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Mid-term outcomes of the fixed-bearing lateral Oxford unicompartmental knee arthroplasty.
AIMS: Mixed clinical results have been reported following the use of lateral unicompartmental knee arthroplasty (UKA) in patients with isolated lateral compartment osteoarthritis (OA) of the knee. Although this procedure may be appropriate for use in about 10% of knees needing arthroplasty, it is only used in about 1%. The aim of this study was to determine the medium-term results for the Fixed Lateral Oxford (FLO) UKA. METHODS: We report the clinical results and survival for 305 consecutive FLO UKAs implanted in 279 patients between July 2015 and August 2022. A total of 283 knees (93%) satisfied the recommended surgical indications. The mean age of the patients was 70.8 years (SD 11), their mean BMI was 28.4 kg/m2 (SD 5.4), and 219 (72%) were female. Isolated lateral compartment OA was the indication for 298 operations (98%). The mean follow-up was 4.3 years (1 to 8). The Oxford Knee Score (OKS) was recorded pre- and postoperatively. The revision status of all knees was known. RESULTS: There were four revisions (1%): two were conversions to a total knee arthroplasty (TKA) for instability and progressive OA and two had the addition of a medial UKA for medial compartment OA. Three other UKAs required a reoperation. At the last follow-up, the mean OKS was 40.9 (SD 7.8), a mean increase of 20 points from the preoperative score. The cumulative rate of survival with any reoperation, including revision, as the endpoint, at seven years, was 96% (95% CI 91 to 100), with revision as the endpoint was 98% (95% CI 94 to 100) and with revision to a TKA as the endpoint was 99% (95% CI 96 to 100). No revisions required revision TKA components. When those who underwent surgery for indications which were outside the recommended indications were excluded, there were only two revisions, both with the addition of a medial UKA for progressive OA, resulting in a seven-year cumulative survival with revision as the endpoint of 99% (95% CI 93 to 100). CONCLUSION: This study involved the largest published cohort of fixed-bearing lateral UKAs. The good clinical outcomes and medium-term survival of the FLO UKA, particularly in patients satisfying the recommended indications, suggest that it is an excellent alternative to TKA for the treatment of patients with isolated OA of the lateral compartment of the knee.
A matched comparison of cementless unicompartmental and total knee replacement outcomes based on the National Joint Registry for England, Wales, Northern Ireland and the Isle of Man.
BACKGROUND AND PURPOSE: The main treatments for severe medial compartment knee arthritis are unicompartmental (UKR) and total knee replacement (TKR). UKRs have higher revision rates, particularly for aseptic loosening, therefore the cementless version was introduced. We compared the outcomes of matched cementless UKRs and TKRs. PATIENTS AND METHODS: The National Joint Registry was linked to the English Hospital Episode Statistics and Patient Reported Outcome Measures (PROMs) databases. 10,552 cementless UKRs and 10,552 TKRs were propensity matched and regression analysis used to compare revision/reoperation risks. 6-month PROMs were compared. UKR results were stratified by surgeon caseload into low- (< 10 UKRs/year), medium- (10 to < 30 UKRs/year), and high-volume (≥ 30 UKRs/year). RESULTS: 8-year cementless UKR revision survival for the 3 respective caseloads were 90% (95% CI 87-93), 93% (CI 91-95), and 96% (CI 94-97). 8-year reoperation survivals were 76% (CI 71-80), 81% (CI 78-85), and 84% (CI 82-86) respectively. For TKR the 8-year implant survivals for revision and reoperation were 96% (CI 95-97) and 81% (CI 80-83). The HRs for the 3 caseload groups compared with TKR for revision were 2.0 (CI 1.3-2.9), 2.0 (CI 1.6-2.7), and 1.0 (CI 0.8-1.3) and for reoperation were 1.2 (CI 1.0-1.4), 0.9 (CI 0.8-1.0), and 0.6 (CI 0.5-0.7). 6-month Oxford Knee Score (OKS) (39 vs. 37) and EQ-5D (0.80 vs. 0.77) were higher (p < 0.001) for the cementless UKR. INTERPRETATION: Cementless UKRs have higher revision and reoperation rates than TKR for low-volume UKR surgeons, similar reoperation but higher revision rates for mid-volume surgeons, and lower reoperation and similar revision rates for high-volume surgeons. Cementless UKR also had better PROMs.
