A common allele of HLA is associated with asymptomatic SARS-CoV-2 infection.

Studies have demonstrated that at least 20% of individuals infected with SARS-CoV-2 remain asymptomatic1-4. Although most global efforts have focused on severe illness in COVID-19, examining asymptomatic infection provides a unique opportunity to consider early immunological features that promote rapid viral clearance. Here, postulating that variation in the human leukocyte antigen (HLA) loci may underly processes mediating asymptomatic infection, we enrolled 29,947 individuals, for whom high-resolution HLA genotyping data were available, in a smartphone-based study designed to track COVID-19 symptoms and outcomes. Our discovery cohort (n = 1,428) comprised unvaccinated individuals who reported a positive test result for SARS-CoV-2. We tested for association of five HLA loci with disease course and identified a strong association between HLA-B*15:01 and asymptomatic infection, observed in two independent cohorts. Suggesting that this genetic association is due to pre-existing T cell immunity, we show that T cells from pre-pandemic samples from individuals carrying HLA-B*15:01 were reactive to the immunodominant SARS-CoV-2 S-derived peptide NQKLIANQF. The majority of the reactive T cells displayed a memory phenotype, were highly polyfunctional and were cross-reactive to a peptide derived from seasonal coronaviruses. The crystal structure of HLA-B*15:01-peptide complexes demonstrates that the peptides NQKLIANQF and NQKLIANAF (from OC43-CoV and HKU1-CoV) share a similar ability to be stabilized and presented by HLA-B*15:01. Finally, we show that the structural similarity of the peptides underpins T cell cross-reactivity of high-affinity public T cell receptors, providing the molecular basis for HLA-B*15:01-mediated pre-existing immunity.

Feasibility of asymmetric flow field-flow fractionation coupled to ICP-MS for the characterization of wear metal particles and metalloproteins in biofluids from hip replacement patients.

Hip replacements are used to improve the quality of life of people with orthopaedic conditions, but the use of metal-on-metal (MoM) arthroplasty has led to poor outcomes for some patients. These problems are related to the generation of micro- to nanosized metal wear particles containing Cr, Co or other elements, but the current analytical methods used to investigate the processes involved do not provide sufficient information to understand the size or composition of the wear particles generated in vivo. In this qualitative feasibility study, asymmetric flow field-flow fractionation (AF(4)) coupled with inductively coupled plasma mass spectrometry (ICP-MS) was used to investigate metal protein binding and the size and composition of wear metal particles present in serum and hip aspirates from MoM hip replacement patients. A well-established HPLC anion exchange chromatography (AEC) separation system coupled to ICP-MS was used to confirm the metal-protein associations in the serum samples. Off-line single particle ICP-MS (spICP-MS) analysis was used to confirm the approximate size distribution indicated by AF(4) of the wear particles in hip aspirates. In the serum samples, AF(4) -ICP-MS suggested that Cr was associated with transferrin (Tf) and Co with albumin (Alb) and an unidentified species; AEC-ICP-MS confirmed these associations and also indicated an association of Cr with Alb. In the hip aspirate sample, AF(4)-ICP-MS suggested that Cr was associated with Alb and Tf and that Co was associated with Alb and two unidentified compounds; AEC analysis confirmed the Cr results and the association of Co with Alb and a second compound. Enzymatic digestion of the hip aspirate sample, followed by separation using AF(4) with detection by UV absorption (280 nm), multi-angle light scattering and ICP-MS, suggested that the sizes of the Cr-, Co- and Mo-containing wear particles in a hip aspirate sample were in the range 40-150 nm. Off-line spICP-MS was used to confirm these findings for the Co- and Cr-containing nanoparticles. Whilst limited in scope, the results are sufficient to show the interaction of ions with transport proteins and give an indication of particle size, providing useful pathological indices. As such, the methods indicate a new way forward for in vivo investigation of the processes which lead to tissue necrosis and hip loosening in patients with MoM hip replacements.

