Causal Relationship of Susceptibility Genes to Ischemic Stroke: Comparison to Ischemic Heart Disease and Biochemical Determinants

Interrelationships between genetic and biochemical factors underlying ischemic stroke and ischemic heart disease are poorly understood. We: 1) undertook the most comprehensive meta-analysis of genetic polymorphisms in ischemic stroke to date; 2) compared genetic determinants of ischemic stroke with those of ischemic heart disease, and 3) compared effect sizes of gene-stroke associations with those predicted from independent biochemical data using a mendelian randomization strategy. Electronic databases were searched up to January 2009. We identified: 1) 187 ischemic stroke studies (37,481 cases; 95,322 controls) interrogating 43 polymorphisms in 29 genes; 2) 13 meta-analyses testing equivalent polymorphisms in ischemic heart disease; and 3) for the top five gene-stroke associations, 146 studies (65,703 subjects) describing equivalent gene-biochemical relationships, and 28 studies (46,928 subjects) describing biochemical-stroke relationships. Meta-analyses demonstrated positive associations with ischemic stroke for factor V Leiden Gln506, ACE I/D, MTHFR C677T, prothrombin G20210A, PAI-1 5G allele and glycoprotein IIIa Leu33Pro polymorphisms (ORs: 1.11 – 1.60). Most genetic associations show congruent levels of risk comparing ischemic stroke with ischemic heart disease, but three genes—glycoprotein IIIa, PAI-1 and angiotensinogen—show significant dissociations. The magnitudes of stroke risk observed for factor V Leiden, ACE, MTHFR and prothrombin, but not PAI-1, polymorphisms, are consistent with risks associated with equivalent changes in activated protein C resistance, ACE activity, homocysteine, prothrombin, and PAI-1 levels, respectively. Our results demonstrate causal relationships for four of the most robust genes associated with stroke while also showing that PAI-1 4G/5G polymorphism influences cardiovascular risk via a mechanism not simply related to plasma levels of PAI-1 (or tPA) alone

Demonstrating an absolute quantum advantage in direct absorption measurement

Engineering apparatus that harness quantum theory promises to offer practical advantages over current technology. A fundamentally more powerful prospect is that such quantum technologies could out-perform any future iteration of their classical counterparts, no matter how well the attributes of those classical strategies can be improved. Here, for optical direct absorption measurement, we experimentally demonstrate such an instance of an absolute advantage per photon probe that is exposed to the absorbative sample. We use correlated intensity measurements of spontaneous parametric downconversion using a commercially available air-cooled CCD, a new estimator for data analysis and a high heralding efficiency photon-pair source. We show this enables improvement in the precision of measurement, per photon probe, beyond what is achievable with an ideal coherent state (a perfect laser) detected with 100% efficient and noiseless detection. We see this absolute improvement for up to 50% absorption, with a maximum observed factor of improvement of 1.46. This equates to around 32% reduction in the total number of photons traversing an optical sample, compared to any future direct optical absorption measurement using classical light

Material Loss at the Head Taper Junction of the Metal-on-Metal Pinnacle Total Hip Replacement

