective was to estimate the potential health impact of HPV vaccination among ten cohorts of 9-year-old girls from 2021–2030 in Ethiopia, India, Nigeria, and Pakistan using two independent mathematical models, and assess similarities and differences in vaccine impact projections through comparative modelling analysis.

Methods

Using two widely published models (Harvard and PRIME) to estimate HPV vaccination impact, we simulated a vaccination scenario of 90% annual coverage among 9-year-old girls from 2021–2030 in Ethiopia, India, Nigeria, and Pakistan. We estimated the potential health impact in terms of cervical cancer cases, deaths, and disability-adjusted life years (DALYs) averted among vaccinated cohorts from the time of vaccination until 2100. We also conducted a comparative modelling analysis to understand the differences in vaccine impact estimates generated by the two models.

Results

Prior to harmonising model assumptions, the range between the PRIME model and the Harvard model for the potential health impact of HPV vaccination in terms of the number of cervical cancer cases averted among girls vaccinated 2021–2030 between the year of vaccination and 2100 was: 262,000 to 270,000 in Ethiopia; 1,640,000 to 1,970,000 in India; 330,000 to 336,000 in Nigeria; and 111,000 to 133,000 in Pakistan. When harmonising model assumptions, alignment on HPV type distribution significantly narrowed the differences in vaccine impact estimates.

Conclusions

The main difference in estimates for cases, deaths, and DALYs averted by vaccination between the models are due to variation in interpretation around data on cervical cancer attribution to HPV-16/18; differences in estimates for DALYs averted are additionally due to differences in age-specific remaining life expectancy over time between the two models. As countries make progress towards the World Health Organization targets for cervical cancer elimination, continued explorations of underlying differences in model inputs, assumptions, and results when examining cervical cancer prevention policy will be critical.
Humoral and cellular immune response against SARS-CoV-2 variants following heterologous and homologous ChAdOx1 nCoV-19/BNT162b2 vaccination
Authors: Barros-Martins Joana , Hammerschmidt Swantje I. , Cossmann Anne , Odak Ivan , Stankov Metodi V. , Ramos Gema Morillas , Dopfer-Jablonka Alexandra , Heidemann Annika , Ritter Christiane , Friedrichsen Michaela , Schultze-Florey Christian , Ravens Inga , Willenzon Stefanie , Bubke Anja , Ristenpart Jasmin , Janssen Anika , Ssebyatika George , Bernhardt Günter , Münch Jan , Hoffmann Markus , Pöhlmann Stefan , Krey Thomas , Bošnjak Berislav , Förster Reinhold , Behrens Georg M. N.
Published: June 2021

Cerebral venous thrombosis was reported as a rare but serious adverse event in young and middle-aged vaccinees following immunization with AstraZeneca’s ChAdOx1-nCov-19 vaccine. As a consequence, several European governments recommended using this vaccine only in individuals older than 60 years leaving millions of ChAd primed individuals with the decision to either receive a second shot of ChAd or a heterologous boost with mRNA-based vaccines. However, such combinations have not been tested so far. We used Hannover Medical School’s COVID-19 Contact (CoCo) Study cohort of health care professionals (HCP) to monitor ChAd primed immune responses before and three weeks after booster with ChAd or BioNTech/Pfizer’s BNT162b2. Whilst both vaccines boosted prime-induced immunity, BNT induced significantly higher frequencies of Spike-specific CD4 and CD8 T cells and, in particular, high titers of neutralizing antibodies against the B.1.1.7, B.1.351 and the P.1 variants of concern of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2).
A co-opted ISG15-USP18 binding mechanism normally reserved for deISGylation controls type I IFN signalling
Authors: Vasou Andri , Nightingale Katie , Cetkovská Vladimíra , Scheler Jonathan , Bamford Connor G.G. , Andrejeva Jelena , Schwarz-Linek Ulrich , Randall Richard E. , McLauchlan John , Weekes Michael P. , Bogunovic Dusan , Hughes David J
Published: June 2021

