bluuebunny/crossref_metadata_2025 huggingface dataset:
CovidStats: Development and Implementation of a Daily COVID-19 Clinical Dashboard in an Urban Teaching Hospital
Authors: Gazivoda Victor , Stolz Adam , Saunders Paul , Marshall John , Lockerman Zachary , Samy Sameh , Motov Sergey , Savel Richard H.
Published: February 2022

Background and Objectives:

Dashboards have been utilized in health care to improve quality and patient care. The purpose of our project was to create a concise, timely, and accurate dashboard for administrative and clinical leadership during the COVID-19 pandemic.

Methods:

Two authors collaborated to identify 14 metrics and design a comprehensive dashboard (CovidStats, CS) using Microsoft Excel. The dashboard was updated daily and distributed to leadership between December 2020 and April 2021. The utility of this quality measure was assessed by survey of hospital leadership.

Results:

The 14 metrics included were as follows: (1) elective surgery census threshold; (2) daily COVID admissions; (3) daily COVID discharges; (4) net COVID admissions; (5) ED (emergency department) bed holds; (6) COVID ED bed holds; (7) hospital census; (8) percent COVID census; (9) active COVID census; (10) COVID ICU (intensive care unit); (11) MICU (medical ICU) census; (12) ventilators in use; (13) high-flow oxygen devices in use; and (14) weekly hospital census. The leadership response survey revealed unanimous approval for CS, with a mean rating of 4.9 ± 0.3 (rated 1-5).

Conclusions:

Effective clinical dashboards can be created using affordable basic computer software. Implementation of the CS dashboard conveyed relevant and timely information, which influenced the decision making of hospital leadership during the COVID-19 pandemic.
Persistent Obstructive Sleep Apnea in Children with Down Syndrome After Adenotonsillectomy: Drug Induced Sleep Endoscopy-Directed Treatment
Authors: Abdel-Aziz Mosaad , Abdel-Naseer Usama , Elshahawy Eslam , Elsherbeeny Motaz , Nassar Ahmed
Published: February 2022

Children with down syndrome (DS) are more liable to develop obstructive sleep apnea (OSA) which is usually treated with adenotonsillectomy. However, OSA may persist in many of those patients after the procedure. The aim of this study was to assess the efficacy of drug-induced sleep endoscopy (DISE)-directed treatment in management of DS children with persistent OSA after adenotonsillectomy. Sixteen DS children with persistent OSA after adenotonsillectomy were evaluated. DISE was done in the operating theatre to identify the site of obstruction, and surgical intervention was performed according to the finding. Polysomnographic study was used pre- and post-operatively to measure the outcome. DISE revealed obstruction in different sites of the airway. DISE-directed treatment was done according to the site of obstruction. Polysomnographic study showed postoperative significant changes for all parameters. The authors achieved improvement of overall apnea-hypopnea index which was normalized in seven patients (44%). In conclusion, DISE-directed treatment is an effective procedure for persistent OSA in DS children who underwent adenotonsillectomy. However, residual obstruction in those children may be due to many characteristic features that cause narrowing of the airway.
Vertical HIV-1 transmission in the setting of maternal broad and potent antibody responses
Authors: Tu Joshua J , Kumar Amit , Giorgi Elena E , Eudailey Josh , LaBranche Celia C , Martinez David R , Fouda Genevieve G , Moreau Yvetane , Thomas Allison , Montefiori David , Gao Feng , Sagar Manish , Permar Sallie R
Published: February 2022

Despite the worldwide availability of antiretroviral therapy (ART), approximately 150,000 pediatric HIV infections continue to occur annually. ART can dramatically reduce HIV mother-to-child transmission (MTCT), but inconsistent drug access and adherence, as well as primary maternal HIV infection during pregnancy and lactation are major barriers to eliminating vertical HIV transmission. Thus, immunologic strategies to prevent MTCT, such as an HIV vaccine, will be required to attain an HIV-free generation. A primary goal of HIV vaccine research has been to elicit broadly neutralizing antibodies (bnAbs) given the ability of passive bnAb immunization to protect against sensitive strains, yet we previously observed that HIV-transmitting mothers have more plasma neutralization breadth than non-transmitting mothers. Additionally, we have identified infant transmitted/founder (T/F) viruses that escape maternal bnAb responses. In this study, we examine a cohort of postpartum HIV-transmitting women with neutralization breadth to determine if certain maternal bnAb specificities drive the selection of infant T/F viruses. Using HIV pseudoviruses that are resistant to neutralizing antibodies targeting common bnAb epitopes, we mapped the plasma bnAb specificities of this cohort. Significantly more transmitting women with plasma bnAb activity had a mappable plasma bnAb specificity (six of seven, or 85.7%), compared to that of non-transmitting women with plasma bnAb activity (seven of twenty-one, or 33.3%, p=0.029 by 2-sided Fisher exact test). Our study suggests that having multispecific broad activity and/or uncommon epitope-specific bnAbs in plasma may be associated with protection against the vertical HIV transmission in the setting of maternal bnAb responses.