Introduction The ASR XL (DePuy) total hip replacement (THR) is a notable example of a modern metal-on-metal (MOM) implant design that has demonstrated unacceptable survival rates, leading to its recall by the manufacturer; national joint registries have reported revision rates at 7 years of 40% when paired with the Corail stem [1]. The ASR XL THR has a considerably greater risk of revision than the ASR resurfacing hip, which used the same bearing design. This suggests that material loss at the head-stem junction may be responsible for the greater percentage of THR failures observed in this design. The Pinnacle MOM-THR (DePuy) however used the same Corail stem as the ASR XL THR but demonstrated better clinical results, with revision rates of less than 10% at 7 years [1]. The ASR XL and MOM Pinnacle are two designs that have been widely used in hip replacement surgery. The reasons for the differences in the failure rates of the two designs are not fully understood. Comparing the mechanisms of failure of both hips will help surgeons understand whether patients with MOM Pinnacle hips will experience the same types of problems as with those seen with the ASR XL. The aims of this retrieval study were to investigate the significance of differences between the ASR XL and MOM Pinnacle in relation to: (1) pre-revision whole blood Co/Cr ratios, (2) visual evidence of taper corrosion, (3) volumetric material loss at the bearing surfaces and (4) volumetric material loss at the taper surfaces. Methods This study involved a series of failed MOM hips consisting of the ASR XL (n=30) and Pinnacle (n=30), all that had been used with a Corail stem. The bearing material in each design was cobalt-chromium and the Corail stem is of a cementless titanium 12/14 design. The ASR XL and Pinnacle had a median head diameter of 47mm (39-55) and 36mm (36-40) respectively, and a median time to revision of 38.5 months (12-74) and 55 months (14-86) respectively. Pre-revision whole blood metal ion levels were collected for each Table 1 summarises patient and implant data for the hips in this study. The female taper surfaces of all 60 heads were examined macroscopically and microscopically to assess the severity of corrosion. Each surface was graded with a score of between 1 (no corrosion) and 4 (severe corrosion) using a well-published scoring system, which has been shown to be statistically reliable. A Zeiss Prismo (Carl Zeiss Ltd, Rugby, UK) coordinate measuring machine (CMM) was used to determine the volume of material loss at the cup and head bearing surfaces. Up to 300,000 data points were collected using a 2mm ruby stylus that was translated along 400 polar scan lines on the surface. The raw data was used to map regions of material loss by comparing with the unworn geometry of the bearing. A Talyrond 365 (Hobson, Leicester, UK) roundness measuring machine was used to measure the volumetric material loss at each of the head taper surfaces. Published protocols were used to take a series of 180 vertical traces along the taper surface using a 5μm diamond stylus; worn and unworn regions were mapped and used to calculate material loss. Neither the volumetric measurement data nor corrosion scores were normally distributed. Therefore non-parametric tests were performed to assess the statistical significance of differences between the two designs in relation to the parameters under investigation in this study. Results Both the whole blood Co ion levels and the Co/Cr ratios, Figure 1, of the ASR XL hips were significantly greater than the Pinnacles (p<0.05). There was no significant difference between the whole blood Cr ion levels between the two designs (p=0.0542). 18 of the ASR XL hips presented evidence of edge wearing of the cup, compared with 14 Pinnacle hips; this difference was not significant (p=0.438). The length of the stem trunnion contact engagement length with the taper was approximated as being 10.5mm for both designs. The median time to revision of the ASR XL hips was significantly less than the Pinnacle hips (p<0.01). There was visual evidence of corrosion in 93% (n=28) and 90% (n=27) of head tapers for the ASR XLs and Pinnacles respectively. Moderate to severe corrosion was observed in 67% (n=20) of ASR XLs compared to 60% (n=18) of Pinnacles. There was however no statistically significant difference between the scores of the two groups (p=0.927). Figure 2 presents the distribution of material loss rates for the bearing and taper surfaces of the two designs in this study. The median total bearing surface (combined cup and head) rate of material loss for the ASR XL and Pinnacle hips was 4.45mm3/year (0.32-22.85) and 4.03mm3/year (0.87-62.12) respectively. There was no significant difference between the two groups (p=0.928). The median material loss rate at the taper surfaces of the ASR XL and Pinnacle hips was 0.62mm3/year (0-4.20) and 0.30mm3/year (0-3.12); this difference was not significant (p=0.198). Discussion The work of this study presents comparisons of retrieval findings between the ASR XL and Pinnacle MOM-THRs; these hip designs were two of the most commonly implanted in patients worldwide. The significantly greater whole blood Co/Cr ratios found in the ASR XL group compared to the Pinnacle group are of interest. It is speculated that a Co/Cr ratio of greater than 1 may be an indicator of corrosion of an implant whereby more Cr ions are retained on the surface, whilst comparatively more Co ions are released into the blood. In the current study we found wear rates at the bearing surfaces of both designs to be comparable, suggesting that the significantly greater Co/Cr ratios in the ASR XL hips must be due to greater corrosion at the taper junction than the Pinnacles. Although the ASR XL hips had been implanted for a significantly shorter period of time, our visual assessment of the corrosion of the taper junctions found that corrosion scores were comparable between the two designs; indeed, a marginally greater number of ASR XL tapers had evidence of moderate to severe corrosion. This finding, coupled with the elevated Co/Cr ratios suggests that the ASR XL design is more susceptible to corrosion at the taper junction than the Pinnacle hip. We found that the median rate of material loss at the ASR XL taper was over twice that of the Pinnacle taper. Whilst not statistically significant, this difference may be due to a greater risk of corrosion at this interface in the ASR XL design. The differences in material loss and corrosion that were observed at the taper junctions may be explained by considering the larger head sizes of the ASR XL hips in comparison to the Pinnacles. It has previously been shown that increasing head size is correlated with greater visual evidence of corrosion and that increased frictional torque along the taper junction due a larger head diameter can increase the risk of fretting-corrosion. It is suggested therefore that the combination of the larger head sizes of the ASR XLs coupled with the comparatively short, rough surface of the Corail trunnion results in a cumulative effect leading to greater corrosion at the taper junction. Significance The results of the study suggest that the combination of (1) increased frictional torque in the larger ASR XLs and (2) the rough Corail trunnion surface, results in greater corrosion at the taper junction in comparison to the Pinnacle hips; this helps to explain the higher risk of revision in this hip design

