Aims. Hip arthroplasty aims to accurately recreate joint biomechanics. Considerable attention has been paid to vertical and horizontal offset, but femoral head centre in the anteroposterior (AP) plane has received little attention. This study investigates the accuracy of restoration of joint centre of rotation in the AP plane. Methods. Postoperative CT scans of 40 patients who underwent unilateral uncemented total hip arthroplasty were analyzed. Anteroposterior offset (APO) and femoral anteversion were measured on both the operated and non-operated sides. Sagittal tilt of the
In computer simulations, the shape of the range of motion (ROM) of a stem with a cylindrical neck design will be a perfect cone. However, many modern stems have rectangular/oval-shaped necks. We hypothesized that the rectangular/oval stem neck will affect the shape of the ROM and the prosthetic impingement. Total hip arthroplasty (THA) motion while standing and sitting was simulated using a MATLAB model (one stem with a cylindrical neck and one stem with a rectangular neck). The primary predictor was the geometry of the neck (cylindrical vs rectangular) and the main outcome was the shape of ROM based on the prosthetic impingement between the neck and the liner. The secondary outcome was the difference in the ROM provided by each neck geometry and the effect of the pelvic tilt on this ROM. Multiple regression was used to analyze the data.Aims
Methods
Aims. There are concerns regarding initial stability and early periprosthetic fractures in cementless hip arthroplasty using short stems. This study aimed to investigate stress on the cortical bone around the stem and micromotions between the stem and cortical bone according to
Objectives. Periprosthetic femoral fractures (PFFs) have a higher incidence with cementless stems. The highest incidence among various cementless stem types was observed with double-wedged stems. Short stems have been introduced as a bone-preserving alternative with a higher incidence of PFF in some studies. The purpose of this study was a direct load-to-failure comparison of a double-wedged cementless stem and a short cementless stem in a cadaveric fracture model. Methods. Eight hips from four human cadaveric specimens (age mean 76 years (60 to 89)) and eight fourth-generation composite femurs were used. None of the cadaveric specimens had compromised quality (mean T value 0.4 (-1.0 to 5.7)). Each specimen from a pair randomly received either a double-wedged stem or a short stem. A materials testing machine was used for lateral load-to-failure test of up to a maximal load of 5000 N. Results. Mean load at failure of the double-wedged stem was 2540 N (1845 to 2995) and 1867 N (1135 to 2345) for the short stem (p < 0.001). All specimens showed the same fracture pattern, consistent with a Vancouver B2 fracture. The double-wedged stem was able to sustain a higher load than its short-stemmed counterpart in all cases. Failure force was not correlated to the bone mineral density (p = 0.718). Conclusion. Short stems have a significantly lower primary load at failure compared with double-wedged stems in both cadaveric and composite specimens. Surgeons should consider this biomechanical property when deciding on the use of short
Arthroplasty surgery of the knee and hip is performed in two to three million patients annually. Periprosthetic joint infections occur in 4% of these patients. Debridement, antibiotics, and implant retention (DAIR) surgery aimed at cleaning the infected prosthesis often fails, subsequently requiring invasive revision of the complete prosthetic reconstruction. Infection-specific imaging may help to guide DAIR. In this study, we evaluated a bacteria-specific hybrid tracer (99mTc-UBI29-41-Cy5) and its ability to visualize the bacterial load on femoral implants using clinical-grade image guidance methods.
