Designing patient-oriented combination therapies for acute myeloid leukemia based on efficacy/toxicity integration and bipartite network modeling.

Acute myeloid leukemia (AML), a heterogeneous and aggressive blood cancer, does not respond well to single-drug therapy. A combination of drugs is required to effectively treat this disease. Computational models are critical for combination therapy discovery due to the tens of thousands of two-drug combinations, even with approved drugs. While predicting synergistic drugs is the focus of current methods, few consider drug efficacy and potential toxicity, which are crucial for treatment success. To find effective new drug candidates, we constructed a bipartite network using patient-derived tumor samples and drugs. The network is based on drug-response screening and summarizes all treatment response heterogeneity as drug response weights. This bipartite network is then projected onto the drug part, resulting in the drug similarity network. Distinct drug clusters were identified using community detection methods, each targeting different biological processes and pathways as revealed by enrichment and pathway analysis of the drugs' protein targets. Four drugs with the highest efficacy and lowest toxicity from each cluster were selected and tested for drug sensitivity using cell viability assays on various samples. Results show that ruxolitinib-ulixertinib and sapanisertib-LY3009120 are the most effective combinations with the least toxicity and the best synergistic effect on blast cells. These findings lay the foundation for personalized and successful AML therapies, ultimately leading to the development of drug combinations that can be used alongside standard first-line AML treatment.

Robust scoring of selective drug responses for patient-tailored therapy selection.

Most patients with advanced malignancies are treated with severely toxic, first-line chemotherapies. Personalized treatment strategies have led to improved patient outcomes and could replace one-size-fits-all therapies, yet they need to be tailored by testing of a range of targeted drugs in primary patient cells. Most functional precision medicine studies use simple drug-response metrics, which cannot quantify the selective effects of drugs (i.e., the differential responses of cancer cells and normal cells). We developed a computational method for selective drug-sensitivity scoring (DSS), which enables normalization of the individual patient's responses against normal cell responses. The selective response scoring uses the inhibition of noncancerous cells as a proxy for potential drug toxicity, which can in turn be used to identify effective and safer treatment options. Here, we explain how to apply the selective DSS calculation for guiding precision medicine in patients with leukemia treated across three cancer centers in Europe and the USA; the generic methods are also widely applicable to other malignancies that are amenable to drug testing. The open-source and extendable R-codes provide a robust means to tailor personalized treatment strategies on the basis of increasingly available ex vivo drug-testing data from patients in real-world and clinical trial settings. We also make available drug-response profiles to 527 anticancer compounds tested in 10 healthy bone marrow samples as reference data for selective scoring and de-prioritization of drugs that show broadly toxic effects. The procedure takes <60 min and requires basic skills in R.

Simultaneous bilateral versus unilateral total hip arthroplasty: Pain and physical function in a one- and five-year follow-up - retrospective patients record study.

BACKGROUND: Total hip arthroplasty (THA) decreases pain and improves function in patients with osteoarthritis. In some cases, both hips have been operated simultaneously. Our aim was to report patients' pain and physical function after one- and five-years post-operatively among patients who underwent unilateral THA and those who underwent bilateral THA at the same time in one orthopaedic hospital in Finland. METHODS: The study group consisted of 488 patients retrospectively selected patients from a single centre; 421 of them underwent unilateral THA and 67 underwent simultaneous bilateral THA. The patients had two clinical examinations one and five years postoperatively. Systematic data about pain and physical function were collected using the scaled Orton Hip Score (sOHS). Register data on revisions and mortality events were from the Finnish Institute of Health and Welfare. RESULTS: At the one-year follow-up, total sOHS was improved remarkably from the preoperative situation, both in the unilateral THA (age and gender adjusted mean improvement 42 points (95% CI: 40 to 44, p < 0.001) and in the bilateral THA groups (age and gender adjusted mean improvement 45 [95% CI: 41 to 49], p < 0.001), with no group differences after five-years of operation (age and gender adjusted p = 0.19). Total sOHS was statistically higher in the bilateral THA compared to the unilateral THA after one year (98 vs. 95, p < 0.001) and five years (97 vs. 95, p = 0.003) of operation. CONCLUSIONS: Patients in unilateral THA and bilateral THA groups had increased their physical function, and pain had decreased after one-year follow-up of the primary THA operation, and condition remained after five years of operation. At follow-ups, patients who underwent bilateral THA had slightly better physical function compared to patients who underwent unilateral THA at follow-up; however, this difference had no clinical relevance.