The impact of femoral head size on the wear evolution at contacting surfaces of total hip prostheses: A finite element analysis.

Total Hip Arthroplasty has been a revolutionary technique in restoring mobility to patients with damaged hip joints. The introduction of modular components of the hip prosthesis allowed for bespoke solutions based on the requirements of the patient. The femoral stem is designed with a conical trunnion to allow for assembly of different femoral head sizes based on surgical requirements. The femoral head diameters for a metal-on-polyethylene hip prosthesis have typically ranged between 22 mm and 36 mm and are typically manufactured using Cobalt-Chromium alloy. A smaller femoral head diameter is associated with lower wear of the polyethylene, however, there is a higher risk of dislocation. In this study, a finite element model of a standard commercial hip arthroplasty prosthesis was modelled with femoral head diameters ranging from 22 mm to 36 mm to investigate the wear evolution and material loss at both contacting surfaces (acetabular cup and femoral stem trunnion). The finite element model, coupled with a validated in-house wear algorithm modelled a human walking for 10 million steps. The results have shown that as the femoral head size increased, the amount of wear on all contacting surfaces increased. As the femoral head diameter increased from 22 mm to 36 mm, the highly cross-linked polyethylene (XLPE) volumetric wear increased by 61% from 98.6 mm3 to 159.5 mm3 while the femoral head taper surface volumetric wear increased by 21% from 4.18 mm3 to 4.95 mm3. This study has provided an insight into the amount of increased wear as the femoral head size increased which can highlight the life span of these prostheses in the human body.

Aseptic loosening of the option stemmed tibial tray in the Zimmer NexGen LPS total knee arthroplasty system.

BACKGROUND: We investigated the relationship between the backside deformation of polyethylene (PE) tibial inserts and aseptic loosening of the Option stemmed tibial tray used with Zimmer NexGen posterior-stabilised (PS) devices. We hypothesized that explanted inserts used in PS designs would exhibit greater extents of PE backside deformation than those used in equivalent cruciate retaining (CR) designs and that PE inserts retrieved from total knee arthroplasties (TKAs) revised for aseptic tibial tray loosening would exhibit greater extents of backside deformation than TKAs revised for other reasons. METHODS: A total of 73 explanted fixed-bearing TKAs (42 CR and 31 PS) were examined. PE components underwent geometric examination with a coordinate measuring machine using validated techniques. Multiple regression modelling was used to identify variables associated with revision secondary to aseptic loosing and to determine factors associated with increased PE backside deformation. RESULTS: PE inserts retrieved from TKAs with aseptic loosening had significantly greater backside deformation than those retrieved from TKAs revised for other reasons (p < 0.001). Greater PE backside deformation was significantly associated with larger tray/insert clearance heights (p < 0.001), thinner inserts (p < 0.001) and PS TKAs (p = 0.001). CONCLUSION: PE backside deformation was significantly greater in the PS TKAs. This may provide one explanation for the increased rate of aseptic loosening reported with the Option tibial tray used with the Legacy Posterior Stabilised (LPS) system.

How does bicycling affect the longevity of Total Hip Arthroplasty? A finite element wear analysis.

As the number of young and active individuals undergoing Total Hip Arthroplasty (THA) are increasing yearly, there is a need for hip prostheses to have increased longevity. Current investigations into the longevity of these prostheses only include walking as the patient's activity as there is limited data on the amount and intensity of other activity performed by the patient. To further understand the evolution of wear and increase the longevity of these implants, the impact of different activities on the hip prosthesis needs to be investigated. In this study, a finite element model and wear algorithm was developed to simulate both walking and bicycling over a 5-year period. The XLPE acetabular cup volumetric wear rate was found to be 33 mm3/yr while the femoral head taper wear rates were between 0.01 - 0.39 mm3/yr. The results showed that by adding bicycling of up to 80 km per week with normal walking activity, the XLPE mean volumetric wear rate increased by 67% and the metallic mean volumetric wear rate by 11%. However, the patient may gain further health benefits from this additional activity. Assistive electric bikes may also be used to further reduce the loads on the hip joint, allowing for lower amounts of wear.

