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.

Oral versus intravenous antibiotics for bone and joint infections: the OVIVA non-inferiority RCT.

BACKGROUND: Management of bone and joint infection commonly includes 4-6 weeks of intravenous (IV) antibiotics, but there is little evidence to suggest that oral (PO) therapy results in worse outcomes. OBJECTIVE: To determine whether or not PO antibiotics are non-inferior to IV antibiotics in treating bone and joint infection. DESIGN: Parallel-group, randomised (1 : 1), open-label, non-inferiority trial. The non-inferiority margin was 7.5%. SETTING: Twenty-six NHS hospitals. PARTICIPANTS: Adults with a clinical diagnosis of bone, joint or orthopaedic metalware-associated infection who would ordinarily receive at least 6 weeks of antibiotics, and who had received ≤ 7 days of IV therapy from definitive surgery (or start of planned curative treatment in patients managed non-operatively). INTERVENTIONS: Participants were centrally computer-randomised to PO or IV antibiotics to complete the first 6 weeks of therapy. Follow-on PO therapy was permitted in either arm. MAIN OUTCOME MEASURE: The primary outcome was the proportion of participants experiencing treatment failure within 1 year. An associated cost-effectiveness evaluation assessed health resource use and quality-of-life data. RESULTS: Out of 1054 participants (527 in each arm), end-point data were available for 1015 (96.30%) participants. Treatment failure was identified in 141 out of 1015 (13.89%) participants: 74 out of 506 (14.62%) and 67 out of 509 (13.16%) of those participants randomised to IV and PO therapy, respectively. In the intention-to-treat analysis, using multiple imputation to include all participants, the imputed risk difference between PO and IV therapy for definitive treatment failure was -1.38% (90% confidence interval -4.94% to 2.19%), thus meeting the non-inferiority criterion. A complete-case analysis, a per-protocol analysis and sensitivity analyses for missing data each confirmed this result. With the exception of IV catheter complications [49/523 (9.37%) in the IV arm vs. 5/523 (0.96%) in the PO arm)], there was no significant difference between the two arms in the incidence of serious adverse events. PO therapy was highly cost-effective, yielding a saving of £2740 per patient without any significant difference in quality-adjusted life-years between the two arms of the trial. LIMITATIONS: The OVIVA (Oral Versus IntraVenous Antibiotics) trial was an open-label trial, but bias was limited by assessing all potential end points by a blinded adjudication committee. The population was heterogenous, which facilitated generalisability but limited the statistical power of subgroup analyses. Participants were only followed up for 1 year so differences in late recurrence cannot be excluded. CONCLUSIONS: PO antibiotic therapy is non-inferior to IV therapy when used during the first 6 weeks in the treatment for bone and joint infection, as assessed by definitive treatment failure within 1 year of randomisation. These findings challenge the current standard of care and provide an opportunity to realise significant benefits for patients, antimicrobial stewardship and the health economy. FUTURE WORK: Further work is required to define the optimal total duration of therapy for bone and joint infection in the context of specific surgical interventions. Currently, wide variation in clinical practice suggests significant redundancy that likely contributes to the excess and unnecessary use of antibiotics. TRIAL REGISTRATION: Current Controlled Trials ISRCTN91566927. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 23, No. 38. See the NIHR Journals Library website for further project information.

Treatment of bone and joint infection usually requires a long course of antibiotics. Doctors usually give these by injection through a vein (intravenously) for the first 4­6 weeks, rather than by mouth (orally). Although intravenous (IV) administration is more expensive and less convenient for patients, most doctors believe that it is more effective. However, there is little evidence to support this. The OVIVA (Oral Versus IntraVenous Antibiotics) trial set out to challenge this assumption. A total of 1054 patients from 26 UK hospitals were randomly allocated to receive the first 6 weeks of antibiotic therapy either intravenously or orally. Irrespective of the route of administration, the choice of antibiotic was left to an infection specialist so as to ensure that the most appropriate antibiotics were given. Patients were followed up for 1 year. Thirty-nine participants were lost to follow-up. Among the remaining 1015 participants, treatment failure occurred in 14.6% of those treated intravenously and 13.2% of those treated with PO antibiotics. This difference could easily have occurred by chance. Even if it was not by chance, the difference does not suggest that PO therapy is associated with worse outcomes than IV therapy and is too small to conclude that PO therapy is better than IV therapy. Participants in the IV group stayed in hospital longer and 10% of them had complications related to the IV line used for administering the antibiotics. In addition, their treatment was, overall, more expensive. We conclude that PO antibiotic therapy has no disadvantages for the early management of bone and joint infection. It is also cheaper and associated with fewer complications.

