bluuebunny/crossref_metadata_2025_split huggingface dataset:
Angiotensin II Type 1 Receptor Antibody-mediated Rejection Following Orthotopic Heart Transplant: A Single-center Experience
Authors: Moreno Jonathan D. , Verma Amanda K. , Kopecky Benjamin J. , Dehner Carina , Kostelecky Nicolas , Vader Justin M. , Lin Chieh-Yu , Schilling Joel D. 
Published: March 2021

Background.
Antibody-mediated rejection (AMR) following orthotopic heart transplant (OHT) causes significant morbidity and mortality. There are limited data on antibodies to the angiotensin II type 1 receptor antibody (AT1R-Ab) causing rejection following OHT.

Methods.
This is a retrospective, single-center study that presents our 2-y experience with a series of 11 patients with evidence of nonspecific graft dysfunction and pathologic levels of AT1R-Ab. The clinical outcomes and treatments were compared to a group of 10 patients, also with evidence of nonspecific graft dysfunction, but who had nonsignificant AT1R-Ab titers.

Results.
The mean age of the AT1R-Ab cohort was 52% and 73% were bridged to transplant with an left ventricular assist device. The average left ventricular ejection fraction at presentation was 45%, and most were not on an angiotensin receptor blocker (ARB). Endomyocardial biopsies in those with elevated AT1R-Ab levels frequently showed reactive endothelium/endocardium without C4d or intravascular CD68 staining. Ten patients (91%) were started on an ARB. Other therapies included plasmapheresis and IVIg (64%), with 4 patients also receiving rituximab. Most patients had symptom improvement, but minimal change in graft function at an average 6 mo of follow-up.

Conclusions.
The role of AT1R-Ab-mediated rejection in OHT recipients remains poorly understood. More than half of patients at our center who presented with graft dysfunction in the absence of acute cellular rejection or AMR were found to have elevated AT1R-Ab titers. Empiric AMR treatment in conjunction with ARB therapy may improve patient outcomes. Future studies are needed to better define the optimal treatment modalities for ATR1-Ab-mediated AMR.
High-resolution Metatranscriptomic Characterization of the Pulmonary RNA Virome After Lung Transplantation
Authors: Mitchell Alicia B. , Li Ci-Xiu , Oliver Brian G.G. , Holmes Edward C. , Glanville Allan R. 
Published: March 2021

Background.
Lung transplantation provides a unique opportunity to investigate the constituents and temporal dynamics of the human pulmonary microbiome after lung transplantation. For methodological reasons, prior studies using metagenomics have detected DNA viruses but not demonstrated the presence of RNA viruses, including those that are common community acquired. In this proof-of-concept study, we aimed to further characterize the pulmonary microbiome after lung transplantation by using metagenomic next-generation sequencing (mNGS), with a particular focus on the RNA virome.

Methods.
We performed a single-center longitudinal study of lower respiratory tract RNA viruses and bacteria using bronchoalveolar lavage at postoperative day 1 and week 6 analyzed with total RNA sequencing (metatranscriptomics). Five primary and 5 repeat transplant recipients were recruited.

Results.
mNGS identified 5 RNA viruses (nil in the normal saline control), including 4 species of human rhinovirus not previously reported in Australia: A7 (HRV-A7), C22 (HRV-C22), B52 (HRV-B52), and B72 (HRV-B72). Overall, 12/20 specimens were virus positive in 7/10 cases. Human parainfluenza virus 3 was the most frequent virus in 7/20 specimens in 5/10 cases. In this small study, we did not detect a significant difference in abundance and diversity of RNA viruses and bacteria at postoperative day 1 and 6 wk, nor differences between retransplant recipients and primary lung transplant recipients.

Conclusions.
Our study demonstrates how mNGS can also identify RNA viruses within the human pulmonary virome, including novel RNA viruses, and paves the way for a greater understanding of the complex relationships among the constituents of the pulmonary infectome.
Multi-spike solutions of a hybrid reaction–transport model
Authors: Bressloff P. C. 
Published: March 2021