Engineering Inflammation-Resistant Cartilage: Bridging Gene Therapy and Tissue Engineering.

Articular cartilage defects caused by traumatic injury rarely heal spontaneously and predispose into post-traumatic osteoarthritis. In the current autologous cell-based treatments the regenerative process is often hampered by the poor regenerative capacity of adult cells and the inflammatory state of the injured joint. The lack of ideal treatment options for cartilage injuries motivated the authors to tissue engineer a cartilage tissue which would be more resistant to inflammation. A clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 knockout of TGF-ß-activated kinase 1 (TAK1) gene in polydactyly chondrocytes provides multivalent protection against the signals that activate the pro-inflammatory and catabolic NF-κB pathway. The TAK1-KO chondrocytes encapsulate into a hyaluronan hydrogel deposit copious cartilage extracellular matrix proteins and facilitate integration onto native cartilage, even under proinflammatory conditions. Furthermore, when implanted in vivo, compared to WT fewer pro-inflammatory M1 macrophages invade the cartilage, likely due to the lower levels of cytokines secreted by the TAK1-KO polydactyly chondrocytes. The engineered cartilage thus represents a new paradigm-shift for the creation of more potent and functional tissues for use in regenerative medicine.

No difference in implant survival between 28-mm M2a RingLoc metal-on-metal and metal-on-polyethylene total hip arthroplasty: results from the Finnish Arthroplasty Register.

BACKGROUND AND PURPOSE: Long-term outcome of small head (28 mm) metal-on-metal (MoM) total hip arthroplasty (THA) is available mainly for Metasul devices (Sulzer Medica, Winterthur, Switzerland). Biomet MoM THA was frequently used in Finland. Therefore, we assessed long-term survivorship of the M2a 28-mm RingLoc MoM THA (Biomet, Warsaw, IN, USA) and compared it with the metal-on-polyethylene (MoP) RingLoc THA from the same manufacturer. PATIENTS AND METHODS: We conducted a register study based on THAs from the Finnish Arthroplasty Register performed between January 1, 2000 and December 31, 2007. 290 28-mm head M2a MoM THAs and 1,647 28-mm head MoP THAs (reference group) were included. The endpoint was revision for any reason, or revision for aseptic loosening, osteolysis, liner wear, or metallosis as one group. Kaplan-Meier survival estimates were calculated, and revision risks were assessed using a Cox multiple regression model, both with 95% confidence intervals (CI). RESULTS: No difference was found in the 15-year Kaplan-Meier survivorship between the 28-mm head M2a RingLoc MoM THA and the reference group for any reason for revision (87.7% [82.9-92.1] and 83.3% [81.0-85.3], respectively). The adjusted hazard ratio (HR) for any reason for revision for the MoM THA group compared with the reference group was at least equal or better (0.70 [0.48-1.02]). Both groups presented similar survival for revision for aseptic loosening of the cup, osteolysis, liner wear, or metallosis, at 96.2% (92.7-98.0) and 95.4% (93.9-96.5), respectively. INTERPRETATION: In the long-term survival there was no difference between the M2a 28-mm RingLoc MoM THA and 28-mm MoP THA. Further follow-up regimens for M2a 28-mm RingLoc THA patients may be unnecessary, but long-term metal ion and radiological data is needed before any formal suggestions.

Growth Response and Differentiation of Bone Marrow-Derived Mesenchymal Stem/Stromal Cells in the Presence of Novel Multiple Myeloma Drug Melflufen.

