Circulating influenza viruses evade neutralization in their human hosts by acquiring escape mutations at epitopes of prevalent antibodies. A goal for next-generation influenza vaccines is to reduce ...escape likelihood by selectively eliciting antibodies recognizing conserved surfaces on the viral hemagglutinin (HA). The receptor-binding site (RBS) on the HA “head” and a region near the fusion peptide on the HA “stem” are two such sites. We describe here a human antibody clonal lineage, designated CL6649, members of which bind a third conserved site (“lateral patch”) on the side of the H1-subtype, HA head. A crystal structure of HA with bound Fab6649 shows the conserved antibody footprint. The site was invariant in isolates from 1977 (seasonal) to 2012 (pdm2009); antibodies in CL6649 recognize HAs from the entire period. In 2013, human H1 viruses acquired mutations in this epitope that were retained in subsequent seasons, prompting modification of the H1 vaccine component in 2017. The mutations inhibit Fab6649 binding. We infer from the rapid spread of these mutations in circulating H1 influenza viruses that the previously subdominant, conserved lateral patch had become immunodominant for individuals with B-cell memory imprinted by earlier H1 exposure. We suggest that introduction of the pdm2009 H1 virus, to which most of the broadly prevalent, neutralizing antibodies did not bind, conferred a selective advantage in the immune systems of infected hosts to recall of memory B cells that recognized the lateral patch, the principal exposed epitope that did not change when pdm2009 displaced previous seasonal H1 viruses.
Affinity maturation of the B cell antigen receptor (BCR) is a conserved and crucial component of the adaptive immune response. BCR lineages, inferred from paired heavy- and light-chain sequences of ...rearranged Ig genes from multiple descendants of the same naive B cell precursor (the lineages’ unmutated common ancestor, “UCA”), make it possible to reconstruct the underlying somatic evolutionary history. We present here an extensive structural and biophysical analysis of a lineage of BCRs directed against the receptor binding site (RBS) of subtype H1 influenza virus hemagglutinin (HA). The lineage includes 8 antibodies detected directly by sequencing, 3 in 1 principal branch and 5 in the other. When bound to HA, the heavy-chain third complementarity determining region (HCDR3) fits with an invariant pose into the RBS, but in each of the 2 branches, the rest of the Fab reorients specifically, from its position in the HA-bound UCA, about a hinge at the base of HCDR3. New contacts generated by the reorientation compensate for contacts lost as the H1 HA mutated during the time between the donor’s initial exposure and the vaccination that preceded sampling. Our data indicate that a “pluripotent” naive response differentiated, in each branch, into 1 of its possible alternatives. This property of naive BCRs and persistence of multiple branches of their progeny lineages can offer broader protection from evolving pathogens than can a single, linear pathway of somatic mutation.
For broad protection against infection by viruses such as influenza or HIV, vaccines should elicit antibodies that bind conserved viral epitopes, such as the receptor-binding site (RBS). RBS-directed ...antibodies have been described for both HIV and influenza virus, and the design of immunogens to elicit them is a goal of vaccine research in both fields. Residues in the RBS of influenza virus hemagglutinin (HA) determine a preference for the avian or human receptor, α-2,3-linked sialic acid and α-2,6-linked sialic acid, respectively. Transmission of an avian-origin virus between humans generally requires one or more mutations in the sequences encoding the influenza virus RBS to change the preferred receptor from avian to human, but passage of a human-derived vaccine candidate in chicken eggs can select for reversion to avian receptor preference. For example, the X-181 strain of the 2009 new pandemic H1N1 influenza virus, derived from the A/California/07/2009 isolate and used in essentially all vaccines since 2009, has arginine at position 226, a residue known to confer preference for an α-2,3 linkage in H1 subtype viruses; the wild-type A/California/07/2009 isolate, like most circulating human H1N1 viruses, has glutamine at position 226. We describe, from three different individuals, RBS-directed antibodies that recognize the avian-adapted H1 strain in current influenza vaccines but not the circulating new pandemic 2009 virus; Arg226 in the vaccine-strain RBS accounts for the restriction. The polyclonal sera of the three donors also reflect this preference. Therefore, when vaccines produced from strains that are never passaged in avian cells become widely available, they may prove more capable of eliciting RBS-directed, broadly neutralizing antibodies than those produced from egg-adapted viruses, extending the established benefits of current seasonal influenza immunizations.