Type I interferon (IFN) signalling induces the expression of several hundred IFN-stimulated genes (ISGs) that provide an unfavourable environment for viral replication. To prevent an overexuberant response and autoinflammatory disease, IFN signalling requires tight control. One critical regulator is the ubiquitin-like protein ISG15, evidenced by autoinflammatory disease in patients with inherited ISG15 deficiencies. Current models suggest that ISG15 stabilises USP18, a well-established negative regulator of IFN signalling. USP18 also functions as an ISG15-specific peptidase that cleaves ISG15 from ISGylated proteins; however, USP18’s catalytic activity is dispensable for controlling IFN signalling. Here, we show that the ISG15-dependent stabilisation of USP18 involves transient hydrophobic interactions. Nonetheless, while USP18 stabilisation is necessary, it is not sufficient for regulation of IFN signalling. USP18 requires non-covalent interactions with the ISG15 C-terminal diGlycine motif to promote its regulatory function. This trait may have been acquired in humans through co-option of a binding mechanism normally reserved for deISGylation, identifying an unexpected new function for human ISG15.
Variant-of-concern-attributable health and health system-related outcomes: a population-level propensity-score matched cohort study
Authors: Erman Aysegul , Mishra Sharmistha , Barrett Kali A , Mac Stephen , Naimark David , Sander Beate
Published: June 2021

Background

As the transmission of SARS-CoV-2 variants intensifies globally, the burden of COVID-19 on the already strained health systems is becoming increasingly concerning. While there is growing literature on the effects of various variants-of-concern (VOC) on increased transmission, the extent to which VOCs may lead to more severe disease remains debated.

Methods

In the current analysis, we use a population-based propensity-score matched cohort study of all incident laboratory-confirmed COVID-19 cases with VOC testing in Ontario, Canada to estimate healthcare resource use and health outcomes attributable to VOCs introduced to Ontario between January 1 and April 9, 2021, relative to the previously circulating wild-type strain.

Results

We find that VOCs are associated with a higher odds of hospitalisation (odds ratio [OR], 2.25; 95% confidence interval [CI], 2.10-2.40) and ICU admission (OR, 3.31; 95%CI, 2.84-3.86); as well as with a higher odds of mortality for both the general COVID-19 population (OR 1.75; 1.47-2.09) and hospitalised cases (OR, 1.62; 95%CI, 1.23-2.15).

Conclusion

Taken together, these findings suggest that health systems may face increased demand for healthcare resources as VOCs predominate worldwide in view of low global vaccination coverage.
COVID-19 Sniffer Dog experimental training: which protocol and which implications for reliable identification?
Authors: Angeletti Silvia , Travaglino Francesco , Spoto Silvia , Pascarella Maria Chiara , Mansi Giorgia , De Cesaris Marina , Sartea Silvia , Giovanetti Marta , Fogolari Marta , Plescia Davide , Macera Massimiliano , Incalzi Raffaele Antonelli , Ciccozzi Massimo
Published: June 2021

The introduction of trained sniffer dogs for COVID-19 disease detection could be an opportunity, as previously described for other diseases. Dogs could be trained to detect volatile organic compounds (VOCs), the whiff of COVDI-19 disease. Dogs involved in the study were three one male and two females from different breeds, Black German Shepherd, German Shepherd and Dutch Shepherd. The training was performed using sweat samples from COVID-19 positive apteints and from covid-19 free patients admitted at the University Hospital Campus Bio-medico of Rome. Gauze with sweat were collected in glass jar with metal top and put in metal boxes used for dog training. The dog training protocol was performed in two phase: the olfactory conditioning and the olfactory discrimintaion research. The training palnning was focused on the switch moment for the sniffer dog, the moment when the dog was able to identify VOCs specific for COVID-19 disease. At this time the dog was able to identify VOCs specific for COVID-19 disease with significant reliability, in terms of number of correct versus uncorrect (p<0.0001) reporting. In conclusion, this protocol could provide a useful tool for sniffer dogs training and their introduction in mass screening context, cheaper and faster than a conventional testing method.
Eating disorder symptoms and their associations with anthropometric and psychiatric polygenic scores
Authors: Abdulkadir Mohamed , Hübel Christopher , Herle Moritz , Loos Ruth J.F. , Breen Gerome , Bulik Cynthia M. , Micali Nadia
Published: June 2021

Background

Eating disorder (ED) symptoms are prevalent in the general population, but their shared genetic underpinnings with psychiatric, metabolic, and anthropometric traits are not known. Here, we examined if polygenic scores (PGS) of traits associated with anorexia nervosa are also associated with adolescent ED symptoms in the Avon Longitudinal Study of Parents and Children (ALSPAC).