Oral versus Intravenous Antibiotics for Bone and Joint Infection.

BACKGROUND: The management of complex orthopedic infections usually includes a prolonged course of intravenous antibiotic agents. We investigated whether oral antibiotic therapy is noninferior to intravenous antibiotic therapy for this indication. METHODS: We enrolled adults who were being treated for bone or joint infection at 26 U.K. centers. Within 7 days after surgery (or, if the infection was being managed without surgery, within 7 days after the start of antibiotic treatment), participants were randomly assigned to receive either intravenous or oral antibiotics to complete the first 6 weeks of therapy. Follow-on oral antibiotics were permitted in both groups. The primary end point was definitive treatment failure within 1 year after randomization. In the analysis of the risk of the primary end point, the noninferiority margin was 7.5 percentage points. RESULTS: Among the 1054 participants (527 in each group), end-point data were available for 1015 (96.3%). Treatment failure occurred in 74 of 506 participants (14.6%) in the intravenous group and 67 of 509 participants (13.2%) in the oral group. Missing end-point data (39 participants, 3.7%) were imputed. The intention-to-treat analysis showed a difference in the risk of definitive treatment failure (oral group vs. intravenous group) of -1.4 percentage points (90% confidence interval [CI], -4.9 to 2.2; 95% CI, -5.6 to 2.9), indicating noninferiority. Complete-case, per-protocol, and sensitivity analyses supported this result. The between-group difference in the incidence of serious adverse events was not significant (146 of 527 participants [27.7%] in the intravenous group and 138 of 527 [26.2%] in the oral group; P=0.58). Catheter complications, analyzed as a secondary end point, were more common in the intravenous group (9.4% vs. 1.0%). CONCLUSIONS: Oral antibiotic therapy was noninferior to intravenous antibiotic therapy when used during the first 6 weeks for complex orthopedic infection, as assessed by treatment failure at 1 year. (Funded by the National Institute for Health Research; OVIVA Current Controlled Trials number, ISRCTN91566927 .).

Clinical Outcome of Massive Endoprostheses Used for Managing Periprosthetic Joint Infections of the Hip and Knee.

BACKGROUND: Endoprosthetic replacement (EPR) is an option for management of massive bone loss resulting from infection around failed lower limb implants. The aim of this study is to determine the mid-term outcome of EPRs performed in the treatment of periprosthetic joint infection (PJI) and infected failed osteosyntheses around the hip and knee joint and identify factors that influence it. METHODS: We retrospectively reviewed all hip and knee EPRs performed between 2007 and 2014 for the management of chronic infection following complex arthroplasty or fracture fixation. Data recorded included indication for EPR, number of previous surgeries, comorbidities, and organism identified. Outcome measures included PJI eradication rate, complications, implant survival, mortality, and functional outcome (Oxford Hip or Knee Score). RESULTS: Sixty-nine EPRs (29 knees and 40 hips) were performed with a mean age of 68 years (43-92). Polymicrobial growth was detected in 36% of cases, followed by coagulase-negative staphylococci (28%) and Staphylococcus aureus (10%). Recurrence of infection occurred in 19 patients (28%): 5 were treated with irrigation and debridement, 5 with revision, 1 with above-knee amputation, and 8 remain on long-term antibiotics. PJI eradication was achieved in 50 patients (72%); the chance of PJI eradication was greater in hips (83%) than in knees (59%) (P = .038). The 5-year implant survivorship was 81% (95% confidence interval 74-88). The mean Oxford Hip Score and Oxford Knee Score were 22 (4-39) and 21 (6-43), respectively. CONCLUSION: This study supports the use of EPRs for eradication of PJI in complex, multiply revised cases. We describe PJI eradication rate of 72% with acceptable functional outcome.

