This study looked to investigate a new quantitative metric, R₂  - R_1ρ (1/T₂  - 1/T_1ρ ), using magnetic resonance (MR) images and voxel-based relaxometry (VBR) for detecting early cartilage degeneration and explore the association with patient-reported outcomes measures (PROMs) in patients 6 months after ACL reconstruction. Sixty-four patients from three sites were bilaterally scanned on a 3T MR with a combined T_1ρ /T₂ protocol to calculate R_1ρ (1/T_1ρ ) and R₂ (1/T₂ ) values at baseline and 6 months after reconstructive surgery. Non-rigid registration was applied to align images onto a template, allowing VBR to determine VBR rate differences and explore cross-sectional and longitudinal differences between injured and uninjured knees, generating Statistical Parametric Maps (SPMs). Baseline R₂  - R_1ρ differences were further correlated with change in PROMs from the Knee Injury and Osteoarthritis Outcome Score (KOOS) from baseline to 6 months. Cross-sectional results demonstrated low relaxation rate differences in the injured patella (baseline: 21%, p = 0.01; 6-months: 18%, p = 0.02), lateral tibia (baseline: 25%, p = 0.01; 6-months: 24%, p = 0.01), and weight-bearing regions of the tibia and femur. The uninjured patella showed significant longitudinal changes (17%, p = 0.02). R₂  - R_1ρ differences showed significant correlations with KOOS PROMs, particularly in the lateral tibia, patella, and trochlea. R₂  - R_1ρ difference VBR analyses provide new and highly sensitive parameters for assessing early cartilage degeneration in patients after ACL injury by integrating findings from both T_1ρ and T₂ , commonly used relaxation time parameters, into a single metric. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:718-729, 2017.

Human seasonal influenza viruses evolve rapidly, enabling the virus population to evade immunity and reinfect previously infected individuals. Antigenic properties are largely determined by the surface glycoprotein hemagglutinin (HA), and amino acid substitutions at exposed epitope sites in HA mediate loss of recognition by antibodies. Here, we show that antigenic differences measured through serological assay data are well described by a sum of antigenic changes along the path connecting viruses in a phylogenetic tree. This mapping onto the tree allows prediction of antigenicity from HA sequence data alone. The mapping can further be used to make predictions about the makeup of the future A(H3N2) seasonal influenza virus population, and we compare predictions between models with serological and sequence data. To make timely model output readily available, we developed a web browser-based application that visualizes antigenic data on a continuously updated phylogeny.

Background

Quantitative MR, including T_1ρ mapping, has been extensively used to probe early biochemical changes in knee articular cartilage of subjects with osteoarthritis (OA) and others at risk for cartilage degeneration, such as those with anterior cruciate ligament (ACL) injury and reconstruction. However, limited studies have been performed aimed to assess the spatial location and patterns of T_1ρ. In this study we used a novel voxel-based relaxometry (VBR) technique coupled with principal component analysis (PCA) to extract relevant features so as to describe regional patterns and to investigate their similarities and differences in T_1ρ maps in subjects with OA and subjects six months after ACL reconstruction (ACLR).

Methods

T_1ρ quantitative MRI images were collected for 180 subjects from two separate cohorts. The OA cohort included 93 osteoarthritic patients and 25 age-matched controls. The ACLR-6M cohort included 52 patients with unilateral ACL tears who were imaged 6 months after ACL reconstruction, and 10 age-matched controls. Non-rigid registration on a single template and local Z-score conversion were adopted for T_1ρ spatial and intensity normalization of all the images in the dataset. PCA was used as a data dimensionality reduction to obtain a description of all subjects in a 10-dimensional feature space. Logistic linear regression was used to identify distinctive features of OA and ACL subjects.

Results

Global prolongation of the Z-score was observed in both OA and ACL subjects compared to controls [higher values in 1^st principal component (PC1); P=0.01]. In addition, relaxation time differences between superficial and deep cartilage layers of the lateral tibia and trochlea were observed to be significant distinctive features between OA and ACL subjects. OA subjects demonstrated similar values between the two cartilage layers [higher value in 2^nd principal component (PC2); P=0.008], while ACL reconstructed subjects showed T_1ρ prolongation specifically in the cartilage superficial layer (lower values in PC2; P<0.0001). T_1ρ elevation located outside of the weight-bearing area, located in the posterior and anterior aspects of the lateral femoral compartment, was also observed to be a key feature in distinguishing OA subjects from controls [higher value in 6^th principal component (PC6); P=0.007].