Mesenchymal stem/stromal cells (MSCs) are self-renewing and multipotent progenitors, which constitute the main cellular compartment of the bone marrow stroma. Because MSCs have an important role in the pathogenesis of multiple myeloma, it is essential to know if novel drugs target MSCs. Melflufen is a novel anticancer peptide-drug conjugate compound for patients with relapsed refractory multiple myeloma. Here, we studied the cytotoxicity of melflufen, melphalan and doxorubicin in healthy human bone marrow-derived MSCs (BMSCs) and how these drugs affect BMSC proliferation. We established co-cultures of BMSCs with MM.1S myeloma cells to see if BMSCs increase or decrease the cytotoxicity of melflufen, melphalan, bortezomib and doxorubicin. We evaluated how the drugs affect BMSC differentiation into adipocytes and osteoblasts and the BMSC-supported formation of vascular networks. Our results showed that BMSCs were more sensitive to melflufen than to melphalan. The cytotoxicity of melflufen in myeloma cells was not affected by the co-culture with BMSCs, as was the case for melphalan, bortezomib and doxorubicin. Adipogenesis, osteogenesis and BMSC-mediated angiogenesis were all affected by melflufen. Melphalan and doxorubicin affected BMSC differentiation in similar ways. The effects on adipogenesis and osteogenesis were not solely because of effects on proliferation, seen from the differential expression of differentiation markers normalized by cell number. Overall, our results indicate that melflufen has a significant impact on BMSCs, which could possibly affect therapy outcome.

Obese people benefit from lumbar spinal stenosis surgery as much as people of normal weight.

BACKGROUND: Lumbar spinal stenosis (LSS) is a common degenerative condition of the spine that causes back pain radiating to the lower extremity. Surgical treatment is indicated to treat progressive radical symptoms. Obesity has been associated with inferior results in the domains of quality of life (QoL) following an LSS operation, but the research findings have been limited. This paper aims to identify whether obesity affects QoL due to back pain among patients who underwent an operation for LSS. METHODS: This study is based on a series of patients operated on for LSS between 2012 and 2018. Operated patients who returned for follow-up forms within the first or second years were included. A total of 359 patients were selected, 163 males (45%) and 196 females (55%). The mean age was 68.9 years. The EuroQol five-dimension scale (EQ-5D) questionnaire was chosen to measure QoL and the Oswestry Disability Index (ODI) for functional disability. RESULTS: QoL, as measured by EQ-5D, was preoperatively lower in those patients with a BMI ≥ 30. One year after the operation, all groups had a similar trend of improved QoL. At the second year, the results in all groups levelled off even though there was no statistical difference in clinical outcomes (p = 0.92). The ODI was preoperatively statistically higher in patients with a BMI ≥ 30 (p < 0.001). Two years after the surgery, all groups had improved ODI scores, but there was no statistical difference in ODI between the BMI groups (p = 0.54). CONCLUSION: Surgical intervention for debilitating or longstanding symptoms of LSS should be considered as a treatment option for suitable patients in spite of an elevated BMI.

Risk factors for prosthetic joint infections following total hip arthroplasty based on 33,337 hips in the Finnish Arthroplasty Register from 2014 to 2018.

Background and purpose - Periprosthetic joint infection (PJI) is a devastating complication and more information on risk factors for PJI is required to find measures to prevent infections. Therefore, we assessed risk factors for PJI after primary total hip arthroplasty (THA) in a large patient cohort.Patients and methods - We analyzed 33,337 primary THAs performed between May 2014 and January 2018 based on the Finnish Arthroplasty Register (FAR). Cox proportional hazards regression was used to estimate hazard ratios with 95% confidence intervals (CI) for first PJI revision operation using 25 potential patient- and surgical-related risk factors as covariates.Results - 350 primary THAs were revised for the first time due to PJI during the study period. The hazard ratios for PJI revision in multivariable analysis were 2.0 (CI 1.3-3.2) for ASA class II and 3.2 (2.0-5.1) for ASA class III-IV compared with ASA class I, 1.4 (1.1-1.7) for bleeding > 500 mL compared with < 500 mL, 0.4 (0.2-0.7) for ceramic-on-ceramic bearing couple compared with metal-on-polyethylene and for the first 3 postoperative weeks, 3.0 (1.6-5.6) for operation time of > 120 minutes compared with 45-59 minutes, and 2.6 (1.4-4.9) for simultaneous bilateral operation. In the univariable analysis, hazard ratios for PJI revision were 2.3 (1.7-3.3) for BMI of 31-35 and 5.0 (3.5-7.1) for BMI of > 35 compared with patients with BMI of 21-25.Interpretation - We found several modifiable risk factors associated with increased PJI revision risk after THA to which special attention should be paid preoperatively. In particular, high BMI may be an even more prominent risk factor for PJI than previously assessed.