Periarticular metal hypersensitivity complications of hip bearings containing cobalt-chromium.

Hip joints with bearings composed of cobalt-chromium alloy (metal-on-metal bearings) have been one of the most widely used implants in joint replacement arthroplasty. Unfortunately, these implants can contribute to a complication called aseptic lymphocyte-dominated vasculitis-associated lesion (ALVAL), a type IV metal hypersensitivity response around the joint. Consistent with such bearings, increased metal debris can be found in the surrounding fluids and in remote tissues and organs, due to wear and corrosion. It is hypothesized that metal ions released from the prosthesis (including Co2+) can potentially form haptens with proteins such as serum albumin in synovial fluid that in turn elicit ALVAL. Generally, elevated cobalt and chromium levels in synovial fluids may indicate implant failure. However, such measurements cannot be used as a reliable tool to predict the onset of ALVAL. To detect ALVAL, some diagnostic tests, questionnaires and imaging techniques have been used clinically with some success, but a standardized approach is lacking. At present, guidelines for implant usage and patient management are ambiguous and inconsistent across health care authorities. To reduce and better manage the development of ALVAL, further research into the precise molecular mechanism(s) by which ALVAL develops is urgently needed. Identification of diagnostic and prognostic biomarkers for ALVAL is required, as are more standardized guidelines for surgery and patient management.

Erratum: Author Correction: The influence of HLA genotype on the development of metal hypersensitivity following joint replacement.

[This corrects the article DOI: 10.1038/s43856-022-00137-0.].

The influence of HLA genotype on the development of metal hypersensitivity following joint replacement.

Background: Over five million joint replacements are performed across the world each year. Cobalt chrome (CoCr) components are used in most of these procedures. Some patients develop delayed-type hypersensitivity (DTH) responses to CoCr implants, resulting in tissue damage and revision surgery. DTH is unpredictable and genetic links have yet to be definitively established. Methods: At a single site, we carried out an initial investigation to identify HLA alleles associated with development of DTH following metal-on-metal hip arthroplasty. We then recruited patients from other centres to train and validate an algorithm incorporating patient age, gender, HLA genotype, and blood metal concentrations to predict the development of DTH. Accuracy of the modelling was assessed using performance metrics including time-dependent receiver operator curves. Results: Using next-generation sequencing, here we determine the HLA genotypes of 606 patients. 176 of these patients had experienced failure of their prostheses; the remaining 430 remain asymptomatic at a mean follow up of twelve years. We demonstrate that the development of DTH is associated with patient age, gender, the magnitude of metal exposure, and the presence of certain HLA class II alleles. We show that the predictive algorithm developed from this investigation performs to an accuracy suitable for clinical use, with weighted mean survival probability errors of 1.8% and 3.1% for pre-operative and post-operative models respectively. Conclusions: The development of DTH following joint replacement appears to be determined by the interaction between implant wear and a patient's genotype. The algorithm described in this paper may improve implant selection and help direct patient surveillance following surgery. Further consideration should be given towards understanding patient-specific responses to different biomaterials.

A common allele of HLA mediates asymptomatic SARS-CoV-2 infection.