A matched comparison of the patient-reported outcome measures of cemented and cementless total knee replacements, based on the National Joint Registry of England, Wales, Northern Ireland, and Isle of Man and England's National PROM collection programme.
Background and purpose - Total knee replacement (TKR) can be implanted with or without bone cement. It is currently unknown how the functional outcomes compare. Therefore, we compared the patient-reported outcome measures (PROMS) of both fixation methods. Patients and methods - We performed a propensitymatched comparison of 14,404 TKRs (7,202 cemented and 7,202 cementless) enrolled in the National Joint Registry and the English National PROMs collection programme. Subgroup analyses were performed in different age groups (1) < 55 years; (2) 55-64 years; (3) 65-74 years; (4) ≥ 75 years. Results - The 6-month postoperative Oxford Knee Score (OKS) was significantly (p < 0.001) higher for cemented TKR (35, SD 9.7) than cementless TKR (34, SD 9.9). The OKS was also significantly higher for the cemented TKR in all age groups, except the 55-64-year group. A significantly higher proportion of cemented TKRs had an excellent OKS (≥ 41) compared with cementless (32% vs. 28%, p < 0.001) and a lower proportion of poor (< 27) scores (19% vs. 22%, p = 0.001). This was also observed for all age subgroups. There were no significant differences in EQ-5D points gained postoperatively between the groups respectively (0.31 vs. 0.30, p = 0.1). Interpretation - Cemented TKRs had a greater proportion of excellent OKS scores and lower proportion of poor scores both overall and across all age groups. However, the absolute differences are small and below the minimally clinically important difference, making both fixation types acceptable. Currently the vast majority of TKRs are cemented and the results from this study suggest that this is appropriate.
Defining the genetic determinants of CD8+ T cell receptor repertoire in the context of immune checkpoint blockade.
The relationship between genetic variation and CD8+ T cell receptor (TCR) repertoire usage in patients receiving immune checkpoint blockade (ICB) therapy for cancer is unexplored. We have conducted a genome-wide and human leukocyte antigen (HLA)-focused analysis of CD8+ TCR repertoire to identify genetic determinants of variable gene (V-gene) and CDR3 K-nucleotide oligomer usage from samples taken before and after ICB (n = 250). We identify 11 cis and 10 trans V-gene associations, primarily to the MHC, that meet genome-wide significance. TCR clones containing HLA associated V-genes were less stable across treatment, while, at the single-cell level, genetically associated clones demonstrate subset enrichment and increased tumor reactivity expression profiles. Notably, patients with HLA-matched TCR clones demonstrate improved overall survival. Our work indicates a complex relationship between genotype and TCR repertoire in the context of ICB treatment, with implications for understanding factors relating to therapeutic response and patient outcomes.
Development and Validation of a Type 1 Diabetes Multi-Ancestry Polygenic Score.
OBJECTIVE: Polygenic scores strongly predict type 1 diabetes risk, but most scores were developed in European-ancestry populations. In this study, we developed a multi-ancestry polygenic score to accurately predict type 1 diabetes risk across diverse populations. RESEARCH DESIGN AND METHODS: We used recent multi-ancestry genome-wide association studies to create a type 1 diabetes multi-ancestry polygenic score (T1D MAPS). We trained the score in the Mass General Brigham (MGB) Biobank (372 individuals with type 1 diabetes) and tested the score in the All of Us program (86 individuals with type 1 diabetes). We evaluated the area under the receiver operating characteristic curve (AUC), and we compared the AUC to two published single-ancestry scores: T1D GRS2EUR and T1D GRSAFR. We also developed an updated score (T1D MAPS2) that combines T1D GRS2EUR and T1D MAPS. RESULTS: Among individuals with non-European ancestry, the AUC of T1D MAPS was 0.90, significantly higher than T1D GRS2EUR (0.82, P = 0.04) and T1D GRSAFR (0.82, P = 0.007). Among individuals with European ancestry, the AUC of T1D MAPS was slightly lower than T1D GRS2EUR (0.89 vs. 0.91, P = 0.02). However, T1D MAPS2 performed equivalently to T1D GRS2EUR in European ancestry (0.91 vs. 0.91, P = 0.45) while still performing better in non-European ancestry (0.90 vs. 0.82, P = 0.04). CONCLUSIONS: A novel polygenic score improves type 1 diabetes risk prediction in non-European ancestry while maintaining high predictive power in European ancestry. These findings advance the accuracy of type 1 diabetes genetic risk prediction across diverse populations.