Preoperative Risk Prediction Models for Short-Term Revision and Death After Total Hip Arthroplasty: Data from the Finnish Arthroplasty Register.

Because of the increasing number of total hip arthroplasties (THAs), even a small proportion of complications after the operation can lead to substantial individual difficulties and health-care costs. The aim of this study was to develop simple-to-use risk prediction models to assess the risk of the most common reasons for implant failure to facilitate clinical decision-making and to ensure long-term survival of primary THAs. METHODS: We analyzed patient and surgical data reported to the Finnish Arthroplasty Register (FAR) on 25,919 primary THAs performed in Finland between May 2014 and January 2018. For the most frequent adverse outcomes after primary THA, we developed multivariable Lasso regression models based on the data of the randomly selected training cohort (two-thirds of the data). The performances of all models were validated using the remaining, independent test set consisting of 8,640 primary THAs (one-third of the data) not used for building the models. RESULTS: The most common outcomes within 6 months after the primary THA were revision operations due to periprosthetic joint infection (1.1%), dislocation (0.7%), or periprosthetic fracture (0.5%), and death (0.7%). For each of these outcomes, Lasso regression identified subsets of variables required for accurate risk predictions. The highest discrimination performance, in terms of area under the receiver operating characteristic curve (AUROC), was observed for death (0.84), whereas the performance was lower for revisions due to periprosthetic joint infection (0.68), dislocation (0.64), or periprosthetic fracture (0.65). CONCLUSIONS: Based on the small number of preoperative characteristics of the patient and modifiable surgical parameters, the developed risk prediction models can be easily used to assess the risk of revision or death. All developed models hold the potential to aid clinical decision-making, ultimately leading to improved clinical outcomes. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

Implant Survival of 6,080 Tritanium Cups in Primary Total Hip Arthroplasty: Data from the Finnish Arthroplasty Register from 2009 to 2017.

BACKGROUND: To enhance osseointegration in total hip arthroplasty (THA), ultraporous or highly porous-coated cups were introduced. Implant survival data on these new devices have been scarce. The aim of our study was to assess the survivorship of ultraporous Tritanium cups (Stryker) in a population-based register study. METHODS: In this study, we collected data on 6,080 primary THAs using a Tritanium cup and 25,670 THAs using a conventional cup (control group) from the Finnish Arthroplasty Register; these procedures were performed from January 1, 2009, to December 31, 2017. We calculated the Kaplan-Meier survival estimates with 95% confidence intervals (CIs). The end point was revision for any reason or for aseptic loosening of the cup. The revision risks were assessed with use of the Cox multiple regression model. The variables assessed in the Cox model were femoral head size, age group, involved side, operation year, sex, diagnosis, and fixation of the stem. The proportional hazards assumption of the Cox model was not fulfilled, so the follow-up time was divided into 3 time periods: 0 to 2 years, >2 to 4 years, and >4 years. RESULTS: When comparing the 2 groups with regard to revision for any reason, the 5-year Kaplan-Meier survivorship of the Tritanium group (94.7% [95% CI, 94.0% to 95.4%]) was inferior to that of the control group (96.0% [95% CI, 95.7% to 96.3%]). In the Cox regression analysis of the 2 groups for the time period of >4 years, the Tritanium group had an increased risk of revision for any reason compared with the control group (hazard ratio [HR], 3.12 [95% CI, 1.82 to 5.35]; p < 0.001). With regard to revision for aseptic loosening of the cup, the Tritanium group had an increased risk of revision compared with the control group for both 0 to 2 years (HR, 3.80 [95% CI, 1.76 to 8.24]; p < 0.001) and >2 to 4 years (HR, 11.2 [95% CI, 3.28 to 38.0]; p < 0.001). CONCLUSIONS: There was no advantage to using the ultraporous-coated Tritanium cup for primary THA compared with conventional uncemented cups. However, wide CIs for some HR estimates may point to a lack of precision. Therefore, further research on subject is needed. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Osteoarthritis and Toll-Like Receptors: When Innate Immunity Meets Chondrocyte Apoptosis.