Outcome Following Debridement, Antibiotics, and Implant Retention in Hip Periprosthetic Joint Infection-An 18-Year Experience.

BACKGROUND: Debridement-antibiotics-and-implant-retention (DAIR) may be considered a suitable surgical option in periprosthetic joint infections (PJIs) with soundly fixed prostheses, despite chronicity. This study aims to define the long-term outcome following DAIR in hip PJI. METHODS: We reviewed all hip DAIRs performed between 1997 and 2013 (n = 122) to define long-term outcome and identify factors influencing it. Data recorded included patient demographics, medical history, type of DAIR performed (+/- exchange of modular components), and organisms identified. Outcome measures included complications and/or mortality rate, implant survivorship, and functional outcome (Oxford Hip Score). RESULTS: Most DAIRs (67%) were of primary arthroplasties and 60% were performed within 6 weeks from the index arthroplasty. Infection eradication was achieved in 68% of the first DAIR procedure. In 32 cases, more than one DAIR was required. Infection eradication was achieved in 85% of the cases (104/122) with the (single or multiple) DAIR approach. The most common complication was PJI-persistence (15%), followed by dislocation (14%). Very good functional outcomes were obtained, especially in primary arthroplasties. All streptococcus infections were resolved with DAIR and had better outcome. Twenty-one hips have been revised (17%) to-date, 16 were for persistence of PJI. The 10-y implant survivorship was 77%. Early PJI and exchanging modular components at DAIR were independent factors for a 4-fold increased infection eradication and improved long-term implant survival. CONCLUSION: DAIR is, therefore, a valuable option in the treatment of hip PJI, especially in the early postoperative period (≤6 weeks), with good outcomes. However, DAIR is associated with increased morbidity; further surgery may be necessary and instability may occur. Where possible, exchange of modular implants should be undertaken.

The John Charnley Award: Highly crosslinked polyethylene in total hip arthroplasty decreases long-term wear: a double-blind randomized trial.

BACKGROUND: The use of highly crosslinked polyethylene (HXLPE) is now commonplace for total hip arthroplasty. Hip simulator studies and short-term in vivo measurements suggest that the wear rate of some types of HXLPE is significantly less than conventional ultrahigh-molecular-weight polyethylene (UHMWPE). However, there are few long-term data to support its use. QUESTIONS/PURPOSES: The aim of this study was to measure the long-term steady-state wear of HXLPE compared with UHMWPE liners in a prospective, double-blind, randomized controlled trial using radiostereometric analysis. METHODS: Fifty-four patients were randomized to receive hip arthroplasties with either UHMWPE liners or HXLPE liners. Complete followup was available on 39 of these patients (72%). All patients received the same cemented stem and an uncemented acetabular component. Three-dimensional penetration of the head into the socket was determined at 10 years using a radiostereometric analysis system, which has an in vivo accuracy of <0.1 mm. Oxford Hip Scores were compared between the groups. RESULTS: At 10 years there was significantly less wear of HXLPE (0.003 mm/year; 95% confidence interval [CI], ±0.010; SD 0.023; range, -0.057 to 0.074) compared with UHMWPE (0.030 mm/year; 95% CI, ±0.012; p<0.001; SD 0.0.27; range, -0.001 to 0.164). The volumetric penetration from 1 to 10 years for the UHMWPE group was 98 mm3 (95% CI, ±46 mm3; SD 102 mm3; range, -4 to 430 mm3) compared with 14 mm3 (95% CI, ±40 mm3; SD 91 mm3; range, -189 to 242 mm3) for the HXLPE group (p=0.01). CONCLUSIONS: This study demonstrates that HXLPE has little detectable steady-state in vivo wear. This may result in fewer reoperations from loosening; however, careful clinical followup into the second decade still needs to be performed. LEVEL OF EVIDENCE: Level I, therapeutic study. See the Guidelines for Authors for a complete description of levels of evidence.

Hip resurfacing and pseudotumour.

Metal on metal hip resurfacing has been used widely over the last ten years but there has been recent concern about destructive soft tissue reactions, which have been called pseudotumours by some authors. This has generated considerable controversy. This review explains why pseudotumours occur after resurfacing and how they can be prevented. It also supports the continued use of resurfacing in appropriate patients by appropriately trained surgeons.