Identifying The Pattern of Material Loss at the Head-Neck Junction Wear Helps Determine the Mechanism of Failure of Metal on Metal Total Hip Replacements

Material loss at the Head-Neck junction accounts for a third of the total volume material loss in contemporary metal-on-metal total hip replacements. It is speculated that the material loss is the result of corrosion and mechanical wear (fretting). High volumes of material loss have been reported, especially from the head taper. There is only one report on characterizing the pattern of material loss and this was in a very small number of cases (n=5). Our aim was to identify the different material loss patterns at the head taper and their corresponding mechanisms We retrospectively analysed a series of retrieved Large Head Metal on Metal Total Hip Replacements (155 cups, 155 femoral heads and 4 stems). We measured material loss on the bearing surfaces and the head-neck junction using well-published metrology methods. Furthermore we collected patient (age, gender and time of primary/revision operations), pre-revision (cobalt and chromium blood metal ion, oxford hip score, cup orientation and implant position) implant (cup and head size, manufacturer and corrosion severity) data. Finally we used surface analysis techniques (microscopy and spectroscopy) to identify fretting, imprinting and the material composition of debris. We devised a novel four-group classification and two blinded engineers classified the material loss patterns using wear maps derived from the metrology analysis We observed four distinct patterns of taper surface material loss at our retrieval centre and we set out to characterize these types and relate them to patient, implant and clinical variables. The four groups of material loss patterns were defined as: (1) Low wear (n= 63), (2) Open-end band (n=32), (3) Stripped material loss (n=54) and (4) Coup-Countercoup (n=6) (Figure). The Interobserver Reliability Kappa score was 0.78 (p<0.001) indicating substantial agreement between the two examiners. Analysis of variables between the groups identified significantly different head sizes (highest: Group 2, p=0.000), corrosion severity (highest: Group 2, p=0.004) and time to revision (highest: Group 3, p=0.040). We identified four different material loss patterns each with its own mechanism. Corrosion was identified as the principal mechanism in Groups 1 and 3. Group 1 head-neck junctions are thought to have a better seal with less fluid ingress in the junction. Group 3 head-neck junctions are attacked by corrosion either circumferentially, or unilaterally, along the whole engagement length. Mechanically assisted corrosion was the principal mechanism in Group 2. The higher friction torque opens up the open-end part of the junction and the ingressing fluid accelerates the corrosion. Extensive fretting was also observed under the scanning electron microscope. Intra-operative surgical damage was identified as the principal mechanism in Group 4, with only 6 components. The patterns and the mechanisms of material loss at the head-neck junction contribute to the understanding of large head metal-on-metal hip replacements. As a result, better implants can be designed in the future. Clinically, these findings suggest that head size and head taper-trunnion fit are the main factors that determine the longevity of the head-neck junction. On the other hand, patients selection does not influence the integrity of the junction

Fish passage hydrodynamics New Zealand context

New Zealand is home to 57 native freshwater fish species, of which a considerable number are diadromous, having to move between freshwater and saltwater at least once during their lifecycle. The economic utilisation of New Zealand rivers has largely been carried out without fish migration behaviour in mind, resulting in thousands of structures that prevent fish migration up- and downriver. Remediation of existing structures, especially culverts, and construction of new, more fish friendly, structures requires in-depth knowledge of the needs of the target fish species. In April 2018, the New Zealand Fish Passage Guidelines were released, providing a design framework to enable fish passage in new and existing structures. In support of the new guidance, our project aims to gain insight into the swimming behaviour and performance of inanga (Galaxias maculatus) under various hydraulic conditions, in particular when swimming upstream, which is not well understood. For this purpose, we are designing a new experimental setup in a 600 mm wide flume at the Water Engineering Laboratory at the University of Auckland. We will study hydrodynamics of fish passes with roughened surfaces, baffles and energy dissipators. We will evaluate sensor equipment used to enable flow and fish tracking, with the intention of tracking individual inanga at critical cross sections. This will allow us to study fish response to turbulence, boundary layers, resting zones and wetted margins. We aim to gain valuable insight into design methods and materials that best help inanga, and potentially other members of the family Galaxiidae, with their migration. Eventually, the project aims to provide guidelines suitable for retrofitting existing and building new structures

