New quality measure for SNP array based CNV detection.

MOTIVATION: Only a few large systematic studies have evaluated the impact of copy number variants (CNVs) on common diseases. Several million individuals have been genotyped on single nucleotide variation arrays, which could be used for genome-wide CNVs association studies. However, CNV calls remain prone to false positives and only empirical filtering strategies exist in the literature. To overcome this issue, we defined a new quality score (QS) estimating the probability of a CNV called by PennCNV to be confirmed by other software. RESULTS: Out-of-sample comparison showed that the correlation between the consensus CNV status and the QS is twice as high as it is for any previously proposed CNV filters. ROC curves displayed an AUC higher than 0.8 and simulations showed an increase up to 20% in statistical power when using QS in comparison to other filtering strategies. Superior performance was confirmed also for alternative consensus CNV definition and through improving known CNV-trait associations. AVAILABILITY AND IMPLEMENTATION: http://goo.gl/T6yuFM CONTACT: zoltan.kutalik@unil.ch or aurelien@mace@unil.chSupplementary information: Supplementary data are available at Bioinformatics online.

Wear in alumina-on-alumina ceramic total hip replacements: a retrieval analysis of edge loading.

We analysed 54 alumina ceramic-on-ceramic bearings from total hip replacements retrieved at one centre after a mean duration of 3.5 years (0.2 to 10.6) in situ. These implants were obtained from 54 patients (16 men and 38 women) with a mean age of 67 years (33 to 88) who underwent revision for a variety of reasons. Posterior edge loading was found in the majority of these retrievals (32 out of 54). Anterosuperior edge loading occurred less often but produced a higher rate of wear. Stripe wear on the femoral heads had a median volumetric wear rate of 0.2 mm(3)/year (0 to 7.2). The wear volume on the femoral heads corresponded to the width of edge wear on the matching liner. Anteversion of the acetabular component was found to be a more important determinant than inclination for wear in ceramic bearings. Posterior edge loading may be considered to be a normal occurrence in ceramic-on-ceramic bearings, with minimal clinical consequences. Edge loading should be defined as either anterosuperior or posterior, as each edge loading mechanism may result in different clinical implications.

Retrieval analysis of squeaking alumina ceramic-on-ceramic bearings.

This multicentre study analysed 12 alumina ceramic-on-ceramic components retrieved from squeaking total hip replacements after a mean of 23 months in situ (11 to 61). The rates and patterns of wear seen in these squeaking hips were compared with those seen in matched controls using retrieval data from 33 'silent' hip replacements with similar ceramic bearings. All 12 bearings showed evidence characteristic of edge-loading wear. The median rate of volumetric wear was 3.4 mm(3)/year for the acetabular component, 2.9 mm(3)/year on the femoral heads and 6.3 mm(3)/year for head and insert combined. This was up to 45 times greater than that of previously reported silent ceramic-on-ceramic retrievals. The rate of wear seen in ceramic components revised for squeaking hips appears to be much greater than in that seen in retrievals from 'silent' hips.

The tribological behaviour of different clearance MOM hip joints with lubricants of physiological viscosities.

Clearance is one of the most influential parameters on the tribological performance of metal-on-metal (MOM) hip joints and its selection is a subject of considerable debate. The objective of this paper is to study the lubrication behaviour of different clearances for MOM hip joints within the range of human physiological and pathological fluid viscosities. The frictional torques developed by MOM hip joints with a 50 mm diameter were measured for both virgin surfaces and during a wear simulator test. Joints were manufactured with three different diametral clearances: 20, 100, and 200 microm. The fluid used for the friction measurements which contained different ratios of 25 percent newborn calf serum and carboxymethyl cellulose (CMC) with the obtained viscosities values ranging from 0.001 to 0.71 Pa s. The obtained results indicate that the frictional torque for the 20 microm clearance joint remains high over the whole range of the viscosity values. The frictional torque of the 100 microm clearance joint was low for the very low viscosity (0.001 Pa s) lubricant, but increased with increasing viscosity value. The frictional torque of the 200 microm clearance joint was high at very low viscosity levels, however, it reduced with increasing viscosity. It is concluded that a smaller clearance level can enhance the formation of an elastohydrodynamic lubrication (EHL) film, but this is at the cost of preventing fluid recovery between the bearing surfaces during the unloaded phase of walking. Larger clearance bearings allow a better recovery of lubricant during the unloaded phase, which is necessary for higher viscosity lubricants. The selection of the clearance value should therefore consider both the formation of the EHL film and the fluid recovery as a function of the physiological viscosity in order to get an optimal tribological performance for MOM hip joints. The application of either 25 per cent bovine serum or water in existing in vitro tribological study should also be revised to consider the relevance of clinic synovial fluid viscosities and to avoid possible misleading results.