99mTc-UBI29-41-Cy5 specificity for Aims
Methods
Periprosthetic hip fractures (PPFs) after total hip arthroplasty are difficult to treat. Therefore, it is important to identify modifiable risk factors such as stem selection to reduce the occurrence of PPFs. This study aimed to clarify differences in fracture torque, surface strain, and fracture type analysis between three different types of cemented stems. We conducted biomechanical testing of bone analogues using six cemented stems of three different types: collarless polished tapered (CPT) stem, Versys Advocate (Versys) stem, and Charnley-Marcel-Kerboull (CMK) stem. Experienced surgeons implanted each of these types of stems into six bone analogues, and the analogues were compressed and internally rotated until failure. Torque to fracture and fracture type were recorded. We also measured surface strain distribution using triaxial rosettes.Aims
Methods
This study aimed to evaluate the accuracy of implant placement with robotic-arm assisted total hip arthroplasty (THA) in patients with developmental dysplasia of the hip (DDH). The study analyzed a consecutive series of 69 patients who underwent robotic-arm assisted THA between September 2018 and December 2019. Of these, 30 patients had DDH and were classified according to the Crowe type. Acetabular component alignment and 3D positions were measured using pre- and postoperative CT data. The absolute differences of cup alignment and 3D position were compared between DDH and non-DDH patients. Moreover, these differences were analyzed in relation to the severity of DDH. The discrepancy of leg length and combined offset compared with contralateral hip were measured.Aims
Methods
To explore the effect of different types of articulating antibiotic-loaded cement spacers in two-stage revision for chronic hip prosthetic joint infection (PJI). A retrospective cohort study was performed involving 36 chronic PJI patients treated with different types of articulating antibiotic-loaded cement spacers between January 2014 and December 2017. The incidence of complications and the therapeutic effects of different types of antibiotic-loaded articulating cement spacers were compared.Aims
Methods
Objectives. Orthopaedic surgeons use stems in revision knee surgery to obtain
stability when metaphyseal bone is missing. No consensus exists
regarding stem size or method of fixation. This in vitro study
investigated the influence of stem length and method of fixation
on the pattern and level of relative motion at the bone–implant
interface at a range of functional flexion angles. Methods. A custom test rig using differential variable reluctance transducers
(DVRTs) was developed to record all translational and rotational
motions at the bone–implant interface. Composite femurs were used.
These were secured to permit variation in flexion angle from 0°
to 90°. Cyclic loads were applied through a tibial component based
on three peaks corresponding to 0°, 10° and 20° flexion from a normal
walking cycle. Three different femoral components were investigated
in this study for cementless and cemented interface conditions. Results. Relative motions were found to increase with flexion angle. Stemmed
implants reduced relative motions in comparison to stemless implants
for uncemented constructs. Relative motions for cemented implants
were reduced to one-third of their equivalent uncemented constructs. Conclusions. Stems are not necessary for cemented implants when the metaphyseal
bone is intact. Short cemented
To investigate the effect of polyethylene manufacturing characteristics and irradiation dose on the survival of cemented and reverse hybrid total hip arthroplasties (THAs). In this registry study, data from the National Joint Registry of England, Wales, Northern Ireland and the Isle of Man (NJR) were linked with manufacturing data supplied by manufacturers. The primary endpoint was revision of any component. Cox proportional hazard regression was a primary analytic approach adjusting for competing risk of death, patient characteristics, head composition, and stem fixation.Aims
Methods
Appropriate acetabular component placement has been proposed for prevention of postoperative dislocation in total hip arthroplasty (THA). Manual placements often cause outliers in spite of attempts to insert the component within the intended safe zone; therefore, some surgeons routinely evaluate intraoperative pelvic radiographs to exclude excessive acetabular component malposition. However, their evaluation is often ambiguous in case of the tilted or rotated pelvic position. The purpose of this study was to develop the computational analysis to digitalize the acetabular component orientation regardless of the pelvic tilt or rotation. Intraoperative pelvic radiographs of 50 patients who underwent THA were collected retrospectively. The 3D pelvic bone model and the acetabular component were image-matched to the intraoperative pelvic radiograph. The radiological anteversion (RA) and radiological inclination (RI) of the acetabular component were calculated and those measurement errors from the postoperative CT data were compared relative to those of the 2D measurements. In addition, the intra- and interobserver differences of the image-matching analysis were evaluated.Aims