Importance

As mother to child transmission (MTCT) of HIV plays a major part in the persistence of the HIV/AIDS epidemic and bnAb-based passive and active vaccines are a primary strategy for HIV prevention, research in this field is of great importance. While previous MTCT research has investigated the neutralizing antibody activity of HIV-infected women, this is to our knowledge the largest study identifying differences in bnAb specificity of maternal plasma between transmitting and non-transmitting women. Here, we show that among HIV-infected women with broad and potent neutralization activity, more postpartum-transmitting women had a mappable plasma broadly neutralizing antibody (bnAb) specificity, compared to that of non-transmitting women, suggesting that the non-transmitting women more often have multi-specific bnAb responses or bnAb responses that target uncommon epitopes. Such responses may be required for protection against vertical HIV transmission in the setting of maternal bnAb responses.
The role of the gut microbiota in patients with Kleefstra syndrome
Authors: Bloemendaal Mirjam , Vlaming Priscilla , de Boer Anneke , Vermeulen-Kalk Karlijn , Bouman Arianne , Kleefstra Tjitske , Vasquez Alejandro Arias
Published: February 2022

Kleefstra Syndrome (KS) is a rare monogenetic syndrome, caused by haploinsufficiency of the EHMT1 gene, an important regulator of neurodevelopment. The clinical features of KS include intellectual disability, autistic behavior and gastrointestinal problems. The gut microbiota may constitute a, yet unexplored, mechanism underlying clinical variation, as they are an important modifier of the gut-brain-axis. To test whether variation in the gut microbiota is part of KS, we investigated the gut microbiota composition of 23 individuals with KS (patients) and 40 of their family members. Both alpha and beta diversity of patients were different from their family members. GenusCoprococcus3 was lower in abundance in patients compared to family members. Moreover, abundance of genusMerdibacterwas lower in patients versus family members, but only in the participants reporting intestinal complaints. Within the patient group, behavioral problems explained 7% variance in the beta diversity. Also, within this group, we detected higher levels ofCoprococcus3 andAtopobiaceae – unculturedassociated with higher symptoms severity. Our results show significant differences in the gut microbiota composition of patients with KS compared to their family members, suggesting that these differences are part of the KS phenotype.
A Workflow for High Through-Put, High Precision Livestock Diagnostic Screening of Locomotor Kinematics
Authors: Mielke Falk , Van Ginneken Chris , Aerts Peter
Published: February 2022

1

Locomotor kinematics have been challenging inputs for automated diagnostic screening of livestock. Locomotion is a highly variable behavior, and influenced by subject characteristics (e.g. body mass, size, age, disease). We assemble a set of methods from different scientific disciplines, composing an automatic, high through-put workflow which can disentangle behavioral complexity and generate precise individual indicators of non-normal behavior for application in diagnostics and research. For this study, piglets (Sus domesticus) were filmed from lateral perspective during their first ten hours of life, an age at which maturation is quick and body mass and size have major consequences for survival. We then apply deep learning methods for point digitization, calculate joint angle profiles, and apply information-preserving transformations to retrieve a multivariate kinematic data set. We train probabilistic models to infer subject characteristics from kinematics. Model accuracy is validated for strides from piglets of normal birth weight (i.e. the category it was trained on), but the models infer the body mass and size of low birth weight piglets (which were left out of training, out-of-sample inference) to be “normal”. The age of some (but not all) low birth weight individuals is underestimated, indicating developmental delay. Such individuals could be identified automatically, inspected, and treated accordingly. This workflow has potential for automatic, precise screening in livestock management.
Absolute Winding Number Differentiates Spatial Navigation Strategies with Genetic Risk for Alzheimer's Disease
Authors: Badea Alexandra , Li Didong , Niculescu Andrei R , Anderson Robert J , Stout Jacques A , Williams Christina L , Colton Carol A , Maeda Nobuyo , Dunson David B
Published: February 2022

Spatial navigation and orientation are emerging as promising markers for altered cognition in prodromal Alzheimer's disease, and even in cognitively normal individuals at risk for Alzheimer's disease. The different APOE gene alleles confer various degrees of risk. The APOE2 allele is considered protective, APOE3 is seen as control, while APOE4 carriage is the major known genetic risk for Alzheimer's disease. We have used mouse models carrying the three humanized APOE alleles and tested them in a spatial memory task in the Morris water maze. We introduce a new metric, the absolute winding number, to characterize the spatial search strategy, through the shape of the swim path. We show that this metric is robust to noise, and works for small group samples. Moreover, the absolute winding number better differentiated APOE3 carriers, through their straighter swim paths relative to both APOE2 and APOE4 genotypes. Finally, this novel metric was sensitive to sex differences, supporting increased vulnerability in females. We hypothesized differences in spatial memory and navigation strategies are linked to differences in brain networks, and showed that different genotypes have different reliance on the hippocampal and caudate putamen circuits, pointing to a role for white matter connections. Moreover, differences were most pronounced in females. This departure from a hippocampal centric to a brain network approach may open avenues for identifying regions linked to increased risk for Alzheimer's disease, before overt disease manifestation. Further exploration of novel biomarkers based on spatial navigation strategies may enlarge the windows of opportunity for interventions. The proposed framework will be significant in dissecting vulnerable circuits associated with cognitive changes in prodromal Alzheimer's disease.
BASH-GN: A new machine learning derived questionnaire for screening obstructive sleep apnea
Authors: Huo Jiayan , Quan Stuart F. , Roveda Janet , Li Ao
Published: February 2022

Purpose

This study aims to develop a machine learning based questionnaire (BASH-GN) to classify obstructive sleep apnea (OSA) risk by considering risk factor subtypes.

Methods

A total of 4,527 participants that met study inclusion criteria were selected from Sleep Heart Health Study Visit 1 (SHHS 1) database. Another 1,120 records from Wisconsin Sleep Cohort (WSC) served as an independent test data set. Participants with an apnea hypopnea index (AHI) ≥ 15/h were considered as high OSA risk. Potential risk factors were ranked using mutual information between each factor and the AHI, and only the top 50% were selected. We classified the subjects into 2 different groups, low- and high phenotype groups, according to their risk scores. We then developed the BASH-GN, a machine learning based questionnaire that consists of two logistic regression classifiers for the 2 different subtypes of OSA risk prediction.