Paired analysis of host and pathogen genomes identifies determinants of human tuberculosis.
Infectious disease is the result of interactions between host and pathogen and can depend on genetic variations in both. We conduct a genome-to-genome study of paired human and Mycobacterium tuberculosis genomes from a cohort of 1556 tuberculosis patients in Lima, Peru. We identify an association between a human intronic variant (rs3130660, OR = 10.06, 95%CI: 4.87 - 20.77, P = 7.92 × 10-8) in the FLOT1 gene and a subclavaluee of Mtb Lineage 2. In a human macrophage infection model, we observe hosts with the rs3130660-A allele exhibited stronger interferon gene signatures. The interacting strains have altered redox states due to a thioredoxin reductase mutation. We investigate this association in a 2020 cohort of 699 patients recruited during the COVID-19 pandemic. While the prevalence of the interacting strain almost doubled between 2010 and 2020, its infection is not associated with rs3130660 in this recent cohort. These findings suggest a complex interplay among host, pathogen, and environmental factors in tuberculosis dynamics.
Genomic and Serological Rheumatoid Arthritis Biomarkers, MUC5B Promoter Variant, and Interstitial Lung Abnormalities.
RATIONALE: Rheumatoid arthritis (RA) has been implicated in interstitial lung disease (ILD) as majority of studies have been comprised of patients with known RA. However, it remains unclear whether an underlying risk for RA in combination with genetic risk for pulmonary fibrosis is associated with radiological markers of early lung injury and fibrosis in broader population samples. OBJECTIVE: Determine whether genetic and serological biomarkers of RA risk in combination with the MUC5B (rs35705950) risk allele (T) are associated with interstitial lung abnormalities (ILA) on computed tomography (CT) scans. METHODS: Associations of RA-risk HLA-DRB1 alleles (*04:01, *04:08, *04:05, *04:04, *10:01) and serum RA autoantibodies with ILA in the Multi-Ethnic Study of Atherosclerosis (MESA, n=4,018) and COPDGene (n=5,963) cohorts were modeled using logistic regression and adjusted for age, sex, self-reported race and ethnicity, smoking history, body mass index, and principal components of genetic ancestry. RESULTS: The prevalence of an RA risk HLA-DRB1 allele was 16.5% and 21.9% in MESA and COPDGene, respectively. ILA was present in 3.9% and 11% in MESA and COPDGene, respectively. An RA risk HLA-DRB1 allele was not significantly associated with ILA in MESA and COPDGene. In MESA, higher serum levels of IgA rheumatoid factor (RF) and anti-cyclic citrullinated peptide were associated with an odds ratio (OR) for ILA of 1.20 (95% CI 1.07-1.35) and 1.19 (95% CI 1.04-1.37), respectively. Among smokers without baseline ILA, per doubling of IgM RF was associated with an OR for ILA 10 years later of 1.25 (95% CI 1.08-1.43). Associations were not significantly different by MUC5B risk allele status. CONCLUSIONS: RA-related HLA-DRB1 alleles were not associated with ILA, whereas higher serum levels of IgM RF among smokers without baseline ILA were associated with subsequent ILA.
History of tuberculosis disease is associated with genetic regulatory variation in Peruvians.
A quarter of humanity is estimated to have been exposed to Mycobacterium tuberculosis (Mtb) with a 5-10% risk of developing tuberculosis (TB) disease. Variability in responses to Mtb infection could be due to host or pathogen heterogeneity. Here, we focused on host genetic variation in a Peruvian population and its associations with gene regulation in monocyte-derived macrophages and dendritic cells (DCs). We recruited former household contacts of TB patients who previously progressed to TB (cases, n = 63) or did not progress to TB (controls, n = 63). Transcriptomic profiling of monocyte-derived DCs and macrophages measured the impact of genetic variants on gene expression by identifying expression quantitative trait loci (eQTL). We identified 330 and 257 eQTL genes in DCs and macrophages (False Discovery Rate (FDR) < 0.05), respectively. Four genes in DCs showed interaction between eQTL variants and TB progression status. The top eQTL interaction for a protein-coding gene was with FAH, the gene encoding fumarylacetoacetate hydrolase, which mediates the last step in mammalian tyrosine catabolism. FAH expression was associated with genetic regulatory variation in cases but not controls. Using public transcriptomic and epigenomic data of Mtb-infected monocyte-derived dendritic cells, we found that Mtb infection results in FAH downregulation and DNA methylation changes in the locus. Overall, this study demonstrates effects of genetic variation on gene expression levels that are dependent on history of infectious disease and highlights a candidate pathogenic mechanism through pathogen-response genes. Furthermore, our results point to tyrosine metabolism and related candidate TB progression pathways for further investigation.
