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.
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.
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.
•An FE wear model was used to analyse the extent of wear damage in hip implants.•Experimental measurement at taper junction of 54 retrievals validated the FE analyses.•The effect of different taper-trunnion mismatches on fretting wear is demonstrated.•A large taper mismatch results in a high wear rate with negative clinical outcomes.•A slight reduction in mismatch to 6´ or less significantly reduced the wear rate.
Studies have demonstrated that at least 20% of individuals infected with SARS-CoV-2 remain asymptomatic
. 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.
Severe asthma is a high-burden disease. Real-world data on mepolizumab in patients with severe eosinophilic asthma is needed to assess whether the data from randomised controlled trials are ...applicable in a broader population.The Australian Mepolizumab Registry (AMR) was established with an aim to assess the use, effectiveness and safety of mepolizumab for severe eosinophilic asthma in Australia.Patients (n=309) with severe eosinophilic asthma (median age 60 years, 58% female) commenced mepolizumab. They had poor symptom control (median Asthma Control Questionnaire (ACQ)-5 score of 3.4), frequent exacerbations (median three courses of oral corticosteroids (OCS) in the previous 12 months), and 47% required daily OCS. Median baseline peripheral blood eosinophil level was 590 cells·µL
Comorbidities were common: allergic rhinitis 63%, gastro-oesophageal reflux disease 52%, obesity 46%, nasal polyps 34%.Mepolizumab treatment reduced exacerbations requiring OCS compared with the previous year (annualised rate ratio 0.34 (95% CI 0.29-0.41); p<0.001) and hospitalisations (rate ratio 0.46 (95% CI 0.33-0.63); p<0.001). Treatment improved symptom control (median ACQ-5 reduced by 2.0 at 6 months), quality of life and lung function. Higher blood eosinophil levels (p=0.003) and later age of asthma onset (p=0.028) predicted a better ACQ-5 response to mepolizumab, whilst being male (p=0.031) or having body mass index ≥30 (p=0.043) predicted a lesser response. Super-responders (upper 25% of ACQ-5 responders, n=61, 24%) had a higher T2 disease burden and fewer comorbidities at baseline.Mepolizumab therapy effectively reduces the significant and long-standing disease burden faced by patients with severe eosinophilic asthma in a real-world setting.
Bronchial thermoplasty (BT) is a novel endoscopic therapy for severe asthma. Traditionally it is performed in three separate treatment sessions, targeting different portions of the lung, and each ...requires an anaesthetic and hospital admission. Compression of treatment into 2 sessions would present a more convenient alternative for patients. In this prospective observational study, the safety of compressing BT into two treatment sessions was compared with the traditional 3 treatment approach.
Sixteen patients meeting ERS/ATS criteria for severe asthma consented to participate in an accelerated treatment schedule (ABT), which treated the whole left lung followed by the right lung four weeks later. The short-term outcomes of these patients were compared with 37 patients treated with conventional BT scheduling (CBT). The outcome measures used to assess safety were (1) the requirement to remain in hospital beyond the electively planned 24-h admission and (2) the need for re-admission for any cause within of 30 days of treatment.
The total number of radiofrequency activations delivered in the ABT group was similar to CBT (187 ± 21 vs 176 ± 40, p = 0.326). With ABT, 11 in 31 admissions (37.9%) required prolonged admission due to wheezing, compared to 5.4% with CBT (p = 0.0025). The mean hospital length of stay with ABT was 1.8 ± 1.3 days, compared to 1.1 ± 0.4 days (p < 0.001). ICU monitoring was required on 5 occasions with ABT (16.1%), compared to 0.9% with CBT (p = 0.002). Subgroup analysis demonstrated that females were more likely to require prolonged admission (OR 11.6, p = 0.0025). The 30-day hospital readmission rate was similar for both groups (6.4% vs 5.4%, p = 0.67). All patients made a complete recovery after treatment with similar outcomes at the 6-month follow-up reassessment.
This study demonstrates that ABT results in greater short-term deterioration in lung function associated with a greater risk of prolonged hospital and ICU stay, predominantly affecting females. Therefore, in females, these risks need to be balanced against the convenience of fewer treatment sessions. In males, it may be an advantage to compress treatment.
The mechanism for symptomatic improvement after bronchial thermoplasty (BT) is unclear, since spirometry reveals little or no change. In this study, the effects of BT on airway resistance were ...examined using two independent techniques.
Eighteen consecutive patients, with severe asthma (57.6 ± 14.2 years) were evaluated by spirometry and plethysmography at three time points: (i) baseline, (ii) left lung treated but right lung untreated and (iii) 6 weeks after both lungs were treated with BT. At each assessment, total and specific airway resistance (Raw, sRaw) were measured. High resolution CT scans were undertaken at the first two assessments, and measurements of lobar volume, airway volume and airway resistance were made. The Asthma Control Questionnaire (ACQ) was administered at each assessment.
The baseline ACQ score was 3.5 ± 0.9, and improved progressively to 1.8 ± 1.2 (p < 0.01). At baseline, severe airflow obstruction was observed, FEV1 44.8 ± 13.7% predicted, together with gas trapping, and elevated Raw at 342 ± 173%predicted. Following BT, significant improvements in Raw and sRaw were observed, as well as a reduction in Residual Volume, increase in Vital Capacity and no change in FEV1. The change in Raw correlated with the change in ACQ (r = 0.56, p < 0.05). CT scans demonstrated reduced airway volume at baseline, which correlated with the increased Raw determined by plethysmography (p = - 0.536, p = < 0.05). Following BT, the airway volume increased in the treated lung, and this was accompanied by a significant reduction in CT-determined local airway resistance.
Symptomatic improvement after BT is mediated by increased airway volume and reduced airway resistance.
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