Results

We evaluated the BASH-GN on the SHHS 1 test set (n = 1237) and WSC set (n = 1120) and compared its performance with four commonly used OSA screening questionnaires, the Four-Variable, Epworth Sleepiness Scale, Berlin, and STOP-BANG. The model outperformed these questionnaires on both test sets regarding the area under the receiver operating characteristic (AUROC) and the area under the precision-recall curve (AUPRC). The model achieved AUROC (SHHS 1: 0.78, WSC: 0.76) and AUPRC (SHHS 1: 0.72, WSC: 0.74), respectively. The questionnaire is available at:https://c2ship.org/bash-gn

Conclusion

Considering OSA subtypes when evaluating OSA risk can improve the accuracy of OSA screening.
Comparison of two T cell assays to evaluate T cell responses to SARS-CoV-2 following vaccination in naïve and convalescent healthcare workers
Authors: Phillips Eloise , Adele Sandra , Malone Tom , Deeks Alexandra , Stafford Lizzie , Dobson Susan L. , Amini Ali , Skelly Donal , Eyre David , Jeffery Katie , Conlon Christopher P. , Dold Christina , Otter Ashley , D’Arcangelo Silvia , Turtle Lance ,   PITCH Consortium, Klenerman Paul , Barnes Eleanor , Dunachie Susanna J.
Published: February 2022

Background

T cell responses to SARS-CoV-2 following infection and vaccination are less characterised than antibody responses, due to a more complex experimental pathway.

Methods

We measured T cell responses in 108 healthcare workers (HCWs) in an observational cohort study, using the commercialised Oxford Immunotec T-SPOT Discovery SARS-CoV-2 assay (OI T-SPOT) and the PITCH ELISpot protocol established for academic research settings.

Results

Both assays detected T cell responses to SARS-CoV-2 spike, membrane and nucleocapsid proteins. Responses were significantly lower when reported by OI T-SPOT than by PITCH ELISpot. Four weeks after two doses of either Pfizer/BioNTech BNT162b or ChAdOx1 nCoV-19 AZD1222 vaccine, the responder rate was 63% for OI T-SPOT Panels1+2 (peptides representing SARS-CoV-2 spike protein excluding regions present in seasonal coronaviruses), 69% for OI T-SPOT Panel 14 (peptides representing the entire SARS-CoV-2 spike), and 94% for the PITCH ELISpot assay. The two OI T-SPOT panels correlated strongly with each other showing that either readout quantifies spike-specific T cell responses, although the correlation between the OI T-SPOT panels and the PITCH ELISpot was moderate.

Conclusion

The standardisation, relative scalability and longer interval between blood acquisition and processing are advantages of the commercial OI T-SPOT assay. However, the OI T-SPOT assay measures T cell responses at a significantly lower magnitude compared to the PITCH ELISpot assay, detecting T cell responses in a lower proportion of vaccinees. This has implications for the reporting of low-level T cell responses that may be observed in patient populations and for the assessment of T cell durability after vaccination.
The influence of biological, epidemiological, and treatment factors on the establishment and spread of drug-resistant Plasmodium falciparum
Authors: Masserey Thiery , Lee Tamsin , Golumbeanu Monica , Shattock Andrew J , Kelly Sherrie L , Hastings Ian M , Penny Melissa A
Published: February 2022

The effectiveness of artemisinin-based combination therapies (ACTs) to treat Plasmodium falciparum malaria is threatened by resistance. The complex interplay between sources of selective pressure – treatment properties, biological factors, transmission intensity, and access to treatment – obscures understanding how, when, and why resistance establishes and spreads across different locations. We developed a disease modelling approach with emulator-based global sensitivity analysis to systematically quantify which of these factors drive establishment and spread of drug resistance. Drug resistance was more likely to evolve in low transmission settings due to the lower levels of (i) immunity and (ii) within-host competition between genotypes. Spread of parasites resistant to artemisinin partner drugs depended on the period of low drug concentration (known as the selection window). Spread of partial artemisinin resistance was slowed with prolonged parasite exposure to artemisinin derivatives and accelerated when the parasite was also resistant to the partner drug. Thus, to slow the spread of partial artemisinin resistance, molecular surveillance should be supported to detect resistance to partner drugs and to change ACTs accordingly. Furthermore, implementing more sustainable artemisinin-based therapies will require extending parasite exposure to artemisinin derivatives, and mitigating the selection windows of partner drugs, which could be achieved by including an additional long-acting drug.

Impact Statement

Detailed models of malaria and treatment dynamics were combined with emulator-based global sensitivity analysis to elucidate how the interplay of drug properties, infection biology, and epidemiological dynamics drives evolution of resistance to artemisinin-based combination therapies. The results identify mitigation strategies.
Is Netrin-1 Associated with the Development of Fibrosis in Systemic Sclerosis?
Authors: Maraş Yüksel , Kor Ahmet , Oğuz Esra Fırat , Sarı Alper , Gök Kevser , Akdoğan Ali
Published: February 2022

Background

Netrin-1 is a laminin class protein that guides the axonal during the first embryonic development, has pushing and pulling properties, and has axonal chemoattractant activity. Netrin-1 has been shown to increase the effect of fibrosis in mouse lung and human SSc lung cell cultures. In this study, we aimed to investigate the relationship between Netrin-1 and Systemic sclerosis (SSc) and to emphasize the role of Netrin-1 in the pathophysiology of SSc by increasing the known VEGF and M2 macrophage expression, which supports the fibrotic process.