Methods

We calculated PGS for 25 traits (16 psychiatric, 4 metabolic, and 5 anthropometric) and investigated their associations with eight ED symptoms, including behaviors such as fasting for weight loss and cognitions such as body dissatisfaction (n range=2,991-6,013).

Results

Higher attention deficit hyperactivity disorder PGS and lower educational attainment PGS were associated with fasting for weight loss. Higher insomnia PGS was associated with increased body dissatisfaction. We found no evidence of an association between metabolic trait PGS and any ED symptom. Regarding anthropometrics, fat-free mass, fat mass, and body fat percentage PGSs, were positively associated with binge eating, excessive exercise, fasting for weight loss, body dissatisfaction, and weight and shape concern.

Conclusions

ED symptoms are genetically associated with psychiatric and anthropometric, but not with metabolic traits. Our findings provide insights for future genetic research investigating why some individuals with ED symptoms progress to develop threshold EDs while others do not.
Raman spectroscopy reveals phenotype switches in breast cancer metastasis
Authors: Paidi Santosh Kumar , Troncoso Joel Rodriguez , Harper Mason G. , Liu Zhenhui , Nguyen Khue G. , Ravindranathan Sruthi , Ivers Jesse D. , Zaharoff David A. , Rajaram Narasimhan , Barman Ishan
Published: June 2021

The accurate analytical characterization of metastatic phenotype at primary tumor diagnosis and its evolution with time are critical for controlling metastatic progression of cancer. Here, we report a label-free optical strategy using Raman spectroscopy and machine learning to identify distinct metastatic phenotypes observed in tumors formed by isogenic murine breast cancer cell lines of progressively increasing metastatic propensities. Our Raman spectra-based random forest analysis provided evidence that machine learning models built on spectral data can allow the accurate identification of metastatic phenotype of independent test tumors. By silencing genes critical for metastasis in highly metastatic cell lines, we showed that the random forest classifiers provided predictions consistent with the observed phenotypic switch of the resultant tumors towards lower metastatic potential. Furthermore, the spectral assessment of lipid and collagen content of these tumors was consistent with the observed phenotypic switch. Overall, our findings indicate that Raman spectroscopy may offer a novel strategy to evaluate metastatic risk during primary tumor biopsies in clinical patients.
Modelling brain representations of abstract concepts
Authors: Kaiser Daniel , Jacobs Arthur M. , Cichy Radoslaw M.
Published: June 2021

Abstract conceptual representations are critical for human cognition. Despite their importance, key properties of these representations remain poorly understood. Here, we used computational models of distributional semantics to predict multivariate fMRI activity patterns during the activation and contextualization of abstract concepts. We devised a task in which participants had to embed abstract nouns into a story that they developed around a given background context. We found that representations in inferior parietal cortex were predicted by concept similarities emerging in models of distributional semantics. By constructing different model families, we reveal the models’ learning trajectories and delineate how abstract and concrete training materials contribute to the formation of brain-like representations. These results inform theories about the format and emergence of abstract conceptual representations in the human brain.
Partial genome assembly of the medicinal plantEphedra sinica
Authors: Li Qiushi , Morris Jeremy S. , Facchini Peter J. , Yeaman Sam
Published: June 2021

Ephedra sinicais a high-value medicinal plant that produces important phenylpropylamino alkaloids pseudoephedrine and ephedrine. Few genomics resources exist forE. sinica, which has been characterized as a tetraploid with a monoploid genome size of 8.56 Gb. Here we reported a partial genome assembly ofE. sinica(12.8 Gb) based on Illumina short-read sequencing at low coverage.
The human ribosomal RNA gene is composed of highly homogenized tandem clusters
Authors: Hori Yutaro , Shimamoto Akira , Kobayashi Takehiko
Published: June 2021