Osteoarthritis (OA) has long been viewed as a degenerative disease of cartilage, but accumulating evidence indicates that inflammation has a critical role in its pathogenesis. In particular, chondrocyte-mediated inflammatory responses triggered by the activation of innate immune receptors by alarmins (also known as danger signals) are thought to be involved. Thus, toll-like receptors (TLRs) and their signaling pathways are of particular interest. Recent reports suggest that among the TLR-induced innate immune responses, apoptosis is one of the critical events. Apoptosis is of particular importance, given that chondrocyte death is a dominant feature in OA. This review focuses on the role of TLR signaling in chondrocytes and the role of TLR activation in chondrocyte apoptosis. The functional relevance of TLR and TLR-triggered apoptosis in OA are discussed as well as their relevance as candidates for novel disease-modifying OA drugs (DMOADs).

Tumor necrosis factor primes and metal particles activate the NLRP3 inflammasome in human primary macrophages.

Aseptic loosening of total joint replacements is driven by a macrophage-mediated inflammatory reaction to implant-derived wear particles. Phagocytosis of implant debris has been suggested to activate the NLRP3 inflammasome leading to secretion of interleukin (IL)-1ß. However, factors and molecular mechanisms driving the particle-induced inflammasome activation are yet to be fully elucidated. In this study, we investigated the inflammasome response of human primary macrophages to titanium, chromium, and molybdenum particles in vitro. We observed that particles alone were not sufficient to induce IL-1ß secretion, but an additional priming signal-such as bacterial lipopolysaccharide (LPS)-was required to license the inflammasome activation. By using specific inhibitors against the inflammasome signaling pathway, we demonstrate that the particle-induced IL-1ß secretion depended upon activation of the NLRP3 inflammasome. We further hypothesized that tumor necrosis factor (TNF) could substitute for LPS as a priming signal, and found that particle stimulation together with preceding TNF treatment resulted in inflammasome-dependent IL-1ß production as well. Our results show that the NLRP3 inflammasome mediates wear particle responses in human primary macrophages, and its activation does not necessarily require the presence of bacterial components, but can be induced under aseptic conditions by TNF priming. STATEMENT OF SIGNIFICANCE: This study was conducted to elucidate the molecular mechanisms of metal particle-induced IL-1ß secretion in human primary macrophages. Production of this pro-inflammatory mediator from wear particle-activated macrophages has been associated with increased bone loss around total joint replacements-a condition eventually requiring revision surgery. Our results confirm that together with a co-stimulatory priming signal, particles of common implant metals elicit macrophage-mediated IL-1ß secretion through activation of the NLRP3 inflammasome pathway. We also present a concept of TNF priming in this context, demonstrating that the particle-related IL-1ß secretion can take place in a truly sterile environment. Thus, inhibition of inflammasome signaling appears a means to prevent wear particle-induced inflammation and development of peri­prosthetic osteolysis.

Implant Survival of Constrained Acetabular Device in Primary Total Hip Arthroplasty Based on Data From the Finnish Arthroplasty Register.

BACKGROUND: Constrained acetabular devices were developed to prevent dislocations after total hip arthroplasty (THA). However, the data on their success have been contradictory. In this study, we aimed to assess implant survival of the constrained acetabular device in primary THA based on the Finnish Arthroplasty Register data. METHODS: A total of 373 primary THAs with constrained acetabular devices inserted from 2006 to 2017 were included. A reference group was formed on a 1:3 basis and matched for age, sex, and diagnosis, consisting of 1118 conventional THAs. Implant survival estimates using death as a competing risk were assessed with revision for any reason and for any aseptic reason as the endpoints. The Cox multiple regression models were adjusted for age, sex, and diagnosis. The mean follow-up time was 3.3 (0-12.4) years for the constrained device group and 3.8 (0-12.0) years for the reference group. RESULTS: Overall, there were 21 revisions in the constrained device group and 49 in the reference group. The 8-year survivorship for any reason was 94% (confidence interval [CI]: 91-96) for the constrained device group and 93% (CI: 89-97) for the reference group. With revision for any aseptic reason as the endpoint, the 8-year survivorships were 97% (CI: 95-99) and 94% (CI: 90-98), respectively. During the first 1.5 years, the constrained acetabular device group had a similar revision risk (hazard ratio: 1.09 [CI: 0.57-2.07], P = .8) to that of the reference group. CONCLUSION: The constrained acetabular device had good survival in primary THA, and our results support its continued use even in high-risk patients.