Conclusions

This study is the first example of T_1ρ local/regional pattern analysis and data-driven feature extraction in knees with cartilage degeneration. Our results revealed similarities and differences between OA and ACL relaxation patterns that could be potentially useful to better understand the pathogenesis of post-traumatic cartilage degeneration and the identification of imaging biomarkers for the early stratification of subjects at risk for developing post-traumatic OA.

In this multi-center study, voxel-based relaxometry (VBR), a novel technique to automatically quantify localized cartilage change, was used to investigate T_1ρ and T₂ relaxation times of patients with anterior cruciate ligament (ACL) tears at the time of injury and 6 months after reconstructive surgery. Sixty-four ACL-injured patients from three sites underwent bilateral 3T MR T_1ρ and T₂ mapping; 56 patients returned 6 months after surgery. Cross-sectional and longitudinal VBR comparisons of relaxation times were calculated. Noyes Score (NS) clinical grades of cartilage lesions were noted at both times and correlated with relaxation times. Lastly, patients were divided into two groups based on baseline NS grades in the injured knee. T_1ρ times of each group were assessed with VBR and compared. Results illustrate the feasibility of VBR for efficiently analyzing data from patients at different sites. Significant relaxation time elevations at baseline were observed in the injured knee compared to the uninjured, particularly in the posterolateral tibia (pLT). Longitudinally, a decrease was observed in the pLT and patella, while an increase was noted in the trochlea. Stratifying patients by baseline lesion presence revealed T_1ρ increased more 6 months after surgery in patients with lesions. Such findings propose that the presence of cartilage lesions at baseline are associated with the longitudinal progression of T_1ρ and T₂ after ACL injury, and may contribute to early cartilage degeneration. Furthermore, the speed and localized specificity of automatic VBR analysis may translate well for clinical application, as seen in this multicenter study. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:688-698, 2017.

Information on global human movement patterns is central to spatial epidemiological models used to predict the behavior of influenza and other infectious diseases. Yet it remains difficult to test which modes of dispersal drive pathogen spread at various geographic scales using standard epidemiological data alone. Evolutionary analyses of pathogen genome sequences increasingly provide insights into the spatial dynamics of influenza viruses, but to date they have largely neglected the wealth of information on human mobility, mainly because no statistical framework exists within which viral gene sequences and empirical data on host movement can be combined. Here, we address this problem by applying a phylogeographic approach to elucidate the global spread of human influenza subtype H3N2 and assess its ability to predict the spatial spread of human influenza A viruses worldwide. Using a framework that estimates the migration history of human influenza while simultaneously testing and quantifying a range of potential predictive variables of spatial spread, we show that the global dynamics of influenza H3N2 are driven by air passenger flows, whereas at more local scales spread is also determined by processes that correlate with geographic distance. Our analyses further confirm a central role for mainland China and Southeast Asia in maintaining a source population for global influenza diversity. By comparing model output with the known pandemic expansion of H1N1 during 2009, we demonstrate that predictions of influenza spatial spread are most accurate when data on human mobility and viral evolution are integrated. In conclusion, the global dynamics of influenza viruses are best explained by combining human mobility data with the spatial information inherent in sampled viral genomes. The integrated approach introduced here offers great potential for epidemiological surveillance through phylogeographic reconstructions and for improving predictive models of disease control.

Influenza viruses undergo continual antigenic evolution allowing mutant viruses to evade host immunity acquired to previous virus strains. Antigenic phenotype is often assessed through pairwise measurement of cross-reactivity between influenza strains using the hemagglutination inhibition (HI) assay. Here, we extend previous approaches to antigenic cartography, and simultaneously characterize antigenic and genetic evolution by modeling the diffusion of antigenic phenotype over a shared virus phylogeny. Using HI data from influenza lineages A/H3N2, A/H1N1, B/Victoria and B/Yamagata, we determine patterns of antigenic drift across viral lineages, showing that A/H3N2 evolves faster and in a more punctuated fashion than other influenza lineages. We also show that year-to-year antigenic drift appears to drive incidence patterns within each influenza lineage. This work makes possible substantial future advances in investigating the dynamics of influenza and other antigenically-variable pathogens by providing a model that intimately combines molecular and antigenic evolution. DOI: http://dx.doi.org/10.7554/eLife.01914.001.