Simulations of classical pattern-forming reaction–diffusion systems indicate that they often operate in the strongly nonlinear regime, with the final steady state consisting of a spatially repeating pattern of localized spikes. In activator–inhibitor systems such as the two-component Gierer–Meinhardt (GM) model, one can consider the singular limit
D

a

≪
D

h

, where
D

a

and
D

h

are the diffusivities of the activator and inhibitor, respectively. Asymptotic analysis can then be used to analyse the existence and linear stability of multi-spike solutions. In this paper, we analyse multi-spike solutions in a hybrid reaction–transport model, consisting of a slowly diffusing activator and an actively transported inhibitor that switches at a rate
α
between right-moving and left-moving velocity states. Such a model was recently introduced to account for the formation and homeostatic regulation of synaptic puncta during larval development in
Caenorhabditis elegans
. We exploit the fact that the hybrid model can be mapped onto the classical GM model in the fast switching limit
α
→ ∞, which establishes the existence of multi-spike solutions. Linearization about the multi-spike solution yields a non-local eigenvalue problem that is used to investigate stability of the multi-spike solution by combining analytical results for
α
→ ∞ with a graphical construction for finite
α
.
Deprivation and Early Involuntary Retirement: Area-Level Analysis across English Local Authorities
Authors: Giri Prosenjit , Basu Subhashis , Giri Abrahjit 
Published: March 2021

AbstractIntroductionRetirement is a major transition point in life. Falling economic support ratios in many countries have led to a rise in the state retirement age and impending changes to eligibility for state and occupational benefit schemes such as pensions as Governments seek to curb expenditure. Permanently incapacitated individuals from work may face increasing challenges in accessing financial support. Such difficulties may impact those most deprived differentially with potentially significant consequences for morbidity and mortality. Few studies thus far have examined early retirement from a societal perspective. This study explores involuntary retirement in this regard.MethodsA retrospective analysis of the association between deprivation with IHR success rates for Local Authorities (LA) in England between 2015-18 was conducted. Deprivation status was assigned according to the proportion of Lower-Layer Super Output Areas in the most deprived 10% nationally using data from the National Statistics SocioEconomic Classification 2015. Freedom of Information Requests were sent to all 326 LAs in England to obtain data on successful IHR applications, number of active members of respective pensions schemes and numbers of applications.Results131 LAs provided complete data for IHR applications, numbers of approved applications and eligible members. Several others provided data on application numbers but not those awarded. he national IHR approval rate was 2.16 per 1000 members, with a range of 0.16 to 8.96. There was a trend towards a greater proportion of approved application per 1000 eligible members in more affluent LAs.ConclusionThe results from this brief analysis suggest that there is an association between increasing rates of ill-health retirement and higher area-level deprivation. Policy should note that those in more deprived areas face a quadruple whammy; a greater risk of becoming incapacitated from public health and occupational exposures, more limited access to medical support, less opportunities for alternative work and potentially disproportionate disadvantage from stringent pension eligibility criteria.
Cytoplasmic domain and enzymatic activity of ACE2 is not required for PI4KB dependent endocytosis entry of SARS-CoV-2 into host cells
Authors: Yang Hang , Zhao Xiaohui , Xun Meng , Xu Lingjie , Liu Bing , Wang Hongliang 
Published: March 2021

AbstractThe recent COVID-19 pandemic poses a global health emergency. Cellular entry of the causative agent SARS-CoV-2 is mediated by its spike protein interacting with cellular receptor- human angiotensin converting enzyme 2 (ACE2). Here, we used lentivirus based pseudotypes bearing spike protein to demonstrate that entry of SARS-CoV-2 into host cells is dependent on clathrin-mediated endocytosis, and phosphoinositides play essential role during this process. In addition, we showed that the intracellular domain and the catalytic activity of ACE2 is not required for efficient virus entry. These results provide new insights into SARS-CoV-2 cellular entry and present potential targets for drug development.
Impact of azithromycin mass drug administration on the antibiotic-resistant gut microbiome: a randomized, controlled trial
Authors: Pickering Harry , Hart John D. , Burr Sarah , Stabler Richard , Maleta Ken , Kalua Khumbo , Bailey Robin L. , Holland Martin J. 
Published: March 2021