Despite some inconsistent reporting of symptoms, studies have demonstrated that at least 20% of individuals infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) will remain asymptomatic. Although most global efforts have focused on understanding factors underlying severe illness in COVID-19 (coronavirus disease of 2019), the examination of asymptomatic infection provides a unique opportunity to consider early disease and immunologic features promoting rapid viral clearance. Owing to its critical role in the immune response, we postulated that variation in the human leukocyte antigen (HLA) loci may underly processes mediating asymptomatic infection. We enrolled 29,947 individuals registered in the National Marrow Donor Program for whom high-resolution HLA genotyping data were available in the UCSF Citizen Science smartphone-based study designed to track COVID-19 symptoms and outcomes. Our discovery cohort (n=1428) was comprised of unvaccinated, self-identified subjects who reported a positive test result for SARS-CoV-2. We tested for association of five HLA loci (HLA-A, -B, -C, -DRB1, -DQB1) with disease course and identified a strong association of HLA-B*15:01 with asymptomatic infection, and reproduced this association in two independent cohorts. Suggesting that this genetic association is due to pre-existing T-cell immunity, we show that T cells from pre-pandemic individuals carrying HLA-B*15:01 were reactive to the immunodominant SARS-CoV-2 S-derived peptide NQKLIANQF, and 100% of the reactive cells displayed memory phenotype. Finally, we characterize the protein structure of HLA-B*15:01-peptide complexes, demonstrating that the NQKLIANQF peptide from SARS-CoV-2, and the highly homologous NQKLIANAF from seasonal coronaviruses OC43-CoV and HKU1-CoV, share similar ability to be stabilized and presented by HLA-B*15:01, providing the molecular basis for T-cell cross-reactivity and HLA-B*15:01-mediated pre-existing immunity.

The influence of HLA genotype on the severity of COVID-19 infection.

The impact of COVID-19 varies markedly, not only between individual patients but also between different populations. We hypothesised that differences in human leukocyte antigen (HLA) genes might influence this variation. Using next generation sequencing, we analysed the class I and class II classical HLA genes of 147 individuals of European descent experiencing variable clinical outcomes following COVID-19 infection. Forty-nine of these patients were admitted to hospital with severe respiratory disease. They had no significant pre-existing comorbidities. We compared the results to those obtained from a group of 69 asymptomatic hospital workers who evidence of COVID exposure based on blood antibody testing. Allele frequencies in both the severe and asymptomatic groups were compared to local and national healthy controls with adjustments made for age and sex. With the inclusion of hospital staff who had reported localised symptoms only (limited to loss of smell/taste, n = 13) or systemic symptoms not requiring hospital treatment (n = 16), we carried out ordinal logistic regression modelling to determine the relative influence of age, BMI, sex and the presence of specific HLA genes on symptomatology. We found a significant difference in the allele frequency of HLA-DRB1*04:01 in the severe patient compared to the asymptomatic staff group (5.1% vs. 16.7%, P = .003 after adjustment for age and sex). There was a significantly lower frequency of the haplotype DQA1*01:01-DQB1*05:01-DRB1*01:01 in the asymptomatic group compared to the background population (P = .007). Ordinal logistic regression modelling confirmed the significant influence of DRB1*04:01 on the clinical severity of COVID-19 observed in the cohorts. These alleles are found in greater frequencies in the North Western European population. This regional study provides evidence that HLA genotype influences clinical outcome in COVID-19 infection. Validation studies must take account of the complex genetic architecture of the immune system across different geographies and ethnicities.

Tibial tray debonding from the cement mantle is associated with deformation of the backside of polyethylene tibial inserts.

AIMS: The aim of this study was to investigate whether wear and backside deformation of polyethylene (PE) tibial inserts may influence the cement cover of tibial trays of explanted total knee arthroplasties (TKAs). METHODS: At our retrieval centre, we measured changes in the wear and deformation of PE inserts using coordinate measuring machines and light microscopy. The amount of cement cover on the backside of tibial trays was quantified as a percentage of the total surface. The study involved data from the explanted fixed-bearing components of four widely used contemporary designs of TKA (Attune, NexGen, Press Fit Condylar (PFC), and Triathlon), revised for any indication, and we compared them with components that used previous generations of PE. Regression modelling was used to identify variables related to the amount of cement cover on the retrieved trays. RESULTS: A total of 114 explanted fixed-bearing TKAs were examined. This included 76 used with contemporary PE inserts which were compared with 15 used with older generation PEs. The Attune and NexGen (central locking) trays were found to have significantly less cement cover than Triathlon and PFC trays (peripheral locking group) (p = 0.001). The median planicity values of the PE inserts used with central locking trays were significantly greater than of those with peripheral locking inserts (205 vs 85 microns; p < 0.001). Attune and NexGen inserts had a characteristic pattern of backside deformation, with the outer edges of the PE deviating inferiorly, leaving the PE margins as the primary areas of articulation. CONCLUSION: Explanted TKAs with central locking mechanisms were significantly more likely to debond from the cement mantle. The PE inserts of these designs showed characteristic patterns of deformation, which appeared to relate to the manufacturing process and may be exacerbated in vivo. This pattern of deformation was associated with PE wear occurring at the outer edges of the articulation, potentially increasing the frictional torque generated at this interface. Cite this article: Bone Joint J 2021;103-B(12):1791-1801.