INTRODUCTION: Malawi is rapidly closing the gap in achieving the UNAIDS 95-95-95 targets, with 90% of people living with HIV in Malawi aware of their status. As we approach epidemic control, interventions to improve coverage will become more costly. There is, therefore, an urgent need to identify innovative and low-cost strategies to maintain and increase testing coverage without diverting resources from other HIV services. The objective of this study is to model different combinations of facility-based HIV testing modalities and determine the most cost-effective strategy to increase the proportion of men and youth testing for HIV. METHODS: A data-driven individual-based model was parameterized with data from a community-representative survey (socio-demographic, health service utilization and HIV testing history) of men and youth in Malawi (data collected August 2019). In total, 79 different strategies for the implementation of HIV self-testing (HIVST) and provider-initiated-testing-and-counselling at the outpatient department (OPD) were evaluated. Outcomes included percent of men/youth tested for HIV in a 12-month period, cost-effectiveness and human resource requirements. The testing yield was assumed to be constant across the scenarios. RESULTS: Facility-based HIVST offered year-round resulted in the greatest increase in the proportion of men and youth tested in the OPD (from 45% to 72%-83%), was considered cost-saving for HIVST kit priced at $1.00, and generally reduced required personnel as compared to the status quo. At higher HIVST kit prices, and more relaxed eligibility criteria, all scenarios that considered year-round HIVST in the OPD remained on the cost-effectiveness frontier. CONCLUSIONS: Facility-based HIVST is a cost-effective strategy to increase the proportion of men/youth tested for HIV in Malawi and decreases the human resource requirements for HIV testing in the OPD-providing additional healthcare worker time for other priority healthcare activities.

It remains poorly understood how SARS-CoV-2 infection influences the physiological host factors important for aerosol transmission. We assessed breathing pattern, exhaled droplets, and infectious virus after infection with Alpha and Delta variants of concern (VOC) in the Syrian hamster. Both VOCs displayed a confined window of detectable airborne virus (24-48 hr), shorter than compared to oropharyngeal swabs. The loss of airborne shedding was linked to airway constriction resulting in a decrease of fine aerosols (1-10 µm) produced, which are suspected to be the major driver of airborne transmission. Male sex was associated with increased viral replication and virus shedding in the air. Next, we compared the transmission efficiency of both variants and found no significant differences. Transmission efficiency varied mostly among donors, 0-100% (including a superspreading event), and aerosol transmission over multiple chain links was representative of natural heterogeneity of exposure dose and downstream viral kinetics. Co-infection with VOCs only occurred when both viruses were shed by the same donor during an increased exposure timeframe (24-48 hr). This highlights that assessment of host and virus factors resulting in a differential exhaled particle profile is critical for understanding airborne transmission.

The threat of an influenza A virus pandemic stems from continual virus spillovers from reservoir species, a tiny fraction of which spark sustained transmission in humans. To date, no pandemic emergence of a new influenza strain has been preceded by detection of a closely related precursor in an animal or human. Nonetheless, influenza surveillance efforts are expanding, prompting a need for tools to assess the pandemic risk posed by a detected virus. The goal would be to use genetic sequence and/or biological assays of viral traits to identify those non-human influenza viruses with the greatest risk of evolving into pandemic threats, and/or to understand drivers of such evolution, to prioritize pandemic prevention or response measures. We describe such efforts, identify progress and ongoing challenges, and discuss three specific traits of influenza viruses (hemagglutinin receptor binding specificity, hemagglutinin pH of activation, and polymerase complex efficiency) that contribute to pandemic risk.

Understanding the spatiotemporal patterns of emergence and circulation of new human seasonal influenza virus variants is a key scientific and public health challenge. The global circulation patterns of influenza A/H3N2 viruses are well characterized, but the patterns of A/H1N1 and B viruses have remained largely unexplored. Here we show that the global circulation patterns of A/H1N1 (up to 2009), B/Victoria, and B/Yamagata viruses differ substantially from those of A/H3N2 viruses, on the basis of analyses of 9,604 haemagglutinin sequences of human seasonal influenza viruses from 2000 to 2012. Whereas genetic variants of A/H3N2 viruses did not persist locally between epidemics and were reseeded from East and Southeast Asia, genetic variants of A/H1N1 and B viruses persisted across several seasons and exhibited complex global dynamics with East and Southeast Asia playing a limited role in disseminating new variants. The less frequent global movement of influenza A/H1N1 and B viruses coincided with slower rates of antigenic evolution, lower ages of infection, and smaller, less frequent epidemics compared to A/H3N2 viruses. Detailed epidemic models support differences in age of infection, combined with the less frequent travel of children, as probable drivers of the differences in the patterns of global circulation, suggesting a complex interaction between virus evolution, epidemiology, and human behaviour.