Methods

The study included 56 SSc patients with a mean age of 48·.08±13.59 years and 58 healthy volunteers with a mean age of 48.01±11.59 years. SSc organ involvements were scanned retrospectively from patient files, and patients were grouped according to SSc complications. Calculation of Netrin-1 levels was performed using a quantitative sandwich enzyme immunoassay method with an ELISA kit (Elabscience, Texas, USA; catalog number: E-EL-H2328; lot number: GZWTKZ5SWK). The modified Rodnan skin score (mRSS) was used for skin thickness scoring in SSc patients.

Results

The median value of Netrin-1 was found to be significantly higher in SSc (268.8 [82.75-1006.64]) than in controls (108.63 [21.02-351.49]) (p<0.0001). In ROC analysis, a cut-off value of 354.24 for Netrin in SSc was found to provide a sensitive confidence interval with 32.8% sensitivity and 98.3% specificity (AUC[95% CI]: 0.746-0.895, p<0.0001). There was no significant correlation between Netrin-1 level, organ involvement in SSc, and mRSS (p>0.05).

Conclusion

We found a significant relationship between Netrin-1 levels and SSc disease in this study. Our study is the first clinical study in which Netrin-1 elevation was demonstrated in SSc patients.
Biologically informed deep learning to infer gene program activity in single cells
Authors: Lotfollahi Mohammad , Rybakov Sergei , Hrovatin Karin , Hediyeh-zadeh Soroor , Talavera-López Carlos , Misharin Alexander V , Theis Fabian J.
Published: February 2022

The increasing availability of large-scale single-cell datasets has enabled the detailed description of cell states across multiple biological conditions and perturbations. In parallel, recent advances in unsupervised machine learning, particularly in transfer learning, have enabled fast and scalable mapping of these new single-cell datasets onto reference atlases. The resulting large-scale machine learning models however often have millions of parameters, rendering interpretation of the newly mapped datasets challenging. Here, we propose expiMap, a deep learning model that enables interpretable reference mapping using biologically understandable entities, such as curated sets of genes and gene programs. The key concept is the substitution of the uninterpretable nodes in an autoencoder’s bottleneck by labeled nodes mapping to interpretable lists of genes, such as gene ontologies, biological pathways, or curated gene sets, for which activities are learned as constraints during reconstruction. This is enabled by the incorporation of predefined gene programs into the reference model, and at the same time allowing the model to learnde novonew programs and refine existing programs during reference mapping. We show that the model retains similar integration performance as existing methods while providing a biologically interpretable framework for understanding cellular behavior. We demonstrate the capabilities of expiMap by applying it to 15 datasets encompassing five different tissues and species. The interpretable nature of the mapping revealed unreported associations between interferon signaling via the RIG-I/MDA5 and GPCRs pathways, with differential behavior in CD8+T cells and CD14+monocytes in severe COVID-19, as well as the role of annexins in the cellular communications between lymphoid and myeloid compartments for explaining patient response to the applied drugs. Finally, expiMap enabled the direct comparison of a diverse set of pancreatic beta cells from multiple studies where we observed a strong, previously unreported correlation between the unfolded protein response and asparagine N-linked glycosylation. Altogether, expiMap enables the interpretable mapping of single cell transcriptome data sets across cohorts, disease states and other perturbations.
Mechanistic origin of different binding affinities of SARS-CoV and SARS-CoV-2 spike RBDs to human ACE2
Authors: Zhang Zhi-Bi , Xia Yuan-Ling , Shen Jian-Xin , Du Wen-Wen , Fu Yun-Xin , Liu Shu-Qun
Published: February 2022

The receptor-binding domain (RBD) of the SARS-CoV-2 spike protein mediates viral entry into host cells through binding to the cell-surface receptor angiotensin-converting enzyme 2 (ACE2). It has been shown that SARS-CoV-2 RBD (RBDCoV2) has a higher binding affinity to human ACE2 than its highly homologous SARS-CoV RBD (RBDCoV), for which the mechanistic reasons still remain to be elucidated. Here, we used the multiple-replica molecular dynamics (MD) simulations, molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) binding free energy calculations, and interface residue contact network (IRCN) analysis approach to explore the mechanistic origin of different ACE2 binding affinities of these two RBDs. The results demonstrate that, when compared to the RBDCoV2-ACE2 complex, the RBDCoV-ACE2 complex features the enhanced overall structural fluctuations and inter-protein positional movements and increased conformational entropy and diversity. The inter-protein electrostatic attractive interactions are a dominant force in determining the high ACE2 affinities of both RBDs, while the significantly strengthened electrostatic forces of attraction of ACE2 to RBDCoV2 determine the higher ACE2 binding affinity of RBDCoV2 than of RBDCoV. Comprehensive comparative analyses of the residue binding free energy components and IRCNs reveal that, although any RBD residue substitution involved in the charge change can significantly impact the inter-protein electrostatic interaction strength, it is the substitutions at the RBD interface that lead to the overall stronger electrostatic attractive force of RBDCoV2-ACE2, which in turn not only tightens the interface packing and suppresses the dynamics of RBDCoV2-ACE2, but also enhances the ACE2 binding affinity of RBDCoV2 compared to that of RBDCoV. Since the RBD residue substitutions involving gain/loss of the positively/negatively charged residues, in particular those near/at the binding interfaces with the potential to form hydrogen bonds and/or salt bridges with ACE2, can greatly enhance the ACE2 binding affinity, the SARS-CoV-2 variants carrying such mutations should be paid special attention to.
Development of Prognostic Models for Survival and Care Status in Sporadic Creutzfeldt-Jakob disease
Authors: Nihat Akın , Ranson Janice M. , Harris Dominique , McNiven Kirsty , Rudge Peter , Collinge John , Llewellyn David J. , Mead Simon
Published: February 2022