AbstractBackgroundMass drug administration (MDA) with azithromycin is the primary strategy for global trachoma control efforts. Numerous studies have reported secondary effects of MDA with azithromycin, including reductions in childhood mortality, diarrhoeal disease and malaria. Most recently, the MORDOR clinical trial demonstrated that MDA led to an overall reduction in all-cause childhood mortality in targeted communities. There is however concern about the potential of increased antimicrobial resistance in treated communities.MethodsThis study evaluated the impact of azithromycin MDA on the prevalence of gastrointestinal carriage of macrolide-resistant bacteria in communities within the MORDOR Malawi study, additionally profiling changes in the gut microbiome after treatment. For faecal metagenomics, 60 children were sampled prior to treatment and 122 children after four rounds of MDA, half receiving azithromycin and half placebo.FindingsThe proportion of bacteria carrying macrolide resistance increased after azithromycin treatment; the effect was enhanced in children treated within six months of sampling. Diversity and global community structure of the gut was minimally impacted by treatment, however abundance of several species was altered by treatment. Notably, the putative human enteropathogen Escherichia albertii was more abundant after treatment.InterpretationThe impacts of MDA with azithromycin, including increased carriage of macrolide-resistant bacteria, were enhanced in children treated more recently, suggesting effects may be transient. Increased abundance of enteropathogenic Escherichia species after treatment requires further, higher resolution investigation. Future studies should focus on the number of treatments and administration schedule to ensure clinical benefits continue to outweigh costs in antimicrobial resistance carriage.FundingBill and Melinda Gates Foundation
Performance evaluation of the Roche Elecsys Anti-SARS-CoV-2 S immunoassay
Authors: Riester Elena , Findeisen Peter , Hegel J. Kolja , Kabesch Michael , Ambrosch Andreas , Rank Christopher M , Langen Florina , Laengin Tina , Niederhauser Christoph 
Published: March 2021

AbstractBackgroundThe Elecsys® Anti-SARS-CoV-2 S immunoassay (Roche Diagnostics International Ltd, Rotkreuz, Switzerland) has been developed for the in vitro quantitative detection of antibodies to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) protein. We evaluated the performance of this assay using samples from seven sites in Germany, Austria, and Switzerland.MethodsAnonymized frozen, residual serum, or plasma samples from blood donation centers or routine diagnostic testing were used for this study. For specificity and sensitivity analyses, presumed negative samples collected before October 2019 and SARS-CoV-2 PCR-confirmed single or sequential samples were tested, respectively. The performance of the Elecsys Anti-SARS-CoV-2 S immunoassay was also compared with other commercial immunoassays.ResultsThe overall specificity (n=7880 pre-pandemic samples) and sensitivity (n=240 PCR-positive samples [≥14 days post-PCR]) for the Elecsys Anti-SARS-CoV-2 S immunoassay were 99.95% (95% confidence interval [CI]: 99.87–99.99) and 97.92% (95% CI: 95.21– 99.32), respectively. Compared with seven other immunoassays, the Elecsys Anti-SARS-CoV-2 S assay had comparable or greater specificity and sensitivity. The Elecsys Anti-SARS-CoV-2 S immunoassay had significantly higher specificity compared with the LIAISON® SARS-CoV-2 S1/S2 IgG, ADVIA Centaur® SARS-CoV-2 Total, ARCHITECT SARS-CoV-2 IgG, iFlash-SARS-CoV-2 IgM, and EUROIMMUN Anti-SARS-CoV-2 IgG and IgA assays, and significantly higher sensitivity (≥14 days post-PCR) compared with the ARCHITECT SARS-CoV-2 IgG, iFlash-SARS-CoV-2 IgG and IgM, and EUROIMMUN Anti-SARS-CoV-2 IgG assays.ConclusionThe Elecsys Anti-SARS-CoV-2 S assay demonstrated a robust and favorable performance across samples from multiple European sites, with a very high specificity and sensitivity for the detection of anti-S antibodies.
Delayed rise of oral fluid antibodies, elevated BMI, and absence of early fever correlate with longer time to SARS-CoV-2 RNA clearance in an longitudinally sampled cohort of COVID-19 outpatients
Authors: Antar Annukka A. R. , Yu Tong , Pisanic Nora , Azamfirei Razvan , Tornheim Jeffrey A. , Brown Diane M. , Kruczynski Kate , Hardick Justin P. , Sewell Thelio , Jang Minyoung , Church Taylor , Walch Samantha N. , Reuland Carolyn , Bachu Vismaya S. , Littlefield Kirsten , Park Han-Sol , Ursin Rebecca L. , Ganesan Abhinaya , Kusemiju Oyinkansola , Barnaba Brittany , Charles Curtisha , Prizzi Michelle , Johnstone Jaylynn R. , Payton Christine , Dai Weiwei , Fuchs Joelle , Massaccesi Guido , Armstrong Derek T. , Townsend Jennifer L. , Keller Sara C. , Demko Zoe O , Hu Chen , Wang Mei-Cheng , Sauer Lauren M. , Mostafa Heba H. , Keruly Jeanne C. , Mehta Shruti H. , Klein Sabra L. , Cox Andrea L. , Pekosz Andrew , Heaney Christopher D. , Thomas David L. , Blair Paul W. , Manabe Yukari C. 
Published: March 2021