The structure of the human ribosomal RNA gene clustering region (rDNA) has traditionally been hard to analyze due to its highly repetitive nature. However, the recent development of long-read sequencing technology, such as Oxford Nanopore sequencing, has enabled us to approach the large-scale structure of the genome. Using this technology, we found that human cells have a quite regular rDNA structure. Although each human rDNA copy has some variations in its non-coding region, contiguous copies of rDNA are similar, suggesting that homogenization through gene conversion frequently occurs between copies. Analysis of rDNA methylation by Nanopore sequencing further showed that all of the non-coding regions are heavily methylated, whereas about half of the coding regions are clearly unmethylated. The ratio of unmethylated copies, which are speculated to be transcriptionally active, was lower in individuals with a higher rDNA copy number, suggesting that there is a mechanism that keeps the active copy number stable. Lastly, the rDNA in progeroid syndrome patient cells with reduced DNA repair activity had more unstable copies as compared with control normal cells, although the rate was much lower than previously reported using a Fiber FISH method. Collectively, our results alter the view of rDNA stability and transcription regulation in human cells, indicating the presence of mechanisms for both homogenization to ensure sequence quality and maintenance of active copies for cellular functions.
Regulation of suberin biosynthesis and Casparian strip development in the root endodermis by two plant auxins
Authors: Cook Sam David , Kimura Seisuke , Wu Qi , Franke Rochus Benni , Kamiya Takehiro , Kasahara Hiroyuki
Published: June 2021

The biological function of the auxin phenylacetic acid (PAA) is not well characterized in plants. Although some aspects of its biology; transport, signaling and metabolism have recently been described. Previous work on this phytohormone has suggested that PAA behaves in an identical manner to IAA (indole-3-acetic acid) in promoting plant growth, yet plants require greater concentrations of PAA to elicit the same physiological responses. Here we show that normalized PAA treatment results in the differential expression of a unique list of genes, suggesting that plants can respond differently to the two auxins. This is further explored in endodermal barrier regulation where the two auxins invoke striking differences in the deposition patterns of suberin. We further show that auxin acts antagonistically on Casparian strip (CS) formation as it can circumvent the CS transcriptional machinery to repress CS related genes. Additionally, altered suberin biosynthesis reduces endogenous levels of PAA and CS deficiency represses the biosynthesis of IAA and the levels of both auxins. These findings implicate auxin as a regulator of endodermal barrier formation and highlight a novel role for PAA in root development and differentiation.
Characterization of the consensus mucosal microbiome of colorectal cancer
Authors: Zhao Lan , Grimes Susan M. , Greer Stephanie U. , Kubit Matthew , Lee HoJoon , Nadauld Lincoln D. , Ji Hanlee P.
Published: June 2021

Recent evidence suggests that dysbiosis, an imbalance of microbiota, is associated with increased risk of colorectal cancer. Diverse microbial organisms are physically associated with the cells found in tumor biopsies. Characterizing this mucosa-associated microbiome through genome sequencing has advantages compared to culture-based profiling. However, there are notable challenges in accurately characterizing the features of tumor microbiomes with methods like transcriptome sequencing. Most sequence reads originate from the host. Moreover, there is a high likelihood of bacterial contaminants being introduced. Another major challenge is the microbiome diversity among different studies. Colorectal tumors demonstrate a significant extent of microbiome variation among individuals from different geographic and ethnic origins. To address these challenges, we identified a consensus microbiome for colorectal cancer through analyzing 924 tumors from eight independent RNA-Seq data sets. A standardized meta-transcriptomic analysis pipeline was established and applied to the complete CRC cohort. Common contaminants were filtered out. Our study involved taxonomic investigation of non-human sequences, linked microbial signatures to phenotypes and the association of microbiome with tumor microenvironment components. Microbiome profiles across different CRC cohorts were compared, and recurrently altered microbial shifts specific to CRC were determined. We identified cancer-specific set of 114 microbial species associated with tumors that were found among all investigated studies. Validating our approach, we found that Fusobacterium nucleatum was one of the most enriched bacterial species in CRC. Firmicutes, Bacteroidetes, Proteobacteria, and Actinobacteria were among the four most abundant phyla for CRC microbiome. Signficant associations between the consensus species and specific immune cell types were noted. Our results are available as a web data resource for other researchers to explore (https://crc-microbiome.stanford.edu).
Distillation of MSA Embeddings to Folded Protein Structures with Graph Transformers
Authors: Costa Allan , Ponnapati Manvitha , Jacobson Joseph M. , Chatterjee Pranam
Published: June 2021