With initiation of transcatheter aortic valve replacement (TAVR) programs, centers may see changes in surgical aortic valve replacement (SAVR) populations and related outcomes because of more ...high-risk patients undergoing TAVR rather than SAVR. Little data exist on the potential changes in the risk profiles and outcomes of SAVR patients from the pre- to post-TAVR eras. As such, this study sought to evaluate changes in the SAVR population at a tertiary referral center after TAVR program initiation.
Using a single-center valve surgical database, annual volume, patient characteristics, operative details, and predicted and observed mortality for patients undergoing isolated SAVR or SAVR + coronary artery bypass grafting (CABG) from 2006 to 2013 were evaluated. Patients were divided into 3 eras: (1) pre-TAVR (January 2006-June 2009), (2) transition (July 2009-March 2011), and (3) TAVR (April 2011-June 2013). The primary analysis compared predicted and observed mortality in pre-TAVR and TAVR eras.
From 2006 to 2013, 1,380 SAVR patients were identified, with 505 (36.6%), 330 (23.9%), and 545 (39.5%) patients from the pre-TAVR, transition, and TAVR eras, respectively. SAVR case volume increased from 131 to 256 cases per year (95.4% increase) from the pre-TAVR to the post-TAVR eras. Predicted risk of mortality (PROM) for SAVR patients from the pre-TAVR to TAVR eras by The Society of Thoracic Surgeons (STS)-PROM was stable near 3.8% (p = 0.82). Crude 30-day SAVR mortality trended down from 2.8% in the pre-TAVR era to 1.5% in the post-TAVR era (p = 0.23).
Consistent with previous studies, initiation of a TAVR program was associated with increased SAVR volume. Risk profiles for SAVR patients in the TAVR era remained similar by the STS-PROM, indicating generally stable risk among surgical patients after launching a TAVR program. These data suggest that significant changes in the risk profiles of SAVR patients should not be expected with the initiation of a TAVR program. Further research will need to reevaluate these changes once TAVR becomes more widely available.
Computer analysis of digitized vertebral body corners on lateral cervical radiographs.
Using elliptical and circular modeling, the geometric shape of the path of the posterior bodies of C2-C7 was ...sought in normal, acute pain, and chronic pain subjects. To determine the least squares error per point for paths of geometric shapes, minor axis to major axis elliptical ratios (b/a), Cobb angles, sagittal balance of C2 above C7, and posterior tangent segmental and global angles.
When restricted to cervical lordotic configurations, normal, acute pain, and chronic pain subjects have not been compared for similarities or differences of these parameters. Conventional Cobb angles provide only a comparison of the endplates of the distal vertebrae, while geometric modeling provides the shape of the entire sagittal curves, the orientation of the spine, and segmental angles.
Radiographs of 72 normal subjects, 52 acute neck pain subjects, and 70 chronic neck pain subjects were digitized. For normal subjects, the inclusion criteria were no kyphotic cervical segments, no cranial-cervical symptoms, and less than +/- 10 mm horizontal displacement of C2 above C7. In pain subjects, inclusion criteria were no kyphotic cervical segments and less than 25 mm of horizontal displacement of C2 above C7. Measurements included segmental angles, global angles of lordosis (C1-C7 and C2-C7), height-to-length ratios, anterior weight bearing, and from modeling, circular center, and radius of curvature.
In the normal group, a family of ellipses was found to closely approximate the posterior body margins of C2-C7 with a least squares error of less than 1 mm per vertebral body point. The only ellipse/circle found to include T1, with a least squares error of less than 1 mm, was a circle. Compared with the normal group, the pain group's mean radiographic angles were reduced and the radius of curvature was larger. For normal, acute, and chronic pain groups, the mean angles between posterior tangents on C2-C7 were 34.5 degrees, 28.6 degrees, and 22.0 degrees, C2-C7 Cobb angles were 26.8 degrees, 16.5 degrees, and 12.7 degrees, and radius of curvature were r = 132.8 mm, r = 179 mm, and r = 245.4 mm, respectively.
The mean cervical lordosis for all groups could be closely modeled with a circle. Pain groups had hypolordosis and larger radiuses of curvature compared with the normal group. Circular modeling may be a valuable tool in the discrimination between normal lordosis and hypolordosis in normal and pain subjects.