Early Results of Our International, Multicenter, Multisurgeon, Double-Blinded, Prospective, Randomized, Controlled Trial Comparing Metal-on-Metal With Ceramic-on-Metal in Total Hip Arthroplasty.

BACKGROUND: The aim of our prospective, multicenter, randomized, controlled trial (titled M2A-38 Ceramic-on-Metal RCT, NCT00754520) is to demonstrate noninferiority of a ceramic-on-metal (CoM) articulation compared with metal-on-metal (MoM) in total hip arthroplasty. The study arms are at 8 years since implantation, with metal ion and functional score analysis at 5 years. METHODS: We recruited 211 patients between 2009 and 2011. The patients were randomized to ceramic or metal. A cohort of these patients had whole blood metal ions performed yearly, and all patients underwent annual radiographic and clinical outcome assessment. All revisions were recorded and some explants were analyzed. Recruitment ceased earlier than planned owing to concerns raised with failure of MoM implants. RESULTS: No significant difference was seen in patient demographics, radiographic parameters, or functional outcomes at any time point. Lower cobalt ion levels were seen in the CoM group (P < .01) at all time points. Chromium levels were significantly lower in the CoM group up to 3 years, but raised at 5 years. There were slightly fewer revisions for adverse reaction to metal debris in the CoM group. Explant analysis suggested a different wear pattern to those seen in the MoM group. CONCLUSION: The results demonstrated that the CoM articulation behaved the same as the MoM in terms of functional outcome and radiographic parameters. The CoM coupling also demonstrates raised metal ions beyond 3 years and increasing revisions for adverse reaction to metal debris. It remains difficult to see a clinical application for CoM and further exploration or use is not warranted.

Short-term survival of cementless Oxford unicondylar knee arthroplasty based on the Finnish Arthroplasty Register.

BACKGROUND: Cementless unicondylar knee arthroplasty (UKA) was introduced to secure long-term fixation and reduce the risk of revision. Experience with cementless UKA fixation is limited. METHODS: The short-term survival (up to five years) of cementless Oxford UKA was assessed using data from the Finish Arthroplasty Register and was compared with that of cemented Oxford 3 UKA and total knee arthroplasty (TKA). Datawere obtained, from the Finnish Arthroplasty Register, on 1076 cementless Oxford UKAs and 2279 cemented Oxford 3 UKAs performed for primary osteoarthritis in 2005-2015. The Kaplan-Meier method, with revision for any reason as the endpoint, was used to assess the survival of these two UKA groups, and the results were compared with that of 65,563 cemented TKAs treated for primary osteoarthritis over the same period. The risk of revision of both Oxford prostheses was compared using Cox regression model, with adjustment for age and sex, with the cemented TKA group as reference. RESULTS: The three-year survival was 93.7% for the cementless Oxford, 92.2% for the cemented Oxford 3, and 97.3% for the cemented TKA. The corresponding figures at five years were 92.3%, 88.9%, and 96.6%, respectively. The revision rate for both the cementless Oxford and the cemented Oxford 3 was significantly increased when compared with the cemented TKA (P < 0.001). CONCLUSIONS: The survival of the cementless Oxford method was higher than that of the cemented Oxford 3 in the short term. The overall survival of Oxford UKA was poor in comparison with contemporary TKAs.

Survival of 11,390 Continuum cups in primary total hip arthroplasty based on data from the Finnish Arthroplasty Register.