Cup anteversion in hip resurfacing: validation of EBRA and the presentation of a simple clinical grading system.

The use of large metal on metal bearings has led to a reduction in the risk of dislocation post hip arthroplasty. Because of this, and also because of the technical difficulties associated with resurfacing surgery in particular, it could be argued that a less meticulous approach to acetabular cup placement has developed in comparison with conventional metal on polyethylene arthroplasty. Resurfacing cups may produce significant clinical problems when placed at the extremes of version, including increased production of metal debris and psoas tendonitis. Presented in this article is evidence that EBRA software (Einzel-Bild-Roentgen-Analysis, University of Innsbruck, Austria) can be used to reliably assess the version of resurfacing cups, when radiographs are of sufficient quality. The cups have characteristic appearances when placed at the extremes of version. These characteristics can allow the surgeon to identify poorly positioned cups without the use of software.

Reliability and reproducibility of classification systems for Legg-Calvé-Perthes disease: a systematic review of the literature.

Several classification systems are in use for Legg-Calvé-Perthes disease. Three of them: Catterall, Salter Thompson and Herring (Lateral Pillar) are most commonly used. There has been debate on which is most reliable. The purpose of this paper was to systematically analyse the literature when the classifications were compared. The Ovid (Medline) Database was used and the MeSH terms Perthes Classification and Reliability were inserted. Eleven studies were retrieved but only five were suitable for analysis as they attempted to compare the classifications. Most studies used kappa agreements as the principal outcome measure, although intraclass coefficients and percentage agreements were also used. Only four studies assessed for both intraobserver reproducibility and interobserver reliability. A further study from the references appendages was found to be suitable, and was included in the analysis. Kappa ranged from poor to fair (Salter Thompson), fair to moderate (Catterall) and moderate to good (Herring). The outcome from Legg-Calvé-Perthes disease is extremely variable. Inconsistent interpretation of the plain films may explain this, although it is likely this is multifactorial. The papers in this study show that on balance, the Lateral Pillar classification was most reliable, probably secondary to ease of use. A persistent theme was that the subchondral fracture line in the Salter Thompson system was difficult to interpret and not always present. It also showed that whilst reliability and reproducibility tended to improve with experience, disagreement was not always restricted to more junior personnel. Each classification has its merits but reliability and reproducibility remains unsatisfactory. Digital technology in the future may help delineate the lesions better and improve agreement.

The influence of age and sex on early clinical results after hip resurfacing: an independent center analysis.

Patient selection is critical to the excellent medium-term clinical results after hip resurfacing. We assessed the influence of age and sex on early survivorship and functional outcome by comparing 100 female hips resurfaced with male hips resurfaced for the same period. In patients older than 55 years, Harris hip score improved to 97.4 in males compared with 91.2 (P < .01) in females with a revision rate of 2.2% and 7.4%, respectively. There was no correlation between age and functional score. Three percent of females and 1.3% of males sustained a femoral neck fracture. Hip resurfacing provides excellent early functional recovery in males and females. However, the revision rate in older females is high. Changes to surgical technique may minimize the risk of early failure in this group.