Methods
There is continued debate as to whether cemented or cementless implants should be utilized in particular cases based upon chronological age. This debate has been rekindled in the UK and other countries by directives mandating certain forms of acetabular and femoral component fixation based exclusively on the chronological age of the patient. This editorial focuses on the literature-based arguments to support the use of cementless total hip arthroplasty (THA), while addressing potential concerns surrounding safety and cost-effectiveness. Cite this article:
Previous studies have evidenced cement-in-cement techniques as reliable in revision arthroplasty. Commonly, the original cement mantle is reshaped, aiding accurate placement of the new stem. Ultrasonic devices selectively remove cement, preserve host bone, and have lower cortical perforation rates than other techniques. As far as the authors are aware, the impact of ultrasonic devices on final cement-in-cement bonds has not been investigated. This study assessed the impact of cement removal using the Orthosonics System for Cemented Arthroplasty Revision (OSCAR; Orthosonics) on final cement-in-cement bonds. A total of 24 specimens were manufactured by pouring cement (Simplex P Bone Cement; Stryker) into stainless steel moulds, with a central rod polished to Stryker Exeter V40 specifications. After cement curing, the rods were removed and eight specimens were allocated to each of three internal surface preparation groups: 1) burr; 2) OSCAR; and 3) no treatment. Internal holes were recemented, and each specimen was cut into 5 mm discs. Shear testing of discs was completed by a technician blinded to the original grouping, recording ultimate shear strengths. Scanning electron microscopy (SEM) was completed, inspecting surfaces of shear-tested specimens.Objectives
Methods
Prosthetic joint infection (PJI) is a devastating complication following total joint arthroplasty. Non-contact induction heating of metal implants is a new and emerging treatment for PJI. However, there may be concerns for potential tissue necrosis. It is thought that segmental induction heating can be used to control the thermal dose and to limit collateral thermal injury to the bone and surrounding tissues. The purpose of this study was to determine the thermal dose, for commonly used metal implants in orthopaedic surgery, at various distances from the heating centre (HC). Commonly used metal orthopaedic implants (hip stem, intramedullary nail, and locking compression plate (LCP)) were heated segmentally using an induction heater. The thermal dose was expressed in cumulative equivalent minutes at 43°C (CEM43) and measured with a thermal camera at several different distances from the HC. A value of 16 CEM43 was used as the threshold for thermal damage in bone.Objectives
Methods
Our primary aim was to describe migration of the Exeter stem with a 32 mm head on highly crosslinked polyethylene and whether this is influenced by age. Our secondary aims were to assess functional outcome, satisfaction, activity, and bone mineral density (BMD) according to age. A prospective cohort study was conducted. Patients were recruited into three age groups: less than 65 years (n = 65), 65 to 74 years (n = 68), and 75 years and older (n = 67). There were 200 patients enrolled in the study, of whom 115 were female and 85 were male, with a mean age of 69.9 years (sd 9.5, 42 to 92). They were assessed preoperatively, and at three, 12 and, 24 months postoperatively. Stem migration was assessed using Einzel-Bild-Röntgen-Analyse (EBRA). Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), Harris Hip Score (HHS), Hip Disability and Osteoarthritis Outcome Score (HOOS), EuroQol-5 domains questionnaire (EQ-5D), short form-36 questionnaire (SF-36,) and patient satisfaction were used to assess outcome. The Lower Extremity Activity Scale (LEAS), Timed Up and Go (TUG) test, and activPAL monitor (energy expelled, time lying/standing/walking and step count) were used to assess activity. The BMD was assessed in Gruen and Charnley zones.Objectives
Patients and Methods
Previous studies have suggested that metal-on-metal (MoM) Pinnacle (DePuy Synthes, Warsaw, Indiana) hip arthroplasties implanted after 2006 exhibit higher failure rates. This was attributed to the production of implants with reduced diametrical clearances between their bearing surfaces, which, it was speculated, were outside manufacturing tolerances. This study aimed to better understand the performance of Pinnacle Systems manufactured before and after this event. A total of 92 retrieved MoM Pinnacle hips were analyzed, of which 45 were implanted before 2007, and 47 from 2007 onwards. The ‘pre-2007’ group contained 45 implants retrieved from 21 male and 24 female patients, with a median age of 61.3 years (interquartile range (IQR) 57.1 to 65.5); the ‘2007 onwards’ group contained 47 implants retrieved from 19 male and 28 female patients, with a median age of 61.8 years (IQR 58.5 to 67.8). The volume of material lost from their bearing and taper surfaces was measured using coordinate and roundness measuring machines. These outcomes were then compared statistically using linear regression models, adjusting for potentially confounding factors.Objectives