Sporadic Creutzfeldt-Jakob disease (sCJD), the most common human prion disease, typically presents as a rapidly progressive dementia and has a highly variable prognosis. Despite this heterogeneity, clinicians need to give timely advice on likely prognosis and care needs. No prognostic models have been developed that predict survival or time to increased care status from the point of diagnosis. We aimed to develop clinically useful prognostic models with data from a large prospective observational cohort study. 537 patients were visited by mobile teams of doctors and nurses from the NHS National Prion Clinic within 5 days of notification of a suspected diagnosis of sCJD, enrolled to the study between October 2008 and March 2020, and followed up until November 2020. Prediction of survival over 10-, 30- and 100-day periods was the main outcome. Escalation of care status over the same time periods was a secondary outcome for a subsample of 113 patients with low care status at initial assessment. 280 (52.1%) patients were female and the median age was 67.2 (IQR 10.5) years. Median survival from initial assessment was 24 days (range 0-1633); 414 patients died within 100 days (77%). Ten variables were included in the final prediction models: sex; days since symptom onset; baseline care status; PRNP codon 129 genotype; MRC (Medical Research Council) Prion Disease Rating Scale, Motor and Cognitive Examination Scales; count of MRI abnormalities; Mini-Mental State Examination score and categorical sCJD phenotype. The strongest predictor was PRNP codon 129 genotype (odds ratio 6.65 for MM compared to MV polymorphism; 95% CI 3.02-14.68 for 30-day mortality). Of 113 patients with lower care status at initial assessment, 88 (78%) had escalated care status within 100 days, with a median of 35 days. Area under the curve for models predicting outcomes within 10, 30 and 100 days was 0.94, 0.92 and 0.91 for survival, and 0.87, 0.87 and 0.95 for care status escalation respectively. Models without PRNP codon 129 genotype, which is not immediately available at initial assessment, were also highly accurate. We have developed a model that can accurately predict survival and care status escalation in sCJD patients using clinical, imaging and genetic data routinely available in a tertiary national referral service. The utility and generalizability of these models to other settings could be prospectively evaluated when recruiting to clinical trials and providing clinical care.
Research Letter: Genetically determined blood pressure traits are associated with increased risk of aortic dissection: a Mendelian randomization study
Authors: Zhou Jiawei , Lin Jianfeng , Zheng Yuehong
Published: February 2022

Objective

To identify blood pressure traits influencing aortic dissection susceptibility using Mendelian randomization (MR).

Methods

Summary statistics of AD genome-wide association studies (GWAS) was obtained from FinnGen R5 release, which included 470 individuals with AD and 206541 controls. Firstly, inverse variance weighted (IVW) was used to calculate the overall OR for blood pressure traits. Further, directional pleiotropy and heterogeneity were tested as well as MR pleiotropy residual sum and outlier (MR-PRESSO) method.

Results

Positive associations were observed between DBP (OR=1.13, 95%CI 1.09-1.18, P-adjusted < 0.001), hypertension (OR=9.71, 95%CI 2.45-38.25, P-adjusted = 0.006) and AD. Further, there was potential causal relationship between MAP and AD (OR=1.15, 95%CI 1.02-1.30, P-unadjusted = 0.020). No significant association between SBP or PP and AD in the European populations were observed. No directional pleiotropy was observed. Heterogeneity was only detected in the genetic instruments for SBP (Cochran’s Q statistics = 491.7, P = 0.010). The MR-PRESSO suggested one outlier SNP for SBP and one for PP which did not affect the result above.

Conclusion

In this study, we identified a forward causation between hypertension, SBP and AD. In addition, there were nominal significant causations between MAP and AD. No significant causal relationships were detected between other investigated blood pressure traits (SBP, PP) and AD.
Protection of COVID-19 vaccination and previous infection against Omicron BA.1, BA.2 and Delta SARS-CoV-2 infections
Authors: Andeweg Stijn P. , de Gier Brechje , Eggink Dirk , van den Ende Caroline , van Maarseveen Noortje , Ali Lubna , Vlaemynck Boris , Schepers Raf ,   RIVM COVID-19 surveillance and epidemiology team, Hahné Susan J.M. , Reusken Chantal B.E.M. , de Melker Hester E. , van den Hof Susan , Knol Mirjam J.
Published: February 2022

Given the emergence of the SARS-CoV-2 Omicron BA.1 and BA.2 variants and the roll-out of booster COVID-19 vaccination, evidence is needed on protection conferred by primary vaccination, booster vaccination and previous SARS-CoV-2 infection by variant.

We employed a test-negative design and used multinomial logistic regression on data from community PCR testing in the Netherlands. S-gene target failure (SGTF) was used as proxy to discern Delta, Omicron BA.1 and Omicron BA.2 infections. Two cohorts were defined to assess protection from vaccination and previous infection by variant: Delta-Omicron BA.1 cohort including data from 22 November 2021 to 7 January 2022 (n = 354,653) and Omicron BA.1-BA.2 cohort including data from 26 January to 31 March 2022 (n = 317,110).

