Selective advantage of mutant stem cells in human clonal hematopoiesis is associated with attenuated response to inflammation and aging.

Clonal hematopoiesis (CH) arises when hematopoietic stem cells (HSCs) acquire mutations, most frequently in the DNMT3A and TET2 genes, conferring a competitive advantage through mechanisms that remain unclear. To gain insight into how CH mutations enable gradual clonal expansion, we used single-cell multi-omics with high-fidelity genotyping on human CH bone marrow (BM) samples. Most of the selective advantage of mutant cells occurs within HSCs. DNMT3A- and TET2-mutant clones expand further in early progenitors, while TET2 mutations accelerate myeloid maturation in a dose-dependent manner. Unexpectedly, both mutant and non-mutant HSCs from CH samples are enriched for inflammatory and aging transcriptomic signatures, compared with HSCs from non-CH samples, revealing a non-cell-autonomous effect. However, DNMT3A- and TET2-mutant HSCs have an attenuated inflammatory response relative to wild-type HSCs within the same sample. Our data support a model whereby CH clones are gradually selected because they are resistant to the deleterious impact of inflammation and aging.

Polyethylene bearing wear is comparable for cemented and cementless Oxford unicompartmental knee replacements: Ten-year results of a randomized controlled trial.

PURPOSE: There is concern that using cementless components may increase polyethylene wear of the Oxford unicompartmental knee replacement (OUKR). Therefore, this study aimed to measure bearing wear at 10 years in patients from a randomized trial comparing Phase 3 cemented and cementless OUKRs and to investigate factors that may affect wear. It was hypothesized that there would be no difference in wear rate between cemented and cementless OUKRs. METHODS: Bearing thickness was determined using radiostereometric analysis at postoperative, 3-month, 6-month, 1-year, 2-year, 5-year and 10-year timepoints. As creep occurs early, wear rate was calculated using linear regression between 6 months and 10 years for 39 knees (20 cemented, 19 cementless). Associations between wear and implant, surgical and patient factors were analysed. RESULTS: The linear wear rate of the Phase 3 OUKR was 0.06 mm/year with no significant difference (p = 0.18) between cemented (0.054 mm/year) and cementless (0.063 mm/year) implants. Age, Oxford Knee Score, component size and bearing thickness had no correlation with wear. A body mass index ≥ 30 was associated with a significantly lower wear rate (p = 0.007) as was having ≥80% femoral component contact area on the bearing (p = 0.003). Bearings positioned ≥1.5 mm from the tibial wall had a significantly higher wear rate (p = 0.002). CONCLUSIONS: At 10 years, the Phase 3 OUKR linear wear rate is low and not associated with the fixation method. To minimize the risk of wear-related bearing fracture in the very long-term surgeons should consider using 4 mm bearings in very young active patients and ensure that components are appropriately positioned, which is facilitated by the current instrumentation. LEVEL OF EVIDENCE: Level III, retrospective comparative study.

Frequent microbiological profile changes are seen in subsequent-revision hip and knee arthroplasty for prosthetic joint infection.

A proportion of patients with hip and knee prosthetic joint infection (PJI) undergo multiple revisions with the aim of eradicating infection and improving quality of life. The aim of this study was to describe the microbiology cultured from multiply revised hip and knee replacement procedures to guide antimicrobial therapy at the time of surgery. Patients and methods: Consecutive patients were retrospectively identified from databases at two specialist orthopaedic centres in the United Kingdom between 2011 and 2019. Patient were included who had undergone repeat-revision total knee replacement (TKR) or total hip replacement (THR) for infection, following an initial failed revision for infection. Results: A total of 106 patients were identified. Of these patients, 74 underwent revision TKR and 32 underwent revision THR. The mean age at first revision was 67 years (SD 10). The Charlson comorbidity index was ≤ 2 for 31 patients, 3-4 for 57 patients, and ≥ 5 for 18 patients. All patients underwent at least two revisions, 73 patients received three, 47 patients received four, 31 patients received five, and 21 patients received at least six. After six revisions, 90 % of patients had different organisms cultured compared with the initial revision, and 53 % of organisms were multidrug resistant. The most frequent organisms at each revision were coagulase-negative Staphylococcus (36 %) and Staphylococcus aureus (19 %). Fungus was cultured from 3 % of revisions, and 21 % of infections were polymicrobial. Conclusion: Patients undergoing multiple revisions for PJI are highly likely to experience a change in organism, with 90 % of patients having a different organism cultured by their sixth revision. It is therefore important to administer empirical antibiotics at each subsequent revision, taking into account known drug resistance from previous cultures. Our results do not support the routine use of empirical antifungals.

The Outcomes of Hip and Knee Fungal Periprosthetic Joint Infections: A Retrospective Cohort Study.

BACKGROUND: Fungal infections are a rare cause of periprosthetic joint infection (PJI), identified in 1% of all of these cases. Outcomes are not well-established due to small cohort sizes in the published literature. The aims of this study were to establish the patient demographics and infection-free survival of patients presenting to 2 high-volume revision arthroplasty centers who had fungal infection of either a hip or knee arthroplasty. We sought to identify risk factors for poor outcomes. METHODS: A retrospective analysis was performed of patients at 2 high-volume revision arthroplasty centers who had confirmed fungal PJI of the total hip arthroplasty (THA) and total knee arthroplasty (TKA). Consecutive patients treated between 2010 and 2019 were included. Patient outcomes were classified as infection eradication or persistence. A total of 67 patients who had 69 fungal PJI cases were identified. There were 47 cases involving the knee and 22 of the hip. Mean age at presentation was 68 years (THA mean 67, range 46 to 86) (TKA mean 69, range, 45 to 88). A history of sinus or open wound was present in 60 cases (89%) (THA 21 cases, TKA 39 cases). The median number of operations prior to the procedure at which fungal PJI was identified was 4 (range, 0 to 9), THA 5 (range, 3 to 9), and TKA 3 (range, 0 to 9). RESULTS: At a mean follow-up 34 months (range, 2 to 121), remission rates were 11 of 24 (45%) and 22 of 45 (49%) for hip and knee, respectively. There were 7 TKA (16%) and 1 THA cases (4%) that failed treatment resulting in amputations. During the study period, 7 THA and 6 TKA patients had died. Two deaths were directly attributable to PJI. Patient outcome was not associated with the number of prior procedures, patient comorbidities, or organisms. CONCLUSION: Eradication of fungal PJI is achieved in less than half of patients, and outcomes are comparable for TKA and THA. The majority of patients who have fungal PJI present with an open wound or sinus. No factors were identified that increase the risk of persistent infection. Patients who have fungal PJI should be informed of the poor outcomes.