ABSTRACTBackgroundSustained molecular detection of SARS-CoV-2 RNA in the upper respiratory tract (URT) in mild to moderate COVID-19 is common. We sought to identify host and immune determinants of prolonged SARS-CoV-2 RNA detection.MethodsNinety-five outpatients self-collected mid-turbinate nasal, oropharyngeal (OP), and gingival crevicular fluid (oral fluid) samples at home and in a research clinic a median of 6 times over 1-3 months. Samples were tested for viral RNA, virus culture, and SARS-CoV-2 and other human coronavirus antibodies, and associations were estimated using Cox proportional hazards models.ResultsViral RNA clearance, as measured by SARS-CoV-2 RT-PCR, in 507 URT samples occurred a median (IQR) 33.5 (17-63.5) days post-symptom onset. Sixteen nasal-OP samples collected 2-11 days post-symptom onset were virus culture positive out of 183 RT-PCR positive samples tested. All participants but one with positive virus culture were negative for concomitant oral fluid anti-SARS-CoV-2 antibodies. The mean time to first antibody detection in oral fluid was 8-13 days post-symptom onset. A longer time to first detection of oral fluid anti-SARS-CoV-2 S antibodies (aHR 0.96, 95% CI 0.92-0.99, p=0.020) and BMI ≥ 25kg/m2 (aHR 0.37, 95% CI 0.18-0.78, p=0.009) were independently associated with a longer time to SARS-CoV-2 viral RNA clearance. Fever as one of first three COVID-19 symptoms correlated with shorter time to viral RNA clearance (aHR 2.06, 95% CI 1.02-4.18, p=0.044).ConclusionsWe demonstrate that delayed rise of oral fluid SARS-CoV-2-specific antibodies, elevated BMI, and absence of early fever are independently associated with delayed URT viral RNA clearance.
Years of Life Lost Associated with COVID-19 Deaths in the United States During the First Year of the Pandemic
Authors: Quast Troy , Andel Ross , Gregory Sean , Storch Eric A. 
Published: March 2021

AbstractBackgroundYears of Life Lost (YLL) measure the shortfall in life expectancy due to a medical condition and have been used in multiple contexts. Previously it was estimated that there were 1.2 million YLLs associated with COVID-19 deaths in the United States through July 11, 2020. The aim of this study is to update YLL estimates for the first full year of the pandemic.MethodsWe employed data regarding COVID-19 deaths in the United States through January 31, 2021 by jurisdiction, gender, and age group. We used actuarial life expectancy tables by gender and age to estimate YLLs.ResultsWe estimated roughly 3.9 million YLLs due to COVID-19 deaths, which corresponds to roughly 9.2 YLLs per death. We observed a large range across states in YLLs per 10,000 capita, with New York City at 298 and Vermont at 12. Nationally, males had a higher number of YLLs per death than females (9.5 versus 8.8), but there was significant variation in gender differences across states.ConclusionsOur estimates provide further insight into the mortality effects of COVID-19. The observed differences across states and genders demonstrate the need for disaggregated analyses of the pandemic’s effects.
SARS-CoV-2 Sequence Characteristics of COVID-19 Persistence and Reinfection
Authors: Choudhary Manish C. , Crain Charles R. , Qiu Xueting , Hanage William , Li Jonathan Z. 
Published: March 2021