Methods
Cement thickness of at least 2 mm is generally associated with more favorable results for the femoral component in cemented hip arthroplasty. However, French-designed stems have shown favorable outcomes even with thin cement mantle. The biomechanical behaviors of a French stem, Charnley-Marcel-Kerboull (CMK) and cement were researched in this study. Six polished CMK stems were implanted into a composite femur, and one million times dynamic loading tests were performed. Stem subsidence and the compressive force at the bone-cement interface were measured. Tantalum ball (ball) migration in the cement was analyzed by micro CTObjective
Methods
Infection of implants is a major problem in elective and trauma surgery. Heating is an effective way to reduce the bacterial load in food preparation, and studies on hyperthermia treatment for cancer have shown that it is possible to heat metal objects with pulsed electromagnetic fields selectively (PEMF), also known as induction heating. We therefore set out to answer the following research question: is non-contact induction heating of metallic implants effective in reducing bacterial load Titanium alloy cylinders (Ti6Al4V) were exposed to PEMF from an induction heater with maximum 2000 watts at 27 kHz after being contaminated with five different types of micro-organisms: Objectives
Methods
We have encountered patients who developed large joint fluid collections with massive elevations in chromium (Cr) and cobalt (Co) concentrations following metal-on-metal (MoM) hip arthroplasties. In some cases, retrieval analysis determined that these ion concentrations could not be explained simply by the wear rates of the components. We hypothesized that these effects may be associated with aseptic lymphocyte-dominated vasculitis-associated lesion (ALVAL). We examined the influence of the ALVAL grade on synovial fluid Co and Cr concentrations following adjustment for patient and device variables, including volumetric wear rates. Initially restricting the analysis to include only patients with one MoM hip resurfacing device, we performed multiple regression analyses of prospectively collected data. We then repeated the same statistical approach using results from a larger cohort with different MoM designs, including total hip arthroplasties.Objectives
Patients and Methods
The objective of this study was to assess all evidence comparing the Thompson monoblock hemiarthroplasty with modular unipolar implants for patients requiring hemiarthroplasty of the hip with respect to mortality and complications. A literature search was performed to identify all relevant literature. The population consisted of patients undergoing hemiarthroplasty of the hip for fracture. The intervention was hemiarthroplasty of the hip with a comparison between Thompson and modular unipolar prostheses. Pubmed, Embase, CINAHL, Web of Science, PROSPERO and the Cochrane Central Register of Controlled Trials. The study designs included were randomised controlled trials (RCTs), well designed case control studies and retrospective or prospective cohort studies. Studies available in any language, published at any time until September 2015 were considered. Studies were included if they contained mortality or complications.Objectives
Methods
This study aimed to characterise and qualitatively grade the severity of the corrosion particles released into the hip joint following taper corrosion. The 26 cases examined were CoC/ABG Modular (n = 13) and ASR/SROM (n = 13). Blood serum metal ion levels were collected before and after revision surgery. The haematoxylin and eosin tissue sections were graded on the presence of fibrin exudates, necrosis, inflammatory cells and corrosion products. The corrosion products were identified based on visible observation and graded on abundance. Two independent observers blinded to the clinical patient findings scored all cases. Elemental analysis was performed on corrosion products within tissue sections. X-Ray diffraction was used to identify crystalline structures present in taper debris.Objectives
Methods
Studies reporting specifically on squeaking in total hip arthroplasty have focused on cementless, and not on hybrid, fixation. We hypothesised that the cement mantle of the femur might have a damping effect on the sound transmitted through the metal stem. The objective of this study was to test the effect of cement on sound propagation along different stem designs and under different fixation conditions. An Objectives
Methods
Preservation of posterior condylar offset (PCO) has been shown to correlate with improved functional results after primary total knee arthroplasty (TKA). Whether this is also the case for revision TKA, remains unknown. The aim of this study was to assess the independent effect of PCO on early functional outcome after revision TKA. A total of 107 consecutive aseptic revision TKAs were performed by a single surgeon during an eight-year period. The mean age was 69.4 years (39 to 85) and there were 59 female patients and 48 male patients. The Oxford Knee Score (OKS) and Short-form (SF)-12 score were assessed pre-operatively and one year post-operatively. Patient satisfaction was also assessed at one year. Joint line and PCO were assessed radiographically at one year.Objectives