36mm Metal-on-Metal Hips have Similar Taper Material Loss Rates as Larger Diameter Hips from the Same Manufacturer

Introduction: There is a two-fold difference in failure rate between the two most commonly used metal-on-metal (MOM) bearing types in the US. We compared these two bearing types; one with a 36mm diameter with a modular cup and one with a diameter >36mm with a monoblock cup. Methods: This was a retrospective study involving 60 retrieved LD-MOM-THR hips of 2 different cobalt-chromium bearing designs (n=30 in each group) from a single manufacturer that had been paired with a single cementless titanium 12/14 stem design from the same manufacturer (Table 1). One group consisted of a monoblock cup whilst the other had a modular cup design with separate metal shell and liner components. Paired t-tests revealed that the two groups were statistically matched in relation to patient age, gender and time to revision. We used a well-published scoring method to visually assess the severity of corrosion at each head taper surface on a scale of 1 (none) to 4 (severe). We then used a roundness-measuring machine to measure the volume of material loss at the taper surfaces. The statistical significance of any differences between the two hip designs in relation to corrosion scores and material loss were then evaluated. Results: We found that 93% (n=28 in each group) of the tapers showed evidence of corrosion, however there was no significant difference between the two groups (p=0.61). The monoblock cup group had a median taper material loss rate of 0.397 mm3/year (0-4.198) and the material loss of the modular cup group was 0.216 mm3/year (0-3.117). There was no significant difference between the two groups (p=0.132). Discussion and Conclusion: We found corrosion and material loss rates for the tapers of 36mm hips to be comparable to larger diameter hips from the same manufacturer. This supports the classification of 36mm hips as large diameter

Charactering taper junction wear helps understand the mechanism of failure of metal on metal hip replacements.

Introduction: Taper junction material loss is the result of corrosion and mechanical wear. The significance of the taper junction material loss is highlighted by studies that compared resurfacing and total hip replacements of the same type and size. High volumes of material loss are reported, especially from the head taper, but the pattern of wear is unknown. One report characterized the material loss pattern of five tapers (n=5) into axisymmetrical and asymmetrical, along the long axis of the taper. We noticed more than two patterns on our retrievals and we set out to characterize these types and relate them to clinical variables. Methods: We retrospectively analysed retrieved cobalt-chromium tapers (n=146) using a roundness measurement machine. We also performed a corrosion classification and collected clinical data (metal ion levels, time to revision, component sizes). A non-blinded author devised a four-group classification (table). Two blinded authors classified the material loss patterns derived from the roundness measurement machine. Results: The four groups of material loss patterns Low wear (n= 62), Open-end band (n=29), Stripped material loss (n=51) and Coup-Countercoup (n=4). Kappa was 0.78 (p<0.001) in the assessment of interobserver reliability. Kruskal-Wallis test revealed: - Significantly higher volumes of wear on the taper of Stripped material loss compared to Low wear (p<0.001) and Open-end band compared to Low wear (p<0.001) groups. - Significantly higher chromium ion blood levels in the open-end band compared to the Stripped material loss group. - Significantly higher Cobalt ion blood levels in the Stripped material loss compared to the Low wear group - Significantly higher Cobalt/Chromium ration in the Open-end band compared to the Low wear group One-way ANOVA analysis revealed: - Significant difference between in the head sizes between the groups (p=0.01). Post-hoc analysis located the difference between the Low wear (median=40, range=20) and Open-end band (median=49, range=20) groups (p<0.001). - Significantly higher time to revision in the Stripped material loss compared to the Low wear group (p=0.05), in the post-hoc analysis. - Significantly higher corrosion scores in the Stripped material loss compared to the Low wear group (p<0.001) and the Open-end band compared to the Low wear group (p<0.001). Discussion: The results suggests that corrosion becomes worse over time and that the material loss pattern evolves gradually from the Low wear to Open-end band and finally to Stripped. Further analysis is required to assess the factors that affect the Coup-countercoup group

Understanding Why Dual-Taper Hips Fail

Our multi-disciplinary team of surgeons and engineers will present the mechanisms of failure of 100 retrieved dual taper hip arthroplasties, identifying surgical, implant and patient risk factor