Neutralizing antibodies elicited by HIV-1 coevolve with viral envelope proteins (Env) in distinctive patterns, in some cases acquiring substantial breadth. We report that primary HIV-1 envelope ...proteins-when expressed by simian-human immunodeficiency viruses in rhesus macaques-elicited patterns of Env-antibody coevolution very similar to those in humans, including conserved immunogenetic, structural, and chemical solutions to epitope recognition and precise Env-amino acid substitutions, insertions, and deletions leading to virus persistence. The structure of one rhesus antibody, capable of neutralizing 49% of a 208-strain panel, revealed a V2 apex mode of recognition like that of human broadly neutralizing antibodies (bNAbs) PGT145 and PCT64-35S. Another rhesus antibody bound the CD4 binding site by CD4 mimicry, mirroring human bNAbs 8ANC131, CH235, and VRC01. Virus-antibody coevolution in macaques can thus recapitulate developmental features of human bNAbs, thereby guiding HIV-1 immunogen design.
Structure-based vaccine design depends on extensive structural analyses of antigen–antibody complexes.Single-particle electron cryomicroscopy (cryoEM) can circumvent some of the problems of x-ray ...crystallography as a pipeline for obtaining the required structures. We have examined the potential of single-particle cryoEM for determining the structure of influenza-virus hemagglutinin (HA):single-chain variable-domain fragment complexes, by studying a complex we failed to crystallize in pursuing an extended project on the human immune response to influenza vaccines.The result shows that a combination of cryoEM and molecular modeling can yield details of the antigen-antibody interface, although small variation in the twist of the rod-likeHA trimer limited the overall resolution to about 4.5Å.Comparison of principal 3D classes suggests ways to modify the HA trimer to overcome this limitation. A closely related antibody from the same donor did yield crystals when bound with the same HA, giving us an independent validation of the cryoEM results.The two structures also augment our understanding of receptor-binding site recognition by antibodies that neutralize a wide range of influenza-virus variants.
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•Single-particle cryoEM of antigen–antibody complexes•Influenza virus HA bound with single-chain Fv•cryoEM and molecular modeling yield details of the antigen:antibody interface.•HA receptor-binding site recognition by broadly neutralizing antibodies
Thirty lateral cervical radiographs were digitized twice by three examiners to compare reliability of the Cobb and posterior tangent methods.
To determine the reliability of the Cobb and Harrison ...posterior tangent methods and to compare and contrast these two methods.
Cobb's method is commonly used on both anteroposterior and lateral radiographs, whereas the posterior tangent method is not widely used.
A blind, repeated-measures design was used. Thirty lateral cervical radiographs were digitized twice by each of three examiners. To evaluate reliability of determining global and segmental alignment, vertebral bodies of C1-T1 were digitized. Angles created were two global two-line Cobb angles (C1-C7 and C2-C7), segmental Cobb angles from C2 to C7, and posterior tangents drawn at each posterior vertebral body margin. Cobb's method and the posterior tangent method are compared and contrasted with these data.
Of 34 intraclass and interclass correlation coefficients, 28 were in the high range (>0.7), and 6 were in the good range (0.6-0.7). The Cobb method at C1-C7 overestimated the cervical curvature (-54 degrees ) and, at C2-C7 it underestimated the cervical curve (-17 degrees ), whereas the posterior tangents were the slopes along the curve (-26 degrees from C2 to C7). The inferior vertebral endplates and posterior body margins did not meet at 90 degrees (C2: 105 degrees +/- 5.2 degrees, C3: 99.7 degrees +/- 5.2 degrees, C4: 99.9 degrees +/- 5.8 degrees, C5: 96.1 degrees +/- 4.5 degrees, C6: 97.0 degrees +/- 3.8 degrees, C7: 95.4 degrees +/- 4.1 degrees ), which caused the segmental Cobb angles to underestimate lordosis at C2-C3, C4-C5, and C6-C7.
Although both methods are reliable with the majority of correlation coefficients in the high range (ICC > 0.7), from the literature, the posterior tangent method has a smaller standard error of measurement than four-line Cobb methods. Global Cobb angles compare only the ends of the cervical curve and cannot delineate what happens to the curve internally. Posterior tangents are the slopes along the curve and can provide an analysis of any buckled areas of the cervical curve. The posterior tangent method is part of an engineering analysis (first derivative) and more accurately depicts cervical curvature than the Cobb method.
Sagittal profiles of the spine have been hypothesized to influence spinal coupling and loads on spinal tissues.
To assess the relationship between thoracolumbar spine sagittal morphology and ...intervertebral disc loads and stresses.
A cross-sectional study evaluating sagittal X-ray geometry and postural loading in asymptomatic men and women.