Does a micro-grooved trunnion stem surface finish improve fixation and reduce fretting wear at the taper junction of total hip replacements? A finite element evaluation.

The generation of particulate debris at the taper junction of total hip replacements (THRs), can cause failure of the artificial hip. The taper surfaces of femoral heads and trunnions of femoral stems are generally machined to a certain roughness to enhance fixation. However, the effect of the surface roughness of these surfaces on the fixation, wear and consequently clinical outcomes of the design is largely unknown. In this study, we asked whether a micro-grooved trunnion surface finish (1) improves the fixation and (2) reduces the wear rate at the taper junction of THRs. We used 3D finite element (FE) models of THRs to, firstly, investigate the effect of initial fixation of a Cobalt-Chromium femoral head with a smooth taper surface mated with a Titanium (1) micro-grooved and (2) smooth, trunnion surface finishes. Secondly, we used a computational FE wear model to compare the wear evolution between the models, which was then validated against wear measurements of the taper surface of explanted femoral heads. The fixation at the taper junction was found to be better for the smooth couplings. Over a 7 million load cycle analysis in-silico, the linear wear depth and the total material loss was around 3.2 and 1.4 times higher for the femoral heads mated with micro-grooved trunnions. It was therefore concluded that smooth taper and trunnion surfaces will provide better fixation at the taper junction and reduce the volumetric wear rates.

A large taper mismatch is one of the key factors behind high wear rates and failure at the taper junction of total hip replacements: A finite element wear analysis.

Total hip replacement (THR) is one of the most successful orthopaedic surgeries; however, failures can occur due to adverse reactions to wear debris. Recently, a large number of failures linked to the release of metal particles from the taper junction between femoral head and femoral stem have been reported. One possible reason for this may be design variations such as taper mismatches associated with the taper and trunnion angles. Could a large taper mismatch lead to inappropriate contact mechanics and increase relative micromotion and thus wear? In this study, 3D finite element (FE) models of a commercial THR from a perfectly matched interface to large taper mismatches and a wear algorithm were used to investigate the extent of wear that could occur at this junction and identify the optimum tolerances in order to reduce the wear. A co-ordinate measuring machine (CMM) was used to analyse the wear depth and volumetric wear rate of the tapers of 54 explanted 36mm diameter Cobalt Chromium femoral heads, which had been in service for 5.1 years in average, to validate the FE analyses. It was found that a large taper mismatch (e.g. 9.12´) results in a high wear rate (2.960mm3 per million load cycles). Such wear rates can have a major negative effect on the clinical outcomes of these implants. It was also found that even a slight reduction in mismatch significantly reduced the magnitude of the wear rates (0.069mm3 per million load cycles on average for 6´ taper mismatch). It is recommended that the cone angles of femoral head and femoral trunnion should be manufactured to produce a taper mismatch of less than 6´ at the taper junction.

The Tribology of Explanted Hip Resurfacings Following Early Fracture of the Femur.

A recognized issue related to metal-on-metal hip resurfacings is early fracture of the femur. Most theories regarding the cause of fracture relate to clinical factors but an engineering analysis of failed hip resurfacings has not previously been reported. The objective of this work was to determine the wear volumes and surface roughness values of a cohort of retrieved hip resurfacings which were removed due to early femoral fracture, infection and avascular necrosis (AVN). Nine resurfacing femoral heads were obtained following early fracture of the femur, a further five were retrieved due to infection and AVN. All fourteen were measured for volumetric wear using a co-ordinate measuring machine. Wear rates were then calculated and regions of the articulating surface were divided into "worn" and "unworn". Roughness values in these regions were measured using a non-contacting profilometer. The mean time to fracture was 3.7 months compared with 44.4 months for retrieval due to infection and AVN. Average wear rates in the early fracture heads were 64 times greater than those in the infection and AVN retrievals. Given the high wear rates of the early fracture components, such wear may be linked to an increased risk of femoral neck fracture.