Serial measurement of the C-reactive protein is a poor predictor of treatment outcome in prosthetic joint infection.

OBJECTIVES: Prosthetic joint infection is usually treated using surgery and antibiotics. The response to the treatment regimen is often evaluated using serial monitoring of plasma C-reactive protein (CRP) concentrations. In order to examine how useful this monitoring is, we calculated the sensitivity and specificity of CRP concentrations for predicting treatment failure. PATIENTS AND METHODS: We examined 3732 CRP measurements from 260 patients who were treated by either two-stage revision or debridement and retention. We tested the association between CRP concentration and outcome using logistic regression models, and assessed sensitivity and specificity by using receiver operator curves. RESULTS: The areas under receiver operator curves for CRP concentrations predicting outcome ranged from 0.55 to 0.65. CONCLUSIONS: CRP concentrations did not accurately predict treatment failure. Serial monitoring may not be of benefit.

A unique peri-prosthetic fracture pattern in well fixed femoral stems with polished, tapered, collarless design of total hip replacement.

Peri-prosthetic fractures (PPF) are a recognised complication following hip arthroplasty. Prosthesis design and type influence PPF pattern. Surgeons rely on classification systems, such as the Vancouver, to aid treatment planning. This study highlights a specific fracture pattern that occurs with cemented well-fixed polished, tapered, collarless (PTC) stems. We reviewed a consecutive series of 21 PPF around well fixed PTC stems. The majority of the fractures were classified pre-operatively as Vancouver B2 (14/21), but there were also B1 (6/21) and A type fractures. The B2 fractures had common radiological and intra-operative findings: a spiral fracture with extensive fragmentation of bone and cement, debonding of cement from the implant, cement fracture, and a well-fixed cement-bone interface. Reconstruction of these fractures was more difficult than suggested by the radiographs. Two of the six patients who were considered to have a Vancouver B1 fracture underwent open reduction and internal fixation (ORIF), and had treatment-related complications. Retrospective review of the radiographs showed subtle features, such as subsidence of the stem into the centraliser, that are characteristic of a B2 fracture pattern. In summary, it is important to recognise this fracture pattern around secure PTC stems in order to prevent misinterpretation of the fracture as a Vancouver B1 rather than a B2, leading to failure of treatment, and to alert the surgeon that complex reconstruction will be required because of the extensive fragmentation.

The management of periprosthetic fractures Oxford trimodular femoral stem. A survivorship study.

A consecutive series of 40 periprosthetic femoral fractures, treated with revision hip surgery using the Oxford trimodular femoral stem, were retrospectively studied, with an average follow-up of 7.9 years. Fractures were classified according to the Vancouver classification. There were 5 type B1 fractures, 28 type B2, and 7 type C. Radiographic union was achieved in 38 (95%) hips. The mean time to fracture union was 3.5 months. The prosthesis survival at 5 years was 95% (confidence interval, 88%-100%). Clinical results were good with a mean Oxford hip score of 30 (hip score maximum, 48). Complications included 1 nonunion, 1 infection, 1 dislocation, and 2 aseptic loosening. The Oxford trimodular femoral component is a safe and reliable prosthesis for the treatment of periprosthetic femoral fractures with satisfactory medium-term results.

Femoral neck fractures after hip resurfacing.

Femoral neck fracture is an important early complication after hip resurfacing. Our aims were firstly to determine the incidence of fracture in an independent series and secondly, in a case control study, to investigate potential risk factors. Fifteen femoral neck fractures occurred in a series of 842 procedures, representing an incidence of 1.8%. No relationship existed between age, sex, and fracture incidence. Mechanical factors such as notching, femoral neck lengthening, and varus alignment of the femoral component were found to have a similar incidence in both fracture and control groups. The proportion of patients that had at least 1 mechanical risk factor was not different between the 2 groups (fracture group, 50%; control group, 41%). Established avascular necrosis of the femoral head was evident in all retrieved femoral heads (n = 9) of patients who sustained postoperative fracture; in none of these patients was avascular necrosis the initial diagnosis. This study suggests that in our practice, mechanical factors, such as neck notching, neck lengthening, or varus angulations, are not the primary cause of femoral neck fractures.