Methods
In total hip arthroplasty (THA), the cementless, tapered-wedge stem design contributes to achieving initial stability and providing optimal load transfer in the proximal femur. However, loading conditions on the femur following THA are also influenced by femoral structure. Therefore, we determined the effects of tapered-wedge stems on the load distribution of the femur using subject-specific finite element models of femurs with various canal shapes. We studied 20 femurs, including seven champagne flute-type femurs, five stovepipe-type femurs, and eight intermediate-type femurs, in patients who had undergone cementless THA using the Accolade TMZF stem at our institution. Subject–specific finite element (FE) models of pre- and post-operative femurs with stems were constructed and used to perform FE analyses (FEAs) to simulate single-leg stance. FEA predictions were compared with changes in bone mineral density (BMD) measured for each patient during the first post-operative year.Objectives
Patients and Methods
Favourable results for collarless polished tapered stems have been reported, and cement creep due to taper slip may be a contributing factor. However, the ideal cement thickness around polished stems remains unknown. We investigated the influence of cement thickness on stem subsidence and cement creep. We cemented six collarless polished tapered (CPT) stems (two stems each of small, medium and large sizes) into composite femurs that had been reamed with a large CPT rasp to achieve various thicknesses of the cement mantle. Two or three tantalum balls were implanted in the proximal cement in each femur. A cyclic loading test was then performed for each stem. The migration of the balls was measured three-dimensionally, using a micro-computed tomography (CT) scanner, before and after loading. A digital displacement gauge was positioned at the stem shoulder, and stem subsidence was measured continuously by the gauge. Final stem subsidence was measured at the balls at the end of each stem.Objectives
Methods
The use of ceramic femoral heads in total hip arthroplasty (THA) has increased due to their proven low bearing wear characteristics. Ceramic femoral heads are also thought to reduce wear and corrosion at the head-stem junction with titanium (Ti) stems when compared with metal heads. We sought to evaluate taper damage of ceramic compared with metal heads when paired with cobalt chromium (CoCr) alloy stems in a single stem design. This retrieval study involved 48 total hip arthroplasties (THAs) with CoCr V40 trunnions paired with either CoCr (n = 21) or ceramic (n = 27) heads. The taper junction of all hips was evaluated for fretting/corrosion damage and volumetric material loss using a roundness-measuring machine. We used linear regression analysis to investigate taper damage differences after adjusting for potential confounding variables.Objectives
Methods
Modular junctions are ubiquitous in contemporary hip arthroplasty. The head-trunnion junction is implicated in the failure of large diameter metal-on-metal (MoM) hips which are the currently the topic of one the largest legal actions in the history of orthopaedics (estimated costs are stated to exceed $4 billion). Several factors are known to influence the strength of these press-fit modular connections. However, the influence of different head sizes has not previously been investigated. The aim of the study was to establish whether the choice of head size influences the initial strength of the trunnion-head connection. Ti-6Al-4V trunnions (n = 60) and two different sizes of cobalt-chromium (Co-Cr) heads (28 mm and 36 mm; 30 of each size) were used in the study. Three different levels of assembly force were considered: 4 kN; 5 kN; and 6 kN (n = 10 each). The strength of the press-fit connection was subsequently evaluated by measuring the pull-off force required to break the connection. The statistical differences in pull-off force were examined using a Kruskal–Wallis test and two-sample Mann–Whitney U test. Finite element and analytical models were developed to understand the reasons for the experimentally observed differences.Objectives
Materials and Methods
Mechanical wear and corrosion at the head-stem junction of total hip arthroplasties (THAs) (trunnionosis) have been implicated in their early revision, most commonly in metal-on-metal (MOM) hips. We can isolate the role of the head-stem junction as the predominant source of metal release by investigating non-MOM hips; this can help to identify clinically significant volumes of material loss and corrosion from these surfaces. In this study we examined a series of 94 retrieved metal-on-polyethylene (MOP) hips for evidence of corrosion and material loss at the taper junction using a well published visual grading method and an established roundness-measuring machine protocol. Hips were retrieved from 74 male and 20 female patients with a median age of 57 years (30 to 76) and a median time to revision of 215 months (2 to 324). The reasons for revision were loosening of both the acetabular component and the stem (n = 29), loosening of the acetabular component (n = 58) and infection (n = 7). No adverse tissue reactions were reported by the revision surgeons.Objectives