In the Delta-Omicron BA.1 cohort, including 39,889 Delta and 13,915 Omicron BA.1 infections, previous infection, primary vaccination or both protected well against Delta infection (76%, 71%, 92%, respectively, at 7+ months after infection or vaccination). Protection against Omicron BA.1 was much lower compared to Delta infections, but BA.1 estimates were imprecise. In the Omicron BA.1-BA.2 cohort, including 67,887 BA.1 and 41,670 BA.2 infections, protection was similar against Omicron BA.1 compared to BA.2 infection for previous infection (34 and 38% at 7+ months post-infection), primary (39 and 32% at 7+ months post-vaccination) and booster vaccination (68 and 63% at 1 month post-vaccination). Higher protection was observed against all variants in individuals with both vaccination and previous infection compared with either one. Protection against all variants by either vaccination or infection decreased over time since last vaccination or infection.

Primary vaccination with current COVID-19 vaccines and previous SARS-CoV-2 infections offer low protection against Omicron BA.1 and BA.2 infection. Booster vaccination considerably increases protection against Omicron infection, but decreases rapidly after vaccination.
Early genomic, epidemiological, and clinical description of the SARS-CoV-2 Omicron variant in Mexico City
Authors: Cedro-Tanda Alberto , Gómez-Romero Laura , Anda-Jauregui Guillermo de , Garnica-López Dora , Alfaro-Mora Yair , Sánchez-Xochipa Sonia , García-García F. Eulices , Mendoza-Vargas Alfredo , Frías-Jiménez J. Emmanuel , Moreno-Quiroga Bernardo , Campos-Romero Abraham , Luis Moreno-Camacho José , Alcantar-Fernández Jonathan , Ortíz-Ramírez Jesús , Benitez-Gonzalez Mariana , Trejo-Gonzalez Roxana , Aguirre-Chavarria Daniel , Núñez-Martínez Marcela E. , Uribe-Figueroa Laura , Angulo Ofelia , Ruiz Rosaura , Hidalgo-Miranda Alfredo , Herrera Luis A
Published: February 2022

Background

Omicron is the most mutated SARS-CoV-2 variant that has emerged, resulting in viral phenotype alterations, which can affect transmissibility, disease severity, and immune evasiveness. Genomic surveillance of a highly transmissible variant is important in cities with millions of inhabitants and an economic center such as Mexico City. In this work, we describe the early effects of the Omicron variant in Mexico City, exploring its genomic profile and clinical description.

Methodology

We sequenced SARS-CoV-2-positive samples in November and December 2021 and we using the public database GISAID. Haplotype and phylogenetic analyses were performed to genomically characterize Omicron. We used the Mexican federal database toexplore the association with clinical information such as symptoms and vaccination status.

Findings

The first case of Omicron was detected on November 16, 2022, and until December 31, 2021, we observed an increase from 88% in sequenced samples. Nineteen nonsynonymous mutations were found in the Omicron RBD, and we further explored the R346K substitution, which was prevalent in 42% of the samples and associated with immune escape by monoclonal antibodies. In the phylogenetic analysis, we found that there were several independent exchanges between Mexico and the world, and there was an event followed by local transmission that gave rise to most of the Omicron diversity in Mexico City. The haplotype analysis allowed us to observe that there was no association between haplotype and vaccination status. Of the patients with clinical data, 66% were vaccinated, none of the reported comorbidities were associated with Omicron, the presence of odynophagia and absence of dysgeusia were significant predictor symptoms for Omicron, and the Ct value on RT–qPCR was lower in Omicron.

Conclusions

Genomic surveillance in highly populated and fast-moving urban regions such as Mexico City is key to detecting the emergence and spread of SARS-CoV-2 variants in a timely manner, even weeks before the onset of an infection wave, to detect patterns that can inform public health decisions. It is also necessary to continue sequencing to detect the spread of any mutation that may affect the therapeutic efficacy or guide it.
Cumulative seroprevalence among healthcare workers after the first wave of the COVID-19 pandemic in El Salvador, Central America
Authors: Nakagama Yu , Rodriguez-Funes Maria-Virginia , Dominguez Rhina , Candray-Medina Katherine-Sofia , Uemura Naoto , Tshibangu-Kabamba Evariste , Nitahara Yuko , Kaku Natsuko , Kaneko Akira , Kido Yasutoshi
Published: February 2022

Background

The impact of novel coronavirus disease 2019 (COVID-19) on healthcare workers (HCWs) has been under-evaluated in Central America. We performed a seroepidemiological survey at a tertiary healthcare facility in El Salvador, where a large number of confirmed and far more suspected cases of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infected HCWs had been documented during the first wave of the pandemic.

Methods

During January–February 2021, a total 973 HCWs were tested for SARS-CoV-2 antibodies. Participants completed a questionnaire asking of their demographic data. Occupational risk was assessed by statistically comparing the seropositivity rates among different occupational categories.

Results

Overall seroprevalence in HCWs reached 52.6% (512 of 973). Of the seropositive individuals, 61.7% (316 of 512) had experienced a documented COVID-19 diagnosis, while the remaining 38.3% (196 of 512) were unrecognized seroconversions. Differences in seropositivity rates existed between occupational categories; nurses demonstrated the highest at 63.8% (222 of 348, risk ratio 1.44, p < 0.0001), followed by auxiliary HCWs assigned to patient-related work (55.9%, 52 of 93), and medical doctors (46.7%, 50 of 107). Several non-patient-related professions showed above-average seroprevalence, suggesting substantial SARS-CoV-2 contacts outside the workplace: 60.0% (6 of 10) and 68.0% (17 of 25) for nutritionists and pharmacists, respectively.

Conclusions

SARS-CoV-2 seroprevalence exceeded 50% among HCWs in El Salvador, with disparity among occupational categories with different workplace exposure risks. Importance of not only nosocomial infection prevention but also screening for transmissions having occurred outside the workplace were highlighted to efficiently control nosocomial spreads during a pandemic wave.