Native hip joint septic arthritis in 20 adults: delayed presentation beyond three weeks predicts need for excision arthroplasty.

OBJECTIVES: Septic arthritis of native hip joints is an uncommon condition in adults in Western Europe, but continues to present a challenge to medical and surgical management. We set out to study the natural history and bacteriology of the disease in this group, with a particular focus on patients requiring excision arthroplasty (EA). METHODS: We retrospectively studied 26 secondary referral cases (20 adults) managed by a specialist bone infection unit over a 12 year period. RESULTS: Our patient cohort was diverse, affecting all age groups in the presence and absence of co-morbid conditions. The commonest pathogen was Staphylococcus aureus. Of 20 adults studied, five (25%) required EA. Symptom duration prior to presentation was a statistical predictor of the requirement for EA (p<0.003); in particular, symptom duration of over three weeks was strongly associated with requirement for this procedure (p<0.0003). CONCLUSIONS: In cases that present promptly, combined surgical drainage and intravenous antibiotics should be expected to eradicate infection and to salvage the femoral head. Cases presenting following a delay are more likely to require EA and subsequent hip reconstruction.

Mediation of the proinflammatory cytokine response in rheumatoid arthritis and spondylarthritis by interactions between fibroblast-like synoviocytes and natural killer cells.

OBJECTIVE: Fibroblast-like synoviocytes (FLS) are potentially directly involved in the propagation of inflammation. We have previously shown evidence of an expanded activated population of natural killer (NK) cells in spondylarthritis (SpA) patients. In the present study, we sought to determine whether the interaction between NK cells and FLS from SpA patients results in a proinflammatory response. METHODS: Autologous NK cells and FLS were obtained from 6 patients with SpA, 4 patients with rheumatoid arthritis (RA), and 8 patients with osteoarthritis (OA). Physical interactions between NK cells and FLS were studied by time-lapse phase-contrast microscopy. Fluorescence-activated cell sorting was used to study the activation, proliferation, and survival of NK cells in contact with FLS. Cytokine and stromal factor production were measured by a multiple cytokine bead assay. RESULTS: NK cells both adhered to and migrated beneath the FLS monolayer (pseudoemperipolesis). FLS from SpA and RA patients supported increased pseudoemperipolesis, activation, cytokine production, and survival of NK cells. The production of proinflammatory cytokines, including interleukin-6 (IL-6), IL-8, IL-1beta, and IL-15, was increased in cocultures of NK cells and FLS, particularly in those from RA and SpA patients. Production of interferon-gamma, RANTES, and matrix metalloproteinase 3 (MMP-3) by NK cell and FLS coculture was greatest in SpA patients. Surface expression of IL-15 on FLS was significantly increased in SpA and RA patients, but not OA patients. Blockade with an IL-15 monoclonal antibody resulted in increased apoptosis of NK cells. CONCLUSION: FLS promote the migration, activation, and survival of NK cells. The interaction of NK cells with FLS results in increased IL-15 expression by FLS and the production of proinflammatory chemokines, cytokines, and MMPs, which may contribute to joint inflammation. This response was much more marked in SpA and RA patients as compared with OA patients.

CD56bright NK cells are enriched at inflammatory sites and can engage with monocytes in a reciprocal program of activation.

Human NK cells may be divided into a CD56(dim) subset and a CD56(bright) subset. In peripheral blood, CD56(dim) NK cells dominate, whereas in lymph nodes, CD56(bright) NK cells are more common. In this study we show that CD56(bright) NK cells accumulate within inflammatory lesions in a wide variety of clinical diseases affecting several different anatomical sites. We demonstrate that when activated by the monokines IL-12, IL-15, and IL-18, these NK cells promote TNF-alpha production by CD14(+) monocytes in a manner that is dependent on cell:cell contact. Conversely, CD14(+) monocytes synergize with monokines to promote IFN-gamma production by these NK cells. Again, this interaction is dependent on cell:cell contact. The experiments show that CD56(bright) NK cells accumulate in inflammatory lesions and, in the appropriate cytokine environment, can engage with CD14(+) monocytes in a reciprocal activatory fashion, thereby amplifying the inflammatory response. Such a positive feedback loop is likely to be important in the pathogenesis of chronic inflammatory conditions such as rheumatoid arthritis.