Methods
The high revision rates of the DePuy Articular Surface Replacement (ASR) and the DePuy ASR XL (the total hip arthroplasty (THA) version) have led to questions over the viability of metal-on-metal (MoM) hip joints. Some designs of MoM hip joint do, however, have reasonable mid-term performance when implanted in appropriate patients. Investigations into the reasons for implant failure are important to offer help with the choice of implants and direction for future implant designs. One way to assess the performance of explanted hip prostheses is to measure the wear (in terms of material loss) on the joint surfaces. In this study, a coordinate measuring machine (CMM) was used to measure the wear on five failed cementless Biomet Magnum/ReCap/ Taperloc large head MoM THAs, along with one Biomet ReCap resurfacing joint. Surface roughness measurements were also taken. The reason for revision of these implants was pain and/or adverse reaction to metal debris (ARMD) and/or elevated blood metal ion levels.Objectives
Methods
The purpose of this study was to develop an accurate, reliable and easily applicable method for determining the anatomical location of the joint line during revision knee arthroplasty. The transepicondylar width (TEW), the perpendicular distance between the medial and lateral epicondyles and the distal articular surfaces (DMAD, DLAD) and the distance between the medial and lateral epicondyles and the posterior articular surfaces (PMAD, DLAD) were measured in 40 knees from 20 formalin-fixed adult cadavers (11 male and nine female; mean age at death 56.9 years, Objectives
Methods
High failure rates of metal-on-metal hip arthroplasty implants have highlighted the need for more careful introduction and monitoring of new implants and for the evaluation of the safety of medical devices. The National Joint Registry and other regulatory services are unable to detect failing implants at an early enough stage. We aimed to identify validated surrogate markers of long-term outcome in patients undergoing primary total hip arthroplasty (THA). We conducted a systematic review of studies evaluating surrogate markers for predicting long-term outcome in primary THA. Long-term outcome was defined as revision rate of an implant at ten years according to National Institute of Health and Care Excellence guidelines. We conducted a search of Medline and Embase (OVID) databases. Separate search strategies were devised for the Cochrane database and Google Scholar. Each search was performed to include articles from the date of their inception to June 8, 2015.Objectives
Methods
Third-body wear is believed to be one trigger for adverse results
with metal-on-metal (MOM) bearings. Impingement and subluxation
may release metal particles from MOM replacements. We therefore
challenged MOM bearings with relevant debris types of cobalt–chrome
alloy (CoCr), titanium alloy (Ti6Al4V) and polymethylmethacrylate
bone cement (PMMA). Cement flakes (PMMA), CoCr and Ti6Al4V particles (size range
5 µm to 400 µm) were run in a MOM wear simulation. Debris allotments
(5 mg) were inserted at ten intervals during the five million cycle
(5 Mc) test. Objectives
Methods
An ongoing prospective study to investigate failing metal-on-metal
hip prostheses was commenced at our centre in 2008. We report on
the results of the analysis of the first consecutive 126 failed
mated total hip prostheses from a single manufacturer. Analysis was carried out using highly accurate coordinate measuring
to calculate volumetric and linear rates of the articular bearing
surfaces and also the surfaces of the taper junctions. The relationship
between taper wear rates and a number of variables, including bearing
diameter and orientation of the acetabular component, was investigated.Objectives
Methods
An experimental rabbit model was used to test the null hypothesis,
that there is no difference in new bone formation around uncoated
titanium discs compared with coated titanium discs when implanted
into the muscles of rabbits. A total of three titanium discs with different surface and coating
(1, porous coating; 2, porous coating + Bonemaster (Biomet); and
3, porous coating + plasma-sprayed hydroxyapatite) were implanted
in 12 female rabbits. Six animals were killed after six weeks and
the remaining six were killed after 12 weeks. The implants with
surrounding tissues were embedded in methyl methacrylate and grinded
sections were stained with Masson-Goldners trichrome and examined
by light microscopy of coded sections.Objectives
Methods
The accuracy and precision of two new methods of model-based
radiostereometric analysis (RSA) were hypothesised to be superior
to a plain radiograph method in the assessment of polyethylene (PE)
wear. A phantom device was constructed to simulate three-dimensional
(3D) PE wear. Images were obtained consecutively for each simulated
wear position for each modality. Three commercially available packages
were evaluated: model-based RSA using laser-scanned cup models (MB-RSA),
model-based RSA using computer-generated elementary geometrical
shape models (EGS-RSA), and PolyWare. Precision (95% repeatability
limits) and accuracy (Root Mean Square Errors) for two-dimensional
(2D) and 3D wear measurements were assessed.Objectives
Methods