Key points

Healthcare workers in El Salvador were tested for SARS-CoV-2 antibodies. Seroprevalence reached 52.6%, with disparity among occupation; nurses ranked highest at 63.8% seropositivity. Alongside nosocomial transmissions, high seroprevalence associated with non-patient-related work suggested substantial SARS-CoV-2 contacts outside the workplace.
Development of a Ribosome Profiling Protocol to Study Translation in the yeast Kluyveromyces marxianus
Authors: Fenton Darren A , Kiniry Stephen J , Yordanova Martina M , Baranov Pavel V , Morrissey John P
Published: February 2022

Kluyveromyces marxianus is an interesting and important yeast because of particular traits like thermotolerance and rapid growth, and applications in food and industrial biotechnology. Knowing how K. marxianus responds and adapts to changing environments is important to achieve a full understanding of the its biology and to develop bioprocesses. For this, a full suite of omics tools to measure and compare global patterns of gene expression and protein synthesis is needed. Whereas transcriptome analysis by RNA-Seq quantifies mRNA abundance, ribosome profiling allows codon-resolution of translation on a genome-wide scale by deep sequencing of ribosome locations on mRNAs and is emerging as a valuable tool to study translation control of gene expression. We report here the development of a ribosome profiling method for K. marxianus and we make the procedure available as a step by step protocol. To aid in the analysis and sharing of ribosome profiling data, we also added the K. marxianus genome as well as transcriptome and ribosome profiling data to the publicly accessible GWIPS-viz and Trips-Viz browsers. Users are able to upload custom ribosome profiling and RNA-Seq data to both browsers, therefore allowing easy analysis and sharing of data. As many studies only focus on the use of RNA-Seq to study K. marxianus in different environments, the availability of ribosome profiling is a powerful addition to the K. marxianus toolbox.

Graphical abstract

Development of a Ribosome Profiling protocol to study gene expression in the thermotolerant yeast Kluyveromyces marxianus.
Entrainment to sleep spindles reflects dissociable patterns of connectivity between cortex and basal ganglia
Authors: Mizrahi-Kliger Aviv D. , Kaplan Alexander , Israel Zvi , Bergman Hagai
Published: February 2022

Communication between the basal ganglia (BG) and cortex is crucial for behavior as it allows learning through external reinforcement. Non-REM sleep benefits learning in the corticostriatal system through the sleep spindle-associated reactivation of previously active neuronal ensembles and the subsequent modification of synaptic weights. However, how sleep spindles coordinate cross-region spiking, and whether spindle-driven reactivation occurs in other BG structures, remains unknown. We recorded field potentials (FP) and spiking activity in cortex and BG during sleep in two non-human primates immediately following a task that involved the learning of new cue-reward contingencies. FP sleep spindles were widespread in the BG, and they were similar to cortical spindles in morphology, spectral content and response to learning prior to sleep. Further, BG FP spindles were concordant with EEG spindles and associated with increased cortico-BG correlation. However, spindles across the BG differed markedly in their entrainment of local spiking. The spiking activity of striatal projection neurons exhibited consistent phase locking to striatal FP spindles and EEG spindles, producing phase windows of peaked cross-region spindling. In contrast, in the subthalamic nucleus (STN), which like the striatum receives substantial thalamocortical input, and in BG nuclei downstream to the striatum and STN, neuronal firing was not entrained to either local or EEG sleep spindles. These results dissociate striatal projection neurons from the rest of the BG, and suggest corticostriatal synapses as the main hub for offline communication between cortex and BG.
Assessing human genome-wide variation in the Massim region of Papua New Guinea and implications for the Kula trading tradition
Authors: Liu Dang , Peter Benjamin M. , Schiefenhövel Wulf , Kayser Manfred , Stoneking Mark
Published: February 2022

The Massim, a cultural region encompassing the southeastern tip of mainland Papua New Guinea (PNG) and nearby islands, is famous for the Kula trading network, in which different valuables circulate in different directions among the islands. To explore Massim genetic history, we generated genome-wide data from across the region and found variable levels of Papuan-related (indigenous) ancestry, including a novel ancestry associated with Rossel Island, and Austronesian-related ancestry that arrived later. We find genetic evidence for different patterns of contact across PNG, the Massim, and the Bismarck and Solomon Archipelagoes for Austronesian-related vs. Papuan-related ancestry, with more geographic restriction for the latter. Moreover, Kula-practicing groups share more genetic similarity than do other groups, and this likely predates the origin of Kula, suggesting that high between-group contact facilitated the formation of Kula. Our study provides the first comprehensive genome-wide assessment of Massim inhabitants and new insights into the fascinating Kula system.
Vaccine Protection Against the SARS-CoV-2 Omicron Variant in Macaques
Authors: Chandrashekar Abishek , Yu Jingyou , McMahan Katherine , Jacob-Dolan Catherine , Liu Jinyan , He Xuan , Hope David , Anioke Tochi , Barrett Julia , Chung Benjamin , Hachmann Nicole P. , Lifton Michelle , Miller Jessica , Powers Olivia , Sciacca Michaela , Sellers Daniel , Siamatu Mazuba , Surve Nehalee , VanWyk Haley , Wan Huahua , Wu Cindy , Pessaint Laurent , Valentin Daniel , Van Ry Alex , Muench Jeanne , Boursiquot Mona , Cook Anthony , Velasco Jason , Teow Elyse , Boon Adrianus C.M. , Suthar Mehul S. , Jain Neharika , Martinot Amanda J. , Lewis Mark G. , Andersen Hanne , Barouch Dan H.
Published: February 2022

Background

The rapid spread of the SARS-CoV-2 Omicron (B.1.1.529) variant, including in highly vaccinated populations, has raised important questions about the efficacy of current vaccines. Immune correlates of vaccine protection against Omicron are not known.