Wear and acetabular component orientation in third generation alumina-on-alumina ceramic bearings: an analysis of 33 retrievals [corrected].

We studied 33 third generation, alumina ceramic-on-ceramic bearings retrieved from cementless total hip replacements after more than six months in situ. Wear volume was measured with a Roundtest machine, and acetabular orientation from the anteroposterior pelvic radiograph. The overall median early wear rate was 0.1 mm(3)/yr for the femoral heads, and 0.04 mm(3)/yr for the acetabular liners. We then excluded hips where the components had migrated. In this stable subgroup of 22 bearings, those with an acetabular anteversion of < 15 degrees (seven femoral heads) had a median femoral head wear rate of 1.2 mm(3)/yr, compared with 0 mm(3)/yr for those with an anteversion of > or =15 degrees (15 femoral heads, p < 0.001). Even under edge loading, wear volumes with ceramic-on-ceramic bearings are small in comparison to other bearing materials. Low acetabular anteversion is associated with greater wear.

In vivo biocompatibility and mechanical study of novel bone-bioactive materials for prosthetic implantation.

Two epoxy materials with or without adhesively bonded hydroxyapatite (HA) coatings were studied for their biocompatibility and mechanical pushout strength using in vivo implantation in the rabbit lower femur for a duration of 10 days to 6 months. Both were two-part epoxies cured at room temperature for 24 h, with material 1 (Ampreg 26; SP Systems Limited, Cowes, UK) postcured at 110 degrees C (Tg approximately 80 degrees C) and Material 2 (CG5052; Ciba Geigy Limited, Cambridge, UK) at 125 degrees C (Tg approximately 120 degrees C). Implantation in dead rabbit bone was performed to provide mechanical baseline levels. Polymethylmethacrylate (PMMA) and conventionally HA-coated titanium alloy (Ti-6Al-4V) were used as control materials. In the biological study, different fluorescent dyes were used to label newly formed bone. After 6 weeks of implantation, results from mechanical pushout tests showed that the interfacial shear strength (ISS) values were significantly higher than for dead bones with each of the different implants (p < .01-.001). HA-coated material 2 showed a significantly higher ISS value than the uncoated material (p < .05) after 6 weeks' implantation. However, the ISS value for the uncoated material 2 was significantly higher than for PMMA controls (p < .05). No significant differences in the ISS values were shown between HA-coated materials 1 and 2 and Ti-6Al-4V on in vivo implantation for 6 weeks. Failure points of the pushout test from the three HA-coated materials were defined by scanning electron microscopy. Specimens implanted with both HA-coated epoxies were fractured within the HA-coatings or the bone, while with HA-coated Ti-6Al-4V cracked between the coating and metal implant. The percentage of bone in contact with the implant surface was obtained by image analysis which showed that there were no significant differences between different materials after short time implantation (up to 6 week). Long-term implantation of the HA-coated material 2 showed that the percentage of bone contact had increased from 52.8+/-1.1% (6 week) to 80.0+/-0.3% (3 months) (p < .01) and remained at 81.0+/-0.8% (6 months). Measurements of bone mineralization rate (BMR) showed that after 3 weeks of implantation, there were no significant differences between PMMA and uncoated materials 1 and 2. After 6 weeks, the BMRs in animals implanted with either HA-coated material 1 or 2 were significantly higher than with HA-coated Ti-6Al-4V (p < .05-.0001 in both cases), but with HA-coated material 2 was lower than with this material uncoated (p < .05-.001). No significant differences were found between the two HA-coated epoxy materials. In addition, there were always lower BMRs during the third week of implantation than other periods regardless of biomaterial implanted. The study indicated that the adhesively bonded HA-coated novel epoxy materials were superior to conventional plasma-sprayed Ti-6Al-4V implants with respect to both BMR and bone integration with the implant surfaces. Adhesively bonded HA-coated epoxy materials had similar ISS values to HA-coated Ti-6Al-4V, but the former failed within the bone and coating, while the latter showed splitting between coating and metal.

Can a total knee replacement prosthesis be made entirely of polymers?

We have prospectively studied 63 total knee replacements (TKR) in which the femoral component was polyacetal, and 138 TKRs in which the femoral component was conventional cobalt chrome. The tibial and patellar components were of ultrahigh molecular weight polyethylene (UHMWPE). Patients were followed-up for at least 10 years. In the polyacetal group, a number of patients have died or have been revised, for reasons unrelated to the presence of polyacetal. There were no instances of femoral component fracture, nor failure by wear. One postmortem specimen, retrieved at 9 years after surgery, showed no measurable polyacetal wear and negligible HDP wear. The histology of tissue in contact with polyacetal was indistinguishable from that adjacent to polymethyl methacrylate and UHMWPE in the same knee. We believe that polyacetal could be used for the femoral component of a TKR and that a further trial should be undertaken.