Sixty-seven young and asymptomatic subjects (chiropractic students) formed the study group.
Morphological data derived from radiographs (anatomic angles and sagittal balance parameters) and biomechanical parameters (intervertebral disc loads and stresses) derived from a postural loading model.
An anatomically accurate, sagittal plane, upright posture, quadrilateral element model of the anterior spinal column (C2-S1) was created by digitizing lateral full-spine X-rays of 67 human subjects (51 males, 16 females). Morphological measurements of sagittal curvature and balance were compared with intervertebral disc loads and stresses obtained using a quadrilateral element postural loading model.
In this young (mean 26.7, SD 4.8 years), asymptomatic male and female population, the neutral posture spine was characterized by an average thoracic angle (T1-T12)=+43.7° (SD 11.4°), lumbar angle (T12-S1)=−63.2° (SD 10.0°), and pelvic angle=+49.4° (SD 9.9°). Sagittal curvatures exhibited relatively broad frequency distributions, with the pelvic angle showing the least variance and the thoracic angle showing the greatest variance. Sagittal balance parameters, C7-S1 and T1-T12, showed the best average vertical alignment (5.3 mm and −0.04 mm, respectively). Anterior and posterior disc postural loads were balanced at T8-T9 and showed the greatest difference at L5-S1. Disc compressive stresses were greatest in the mid-thoracic region of the spine, whereas shear stresses were highest at L5-S1. Significant linear correlations (p<.001) were found between a number of biomechanical and morphological parameters. Notably, thoracic shear stresses and compressive stresses were correlated to T1-T12 and T4-hip axis (HA) sagittal balance, respectively, but not to sagittal angles. Lumbar shear stresses and body weight (BW) normalized shear loads were correlated with T12-S1 balance, lumbar angle, and sacral angle. BW normalized lumbar compressive loads were correlated with T12-S1 balance and sacral angle. BW normalized lumbar disc shear (compressive) loads increased (decreased) significantly with decreasing lumbar lordosis. Cervical compressive stresses and loads were correlated with all sagittal balance parameters except S1-HA and T12-S1. A neutral spine sagittal model was constructed from the 67 subjects.
The analyses suggest that sagittal spine balance and curvature are important parameters for postural load balance in healthy male and female subjects. Morphological predictors of altered disc load outcomes were sagittal balance parameters in the thoracic spine and anatomic angles in the lumbar spine.
Sitting biomechanics Part I: Review of the Literature Harrison, Donald D.; Harrison, Sanghak O.; Croft, Arthur C. ...
Journal of manipulative and physiological therapeutics,
11/1999, Letnik:
22, Številka:
9
Journal Article
Recenzirano
Objective: To develop a new sitting spinal model and an optimal driver's seat by using review of the literature of seated positions of the head, spine, pelvis, and lower extremities.
Data Selection: ...Searches included MED-LINE for scientific journals, engineering standards, and textbooks. Key terms included sitting ergonomics, sitting posture, spine model, seat design, sitting lordosis, sitting electromyography, seated vibration, and sitting and biomechanics.
Data Synthesis: In part I, papers were selected if (1) they contained a first occurrence of a sitting topic, (2) were reviews of the literature, (3) corrected errors in previous studies, or (4) had improved study designs compared with previous papers. In part II, we separated information pertaining to sitting dynamics and drivers of automobiles from part I.
Results: Sitting causes the pelvis to rotate backward and causes reduction in lumbar lordosis, trunk-thigh angle, and knee angle and an increase in muscle effort and disc pressure. Seated posture is affected by seat-back angle, seat-bottom angle and foam density, height above floor, and presence of armrests.
Conclusion: The configuration of the spine, postural position, and weight transfer is different in the 3 types of sitting: anterior, middle, and posterior. Lumbar lordosis is affected by the trunk-thigh angle and the knee angle. Subjects in seats with backrest inclinations of 110 to 130 degrees, with concomitant lumbar support, have the lowest disc pressures and lowest electromyography recordings from spinal muscles. A seat-bottom posterior inclination of 5 degrees and armrests can further reduce lumbar disc pressures and electromyography readings while seated. To reduce forward translated head postures, a seat-back inclination of 110 degrees is preferable over higher inclinations. Work objects, such as video monitors, are optimum at eye level. Forward-tilting, seat-bottom inclines can increase lordosis, but subjects give high comfort ratings to adjustable chairs, which allow changes in position. (J Manipulative Physiol Ther 1999;22:594–609)
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