Methods

30 cynomolgus macaques were immunized with homologous and heterologous prime-boost regimens with the mRNA-based BNT162b2 vaccine and the adenovirus vector-based Ad26.COV2.S vaccine. Following vaccination, animals were challenged with the SARS-CoV-2 Omicron variant by the intranasal and intratracheal routes.

Results

Omicron neutralizing antibodies were observed following the boost immunization and were higher in animals that received BNT162b2, whereas Omicron CD8+ T cell responses were higher in animals that received Ad26.COV2.S. Following Omicron challenge, sham controls showed more prolonged virus in nasal swabs than in bronchoalveolar lavage. Vaccinated macaques demonstrated rapid control of virus in bronchoalveolar lavage, and most vaccinated animals also controlled virus in nasal swabs, showing that current vaccines provide substantial protection against Omicron in this model. However, vaccinated animals that had moderate levels of Omicron neutralizing antibodies but negligible Omicron CD8+ T cell responses failed to control virus in the upper respiratory tract. Virologic control correlated with both antibody and T cell responses.

Conclusions

BNT162b2 and Ad26.COV2.S provided robust protection against high-dose challenge with the SARS-CoV-2 Omicron variant in macaques. Protection against this highly mutated SARS-CoV-2 variant correlated with both humoral and cellular immune responses.
Impaired resolution of blood transcriptomes through tuberculosis treatment with diabetes comorbidity
Authors: Eckold Clare , van Doorn Cassandra L.R. , Ruslami Rovina , Ronacher Katharina , Riza Anca-Lelia , van Veen Suzanne , Lee Ji-Sook , Kumar Vinod , Kerry-Barnard Sarah , Malherbe Stephanus T. , Kleynhans Léanie , Stanley Kim , Joosten Simone A. , Critchley Julia A , Hill Philip C. , van Crevel Reinout , Wijmenga Cisca , Haks Mariëlle C. , Ioana Mihai , Alisjahbana Bachti , Walzl Gerhard , Ottenhoff Tom H. M. , Dockrell Hazel M. , Vianello Eleonora , Cliff Jacqueline M.
Published: February 2022

Background

People with diabetes are more likely to develop tuberculosis (TB) and to have poor TB treatment outcomes than those without. We previously showed that blood transcriptomes in people with TB-diabetes (TB-DM) co-morbidity have excessive inflammatory and reduced interferon responses at TB diagnosis. It is unknown whether this persists through treatment, potentially underlying adverse outcomes.

Methods

Pulmonary TB patients were recruited in South Africa, Indonesia and Romania, and classified as having TB-DM, TB with prediabetes, TB-related hyperglycaemia or uncomplicated TB, based on glycated haemoglobin (HbA1c) concentration at TB diagnosis and after 6 months of TB treatment. Gene expression in blood samples collected at diagnosis and at regular intervals throughout treatment was measured by unbiased RNA-Seq and targeted Multiplex Ligation-dependent Probe Amplification.

Results

Gene expression was modulated by TB treatment in all groups but to different extents, such that differences remained in people with TB-DM relative to TB-only throughout, including genes involved in innate responses, anti-microbial immunity and the inflammasome. People with prediabetes or with TB-related hyperglycaemia had gene expression more similar to people with TB-DM than TB-only throughout treatment. The overall pattern of change was similar across clinical groups irrespective of glycaemic index, permitting models predictive of TB treatment to be developed.

Conclusions

The exacerbated transcriptome changes seen in TB-DM take longer to resolve during TB treatment, indicating that prolonged treatment or host-directed therapy may be needed to improve TB treatment outcomes. Development of transcriptome-based biomarker signatures of TB-treatment response should include people with diabetes to be useful across populations.

Key Points

Host blood transcriptomes are altered in tuberculosis, and further altered with diabetes co-morbidity. We have shown that there is similar resolution of transcriptomes through treatment, but with differing magnitude and kinetics in TB patients with or without diabetes.
Increased household transmission and immune escape of the SARS-CoV-2 Omicron variant compared to the Delta variant: evidence from Norwegian contact tracing and vaccination data
Authors: Jalali Neda , Brustad Hilde K. , Frigessi Arnoldo , MacDonald Emily , Meijerink Hinta , Feruglio Siri , Nygård Karin , Rø Gunnar Isaksson , Madslien Elisabeth H. , De Blasio Birgitte Freiesleben
Published: February 2022

Understanding the rapid epidemic growth of the novel SARS-CoV-2 Omicron variant is critical for public health management. We compared the secondary attack rate (SAR) of the Omicron and Delta variants in households using Norwegian contact tracing data from December 2021 to January 2022. Omicron SAR was higher (51%) than Delta (36%), with a relative risk (RR) of 1.41 (95% CI 1.27-1.56). We observed increased susceptibility to Omicron infection in household contacts compared to Delta independent of vaccination status; however, considering booster vaccinated contacts, the mean SAR was lower for both variants. We found increased Omicron transmissibility in all vaccination groups of primary cases, except partially vaccinated, compared to Delta. In particular, Omicron SAR for boosted primary cases was high, 46% vs 11 % for Delta (RR 4.34; 95% CI 1.52-25.16). In conclusion, booster doses decrease the infection risk of Delta and Omicron but have limited effect in preventing Omicron transmission.