Wear induced by motion between bone and titanium or cobalt-chrome alloys.

We studied the wear generated by motion between polished and shot-blasted titanium-alloy (Ti-6Al-4V) or cobalt-chrome alloy (Co-Cr) surfaces and cortical bone in vitro. Semicircular sections of human proximal femoral cortex were reamed to fit metal cylinders of each alloy. The cylinders were then fitted in the bone, loaded and rotated in physiological saline. Ti-alloy resulted in more wear both of the bone and of the metal than did Co-Cr alloy. Metal wear was reduced and bone wear was increased by shot-blasting, a procedure which introduces surface residual stresses and roughens the metal surface. We conclude that when there is gross motion between a metal implant and bone, Ti-alloy is likely to generate more wear debris than Co-Cr alloy. The least wear both of bone and of metal was produced by polished Co-Cr.

Evaluation of wear in an all-polymer total knee replacement. Part 2: clinical evaluation of wear in a polyethylene on polyacetal total knee.

In an effort to improve the long-term result of total joint replacement arthroplasty, we have investigated the use of a polymer-on-polymer articular replacement arthroplasty. Because of their known biocompatibility and previous use in orthopedic surgery, polyethylene and polyacetal (copolymer, Hoechst) were selected. Polyethylene served in its usual role as the concave member of the articulation; polyacetal formed the convex number. Formal wear testing using a multi-channel hip simulator demonstrated superior wear characteristics of the polymer-on-polymer configuration compared to a conventional chrome-cobalt versus polymer (polyethylene) configuration. A clinical series of relatively high-activity patients having a minimum five-year follow-up (N = 26) showed no specific unfavorable reaction to this material combination in a total knee replacement. Given certain potential advantages of polymeric materials, as well as some theoretical disadvantages of metallic materials, a polymer-on-polymer design for a large joint replacement may have some merit.

Effect of surface treatment on the dissolution of titanium-based implant materials.

Titanium and its alloys are widely used in load-bearing implants as a result of their excellent mechanical properties and corrosion resistance, but there is concern over the release of metal ions from the prosthesis. Our research investigated the influence of the surface oxide on the dissolution of the substrate material in saline solution, using a combination of atomic absorption spectroscopy, ellipsometry and transmission electron microscopy techniques. It is demonstrated that a substantial reduction in the release of metal ions may be achieved by ageing the surface oxide in boiling distilled water or by thermal oxidation; this is discussed in terms of the structure of the oxide film.

The effect of hydroxyapatite coating on ingrowth of bone into cavities in an implant.

A canine implant study was performed to assess whether hydroxyapatite (HA) could induce bone to close gaps at the bone-prosthesis junction. Titanium alloy (TiAlV) plates with varying grooves cut into them (1, 2, and 3 mm deep) and identical on both sides were sprayed on one side with HA and left as bare metal on the other. These were then implanted into the distal femora of dogs that were killed 4 and 8 weeks afterwards. Specimens were analyzed using optical microscopy and microradiography. Results show that the presence of HA induces bone to grow almost completely down the deepest groove by 8 weeks. In the 1- and 2-mm grooves at 4 weeks the depth of penetration of bone into the grooves was greater on the HA coated side (but the actual volume of bone in the grooves was greater on the TiAlV side because the bone present was more dense). We conclude that the presence of HA induces bone to close relatively large gaps. Although bone does not grow all the way into uncoated defects there can be more bone here in the short term. This feature of HA may be of great value in hip implant fixation.

The patellofemoral joint in total knee prostheses. Design considerations.

Some desirable design features of the patellofemoral joint in a total knee arthroplasty condylar prosthesis are proposed. These are that the femoral element should be grooved, have a high anterior flange, and be circular as viewed from the side. The groove should be about 5 mm deep and have relatively vertical walls. The patellar component should have a saddle-shaped articular surface matching the femur and should be countersunk into the patella. The components should be placed so as to position the joint automatically. Results with such a design are reported; loosening, wear, dislocation, and fracture have been rare. Osteolysis of the patella has not been seen after 9 years, so that the cementless press-fit fixation of an H.D.P. patellar prosthesis to date seems safe and efficacious.

Application of PVD TiN coating to Co-Cr-Mo based surgical implants.

The requirements for successful joint arthroplasty are particularly exacting; a balanced combination of mechanical properties together with good biocompatibility are essential. Co-Cr based alloys have been used for many years on account of their relative inertness, good load bearing properties and excellent wear resistance. There is, however, concern that a slow accumulation of metal ions such as cobalt and chromium can lead to adverse clinical reactions; modern cementless fixation techniques may exacerbate this problem. In an attempt to reduce the release of potentially harmful metal ions from Co-Cr-Mo based surgical implants, a thin coating of TiN has been applied via Physical Vapour Deposition (PVD). In vitro corrosion performance has been investigated using electrochemical techniques, and also by atomic absorption analysis. The release of cobalt and chromium ions is shown to be reduced by the presence of the TiN coating, and these results are discussed in terms of the electrochemistry and microstructure of the coating and substrate.