ABSTRACTBackgroundBoth SARS-CoV-2 reinfection and persistent infection have been reported, but sequence characteristics in these scenarios have not been described. We assessed published cases of SARS-CoV-2 reinfection and persistence, characterizing the hallmarks of reinfecting sequences and the rate of viral evolution in persistent infection.MethodsA systematic review of PubMed was conducted to identify cases of SARS-CoV-2 reinfection and persistence with available sequences. Nucleotide and amino acid changes in the reinfecting sequence were compared to both the initial and contemporaneous community variants. Time-measured phylogenetic reconstruction was performed to compare intra-host viral evolution in persistent SARS-CoV-2 to community-driven evolution.ResultsTwenty reinfection and nine persistent infection cases were identified. Reports of reinfection cases spanned a broad distribution of ages, baseline health status, reinfection severity, and occurred as early as 1.5 months or >8 months after the initial infection. The reinfecting viral sequences had a median of 17.5 nucleotide changes with enrichment in the ORF8 and N genes. The number of changes did not differ by the severity of reinfection and reinfecting variants were similar to the contemporaneous sequences circulating in the community. Patients with persistent COVID-19 demonstrated more rapid accumulation of sequence changes than seen with community-driven evolution with continued evolution during convalescent plasma or monoclonal antibody treatment.ConclusionsReinfecting SARS-CoV-2 viral genomes largely mirror contemporaneous circulating sequences in that geographic region, while persistent COVID-19 has been largely described in immunosuppressed individuals and is associated with accelerated viral evolution.SummaryReinfecting SARS-CoV-2 viral genomes largely mirror contemporaneous circulating sequences in that geographic region, while persistent COVID-19 has been largely described in immunosuppressed individuals and is associated with accelerated viral evolution.FundingThis study was funded in part by the NIH grant 106701.DisclosuresDr. Li has consulted for Abbvie.
Vaccination with SARS-CoV-2 Spike Protein and AS03 Adjuvant Induces Rapid Anamnestic Antibodies in the Lung and Protects Against Virus Challenge in Nonhuman Primates
Authors: Francica Joseph R. , Flynn Barbara J. , Foulds Kathryn E. , Noe Amy T. , Werner Anne P. , Moore Ian N. , Gagne Matthew , Johnston Timothy S. , Tucker Courtney , Davis Rachel L. , Flach Britta , O’Connell Sarah , Andrew Shayne F. , Lamb Evan , Flebbe Dillon R. , Nurmukhambetova Saule T. , Donaldson Mitzi M. , Todd John-Paul M. , Zhu Alex Lee , Atyeo Caroline , Fischinger Stephanie , Gorman Matthew J , Shin Sally , Edara Venkata Viswanadh , Floyd Katharine , Lai Lilin , Tylor Alida , McCarthy Elizabeth , Lecouturier Valerie , Ruiz Sophie , Berry Catherine , Tibbitts Timothy , Andersen Hanne , Cook Anthony , Dodson Alan , Pessaint Laurent , Ry Alex Van , Koutsoukos Marguerite , Gutzeit Cindy , Teng I-Ting , Zhou Tongqing , Li Dapeng , Haynes Barton F. , Kwong Peter D. , McDermott Adrian , Lewis Mark G. , Fu Tong Ming , Chicz Roman , van der Most Robbert , Corbett Kizzmekia S. , Suthar Mehul S. , Alter Galit , Roederer Mario , Sullivan Nancy J. , Douek Daniel C. , Graham Barney S. , Casimiro Danilo , Seder Robert A. 
Published: March 2021

AbstractAdjuvanted soluble protein vaccines have been used extensively in humans for protection against various viral infections based on their robust induction of antibody responses. Here, soluble prefusion-stabilized spike trimers (preS dTM) from the severe acute respiratory syndrome coronavirus (SARS-CoV-2) were formulated with the adjuvant AS03 and administered twice to nonhuman primates (NHP). Binding and functional neutralization assays and systems serology revealed that NHP developed AS03-dependent multi-functional humoral responses that targeted multiple spike domains and bound to a variety of antibody FCreceptors mediating effector functionsin vitro. Pseudovirus and live virus neutralizing IC50titers were on average greater than 1000 and significantly higher than a panel of human convalescent sera. NHP were challenged intranasally and intratracheally with a high dose (3×106PFU) of SARS-CoV-2 (USA-WA1/2020 isolate). Two days post-challenge, vaccinated NHP showed rapid control of viral replication in both the upper and lower airways. Notably, vaccinated NHP also had increased spike-specific IgG antibody responses in the lung as early as 2 days post challenge. Moreover, vaccine-induced IgG mediated protection from SARS-CoV-2 challenge following passive transfer to hamsters. These data show that antibodies induced by the AS03-adjuvanted preS dTM vaccine are sufficient to mediate protection against SARS-CoV-2 and support the evaluation of this vaccine in human clinical trials.