Background and purpose - The use of trabecular metal (TM) cups for primary total hip arthroplasty (THA) is increasing. Some recent data suggest that the use of TM in primary THA might be associated with an increased risk of revision. We compared implant survival of Continuum acetabular cups with other commonly used uncemented cups. Patients and methods - Data on 11,390 primary THAs with the Continuum cup and 30,372 THAs with other uncemented cups (reference group) were collected from the Finnish Arthroplasty Register. Kaplan-Meier survival estimates were calculated; the endpoint was revision for any reason, for infection, or for dislocation. Revision risks were assessed with adjusted Cox multiple regression models. A subgroup analysis on the use of neutral or elevated liners in the Continuum group was made. Results - The 7-year survivorship of the Continuum group was 94.6% (95% CI 94.0-95.2) versus 95.6% (CI 95.3-95.8) in the reference group for revision for any reason. The risk for revision was higher in the Continuum group than in the reference group both for revision for any reason (HR 1.3 [CI 1.2-1.5)]) and for revision for dislocation (HR 1.9 [CI 1.5-2.3]). There was no difference in the rates of revision because of infection (HR 0.99 [CI 0.78-1.3]). Use of a neutral liner increased the risk for revision due to dislocation in comparison with the use of an elevated rim liner in the Continuum group (HR 1.7 [CI 1.2-2.5]). Interpretation - THA with Continuum cups is associated with an increased risk of revision compared with other uncemented cups, mainly due to revisions because of dislocation. Our results support the use of an elevated liner when Continuum cups are used for primary THA.

Novel osteoconductive ß-tricalcium phosphate/poly(L-lactide-co-e-caprolactone) scaffold for bone regeneration: a study in a rabbit calvarial defect.

The advantages of synthetic bone graft substitutes over autogenous bone grafts include abundant graft volume, lack of complications related to the graft harvesting, and shorter operation and recovery times for the patient. We studied a new synthetic supercritical CO2 -processed porous composite scaffold of ß-tricalcium phosphate and poly(L-lactide-co-caprolactone) copolymer as a bone graft substitute in a rabbit calvarial defect. Bilateral 12 mm diameter critical size calvarial defects were successfully created in 18 rabbits. The right defect was filled with a scaffold moistened with bone marrow aspirate, and the other was an empty control. The material was assessed for applicability during surgery. The follow-up times were 4, 12, and 24 weeks. Radiographic and micro-CT studies and histopathological analysis were used to evaluate new bone formation, tissue ingrowth, and biocompatibility. The scaffold was easy to shape and handle during the surgery, and the bone-scaffold contact was tight when visually evaluated after the implantation. The material showed good biocompatibility and its porosity enabled rapid invasion of vasculature and full thickness mesenchymal tissue ingrowth already at four weeks. By 24 weeks, full thickness bone ingrowth within the scaffold and along the dura was generally seen. In contrast, the empty defect had only a thin layer of new bone at 24 weeks. The radiodensity of the material was similar to the density of the intact bone. In conclusion, the new porous scaffold material, composed of microgranular ß-TCP bound into the polymer matrix, proved to be a promising osteoconductive bone graft substitute with excellent handling properties.

Hemostatic profile under fluid resuscitation during rivaroxaban anticoagulation: an in vitro survey.

BACKGROUND: Uncontrollable bleeding is the leading cause of death in traumatically injured patients. The extent to which direct factor Xa inhibitors interfere with the applied resuscitation measures is presently unknown. STUDY DESIGN AND METHODS: In this study, we investigated the effect of the resuscitation fluids saline, albumin, fresh frozen plasma (FFP) and solvent/detergent (S/D)-treated plasma, fibrinogen concentrate, prothrombin complex concentrate (PCC), and combinations thereof on the hemostatic profile of rivaroxaban-anticoagulated whole blood and plasma. We used rivaroxaban-spiked whole blood and plasma from healthy donors, as well as plasma from patients on rivaroxaban, and mimicked a resuscitation approach in a 50% plasma dilution setting. Thromboelastography, thrombin generation, and fibrin generation clot lysis test were assessed using tissue factor to initiate coagulation and tissue plasminogen activator to induce clot lysis. RESULTS: Rivaroxaban resulted in a hypocoagulant state that remained largely unaltered upon subsequent 50% dilution with S/D-treated plasma or FFP. Using S/D-treated plasma as a diluent, clot stability decreased due to its low α2 -antiplasmin. Dilution with saline and albumin induced a profibrinolytic state and further deteriorated the impaired hemostatic potential of rivaroxaban-anticoagulated blood, even after PCC and fibrinogen support. Combined use of plasma (either FFP or S/D treated) and PCC, however, considerably improved both coagulation and clot stability. CONCLUSION: In the setting of rivaroxaban anticoagulation and major blood loss, transfusing plasma together with PCC may provide the most effective resuscitation approach with the notion that additional antifibrinolytic drug support (e.g., tranexamic acid) is likely required.