Human leukocyte antigen-DQA1*04:01 and rs2040406 variants are associated with elevated risk of childhood Burkitt lymphoma.
Burkitt lymphoma (BL) is responsible for many childhood cancers in sub-Saharan Africa, where it is linked to recurrent or chronic infection by Epstein-Barr virus or Plasmodium falciparum. However, whether human leukocyte antigen (HLA) polymorphisms, which regulate immune response, are associated with BL has not been well investigated, which limits our understanding of BL etiology. Here we investigate this association among 4,645 children aged 0-15 years, 800 with BL, enrolled in Uganda, Tanzania, Kenya, and Malawi. HLA alleles are imputed with accuracy >90% for HLA class I and 85-89% for class II alleles. BL risk is elevated with HLA-DQA1*04:01 (adjusted odds ratio [OR] = 1.61, 95% confidence interval [CI] = 1.32-1.97, P = 3.71 × 10-6), with rs2040406(G) in HLA-DQA1 region (OR = 1.43, 95% CI = 1.26-1.63, P = 4.62 × 10-8), and with amino acid Gln at position 53 versus other variants in HLA-DQA1 (OR = 1.36, P = 2.06 × 10-6). The associations with HLA-DQA1*04:01 (OR = 1.29, P = 0.03) and rs2040406(G) (OR = 1.68, P = 0.019) persist in mutually adjusted models. The higher risk rs2040406(G) variant for BL is associated with decreased HLA-DQB1 expression in eQTLs in EBV transformed lymphocytes. Our results support the role of HLA variation in the etiology of BL and suggest that a promising area of research might be understanding the link between HLA variation and EBV control.
Viridans Streptococcal Biofilm Evades Immune Detection and Contributes to Inflammation and Rupture of Atherosclerotic Plaques.
BACKGROUND: Bacterial DNA from the oral cavity, respiratory tract, gut, and skin has been detected in atherosclerotic plaques, suggesting a role in chronic inflammation linked to atherosclerosis. Chronic bacterial infections often form biofilms resistant to antibiotics and immune detection, giving rise to a new generation of virulent bacteria in suitable conditions. This study explores the role of the immune system in bacterial-induced inflammation of atherosclerotic plaques. METHODS: Coronary plaques from 121 sudden death victims and endarterectomy samples from 96 surgical patients were analyzed using bacterial real-time quantitative polymerase chain reaction, immunohistochemistry, and genome-wide expression analysis. TLR (toll-like receptor) signaling was examined in bacterial-activated TLR cell lines. RESULTS: Of the bacteria detected, oral viridans group streptococcal DNA was the most common, being found in 42.1% of coronary plaques and 42.9% of endarterectomies. Immunopositivity for viridans streptococci correlated with severe atherosclerosis (P<0.0001) in both series and death from coronary heart disease (P=0.021) or myocardial infarction (P=0.042). Viridans streptococci colonized the core of the atheroma as a biofilm unrecognized by macrophages of the innate immune system. In contrast, immunopositive streptococci that appeared to have originated from the biofilm infiltrated the ruptured fibrous cap of the atheroma in endarterectomy samples and coronary plaques and were detected by pattern-recognizing receptors and coexpressed with the adaptive immune response. Among the viridans streptococcal strains, TLR2 was the most activated bacterial-signaling pathway. Genome-wide expression analysis of endarterectomy samples showed upregulation of bacterial recognition pathways. CONCLUSIONS: Latent chronic bacterial inflammation evades immune detection and may contribute to the pathogenesis of complicated atherosclerotic plaques and fatal myocardial infarction.