A new unconstrained elbow. A prospective review of 60 replacements.

Sixty unconstrained elbow replacements of a new design have been followed prospectively for three to nine years. Review showed that 50% had excellent relief of pain and return of function, 27% had had major complications requiring removal or revision of the prosthesis and 23% had minor complications which marred the result. Further research in this field seems worthwhile.

Implant arthroplasty in the adult hindfoot.

In patients with mild to moderate valgus deformity and localized pain due to lateral impingement, the subtalar implant has been effective in controlling position and relieving localized pain. When used in conjunction with a talonavicular resurfacing prosthesis in the absence of talonavicular subluxation, the implant has been effective in relieving pain and maintaining the foot in a normal or nearly normal position. In feet with valgus deformity and talonavicular subluxation, both the subtalar implant and the talonavicular prosthesis with a built-in stop must be used. Use of these implants requires that the foot be supple and correctable to at least neutral position at surgery. The valgus hindfoot with a subluxated but otherwise normal talonavicular joint presents a greater problem. In this condition correction can be maintained only if the subtalar implant is used in conjunction with the modified talonavicular joint with a built-in stop. External supports in the shoe have not been routinely used in all patients after operation for a variety of reasons (mostly nonmedical). It may be advisable in patients who have had correction of a deformity to continue to use some sort of support in the shoe for most ambulation. Arthroplasty early in the disease course, before severe deformities develop, may prevent progression of the disorder, but more experience is necessary to validate clinical impressions.

Development and evolution of the ICLH ankle replacement.

In 1972 the original ICLH ankle was first used clinically, and since then the authors have implanted 75 ICLH ankles. The overall percentage of acceptable results in this series is about 70%. The most frequent complication seen was delayed wound healing. Talomalleolar contact with resultant pain was a significant problem early in the series. Partial collapse of the talus has occurred in five ankles. Our experience has shown that it is possible to replace the ankle and initially achieve a functioning, pain-free arthroplasty. There are many factors that may adversely influence the ultimate outcome; and thus, the procedure should be approached with caution.

The effects of proteolytic enzymes on the mechanical properties of adult human articular cartilage.

The effects of the lysosomal proteinase cathepsin D on the mechanical properties of adult human articular cartilage were examined in detail in 7 joints within the age range 21 to 72 years. The results of a preliminary study on the effects of the lysosomal proteinase cathepsin B1 and clostridial collagenase on the mechanical properties of cartilage are also presented. Cartilage which had been incubated with either cathepsin D or cathepsin B1 showed increased deformation in uniaxial compression perpendicular to the articular surface. The enzyme-treated cartilage also showed decreased tensile stiffness at low values of stress. This effect was more pronounced in specimens from the deeper zone of cartilage than in specimens from the superficial zone. It was also more pronounced in specimens which were aligned perpendicular to the predominant alignment of the collagen fibres in the superficial zone than in specimens which were parallel to the collagen fibres. At higher stresses the tensile stiffness of the treated cartilage was not significantly different from that of the untreated tissue. The tensile fracture stress of the cartilage was also not significantly reduced by the action of cathepsin D. In contrast to the effects observed with the cathepsins, the preliminary results obtained by incubating cartilage for 24 h with clostridial collagenase showed that both the tensile stiffness and the fracture stress were considerably lower than the corresponding values for the untreated tissue. Biochemical analysis of the incubation media, and the specimens, revealed that a large proportion of the proteoglycans was released from the cartilage by each of the three enzymes. The proportion of the total collagen which was released from the cartilage was different for each enzyme: cathepsin D released between 0 and 1.5 per cent, cathepsin B1 released between 2.3 and 4.3 per cent and collagenase released between 5.3 and 27.8 per cent of the collagen after 24 h.

Engineering considerations in the design of an ankle joint.

A prothesis has been designed to replace the articulating surfaces of the human ankle joint. The prothesis is in two parts, each forming a segment of a right circular cylinder with a single axis of rotation. The concave tibial component is manufactured from ultra-high molecular weight polyethylene and the talar component is manufactured from medical grade stainless steel. It is likely, however, that the talar component will be commercially manufactured from cobalt chrome alloy (Vitallium or Vinertia). The two components are secured to the cancellous bone by polymethylmethacrylate bone cement and laboratory tests have indicated that the bond should be strong enough to withstand the loads encountered at the ankle joint in vivo. The tests have also shown that the stability and strength of the ankle are not seriously reduced by implantation of the prosthesis. Laboratory wear tests and clinical experience over the last two years encourage optimism over the long term performance of the prothesis.