High Revision Rate for Large-head Metal-on-metal THA at a Mean of 7.1 Years: A Registry Study.

BACKGROUND: Large-diameter head metal-on-metal (MoM) THA has largely been abandoned as a result of higher than anticipated revision rates. However, the majority of these implants are still in situ. Although earlier reports from the Finnish Arthroplasty Register noted similar short-term survivorship between large-diameter head MoM THA and conventional cemented THA, longer term survivorship of this population is unclear. Although reported revision rates for this implant group have been high, the majority of these implants have not been revised and followup is important to improve long-term management. QUESTIONS/PURPOSES: The purposes of this study were (1) to compare the 10-year competing risk survivorship of large-diameter head MoM THA with the survivorship of conventional THA in the Finnish Arthroplasty Register; (2) to report the large-diameter head MoM THA survival at the manufacturer/brand level; and (3) to identify the most common reasons for revision of large-diameter head MoM THA in the Finnish Arthroplasty Register. METHODS: The six most commonly used large-diameter head (≥ 38 mm) MoM THA devices in Finland between years 2004 and 2013 were selected (n = 10,959 implants). The completeness of the Finnish Registry is > 95% in primary THA and patients are censored from the date of death or at the point of emigration; followup continued until the end of 2015. The conventional THA control group consisted of the two most frequently used devices (Vision/Bimetric and ABG II/ABG II) with metal-on-polyethylene or ceramic-on-ceramic bearing surfaces implanted between 2002 and 2013 (n = 5177). The study group was formed by selecting all pairs of large-diameter head MoM and reference THA protheses within the same age group ( < 49, 50-54, 55-59, 60-64, 65-69, 70-74, and 75+ years), sex, diagnosis (osteoarthritis, other), and hospital yearly operation count (< 100 operations yearly, ≥ 100 operations yearly); 5166 matched pairs were identified. Revision for any reason was considered as the failure endpoint of followup. Implant survival (the proportion not revised) was calculated from corresponding cumulative incidence function adjusted for patient death as a competing event for revision. Large-diameter head MoM implant group revision hazard ratios with 95% confidence intervals were estimated with age group, sex, diagnosis, and hospital yearly operation count as confounding factors in a Cox regression model. RESULTS: Ten-year survivorship free from all-cause revision was lower for THAs that used a large-diameter femoral head than it was for the control group of conventional THA (83% [95% confidence interval {CI}, 82%-84%] versus 92% [95% CI, 91%-93%]). At the implant level, every large-diameter head MoM THA had a higher risk for revision compared with the conventional THA control group from the fourth postoperative year onward. The highest survival of MoM THA was 88% (95% CI, 86%-90%) for the ReCap/Bimetric and the lowest survival was 46% (95% CI, 41%-51%) for the recalled ASR with either the Summit® or Corail® stem. The most common revision reason in the MoM THA group was adverse reaction to metal debris, whereas dislocation was predominant in the conventional THA control group. CONCLUSIONS: The revision rate for all large-diameter head MoM THAs in this timeframe in the Finnish Arthroplasty Register is unacceptably high and in our view supports the decision to abandon their use. In agreement with the directives of other national organizations, we recommend regular followup of all patients with large-diameter head MoM THA. Based on our results, strict guidelines for followup should be maintained over the lifetime of the implant to assess patient symptoms and recommend revision when indicated. LEVEL OF EVIDENCE: Level III, therapeutic study.