Abstract

Determining the structure of proteins has been a long-standing goal in biology. Language models have been recently deployed to capture the evolutionary semantics of protein sequences. Enriched with multiple sequence alignments (MSA), these models can encode protein tertiary structure. In this work, we introduce an attention-based graph architecture that exploits MSA Transformer embeddings to directly produce three-dimensional folded structures from protein sequences. We envision that this pipeline will provide a basis for efficient, end-to-end protein structure prediction.
Activation Mechanism of Strigolactone Receptors And Its Impact On Ligand Selectivity Between Host And Parasitic Plants
Authors: Chen Jiming , Nelson David C. , Shukla Diwakar
Published: June 2021

Parastic weeds such as Striga have led to significant losses in agricultural productivity worldwide. These weeds use the plant hormone strigolactone as a germination stimulant. Strigolactone signaling involves substrate binding and hydrolysis followed by a large conformational change of the receptor to a “closed” or “active” state that is able to associate with a downstream signaling partner MAX2/D3. The crystal structure of the active and inactive AtD14 receptor have helped in elucidating the structural changes involved in activation. However, the mechanism by which the receptor activates remains unknown. The ligand dependence of AtD14 activation has been disputed by mutagenesis studies showing that enzymatically inactive receptors are able to form a complex with MAX2 proteins. Furthermore, activation differences between strigolactone receptor in Striga, ShHTL7 and textitAtD14 could contribute to the high sensitivity to strigolactones exhibited by parasitic plants. Using molecular dynamics simulations, we demonstrate that both AtD14 and ShHTL7 could adopt an active conformation in absence of ligand. However, the ShHTL7 receptor exhibits higher population in the inactive apo state as compared to the AtD14 receptor. We demonstrate that this difference in inactive state population is caused by sequence differences between their D-loops and its interactions with the catalytic histidine that prevents full binding pocket closure in ShHTL7. These results indicate that hydrolysis of a strigolactone ligand would enhance the active state population by destabilizing the inactive state in ShHTL7 as compared to AtD14. We also show that the mechanism of activation is more concerted in AtD14 than in ShHTL7 and that the main barrier to activation in ShHTL7 is closing of the binding pocket.
Haemosporidian taxonomic composition, network centrality and partner fidelity between resident and migratory avian hosts
Authors: de Angeli Dutra Daniela , Fecchio Alan , Braga Érika Martins , Poulin Robert
Published: June 2021

Migration can modify interaction dynamics between parasites and their hosts with migrant hosts able to disperse parasites and impact local community transmission. Thus, studying the relationships among migratory hosts and their parasites is fundamental to elucidate how migration shapes host-parasite interactions. Avian haemosporidian parasites are some of the most prevalent, diverse, and important wildlife parasites, and are also widely used as models in ecological and evolutionary research. Here, we contrast parasite taxonomic composition, network centrality and partner fidelity among resident and non-resident hosts using avian haemosporidians as study model. In order to evaluate parasite taxonomic composition, we performed permutational multivariate analyses of variance to quantify dissimilarity in haemosporidian lineages infecting different host migratory categories. Additionally, we ran multilevel Bayesian models to assess the role of migration in determining centrality and partner fidelity in host-parasite networks of avian hosts and their respective haemosporidian parasites. We observed similar parasite taxonomic composition and partner fidelity among resident and migratory hosts. Conversely, we demonstrate that migratory hosts play a more central role in host-parasite networks than residents. However, when evaluating partially and fully migratory hosts separately, we observed that only partially migratory species presented higher network centrality when compared to resident birds. Therefore, migration does not lead to differences in both parasite taxonomic composition and partner fidelity. However, migratory behavior is positively associated with network centrality, indicating migratory hosts play more important roles in shaping host-parasite interactions and influence local transmission.