Emerging therapeutic opportunities for integrin inhibitors.

Integrins are cell adhesion and signalling proteins crucial to a wide range of biological functions. Effective marketed treatments have successfully targeted integrins αIIbß3, α4ß7/α4ß1 and αLß2 for cardiovascular diseases, inflammatory bowel disease/multiple sclerosis and dry eye disease, respectively. Yet, clinical development of others, notably within the RGD-binding subfamily of αv integrins, including αvß3, have faced significant challenges in the fields of cancer, ophthalmology and osteoporosis. New inhibitors of the related integrins αvß6 and αvß1 have recently come to the fore and are being investigated clinically for the treatment of fibrotic diseases, including idiopathic pulmonary fibrosis and nonalcoholic steatohepatitis. The design of integrin drugs may now be at a turning point, with opportunities to learn from previous clinical trials, to explore new modalities and to incorporate new findings in pharmacological and structural biology. This Review intertwines research from biological, clinical and medicinal chemistry disciplines to discuss historical and current RGD-binding integrin drug discovery, with an emphasis on small-molecule inhibitors of the αv integrins.

Aflatoxin and ochratoxin A residues in supplementary foods used for wild birds.

Provision of supplementary food for garden birds is practiced on a large scale in multiple countries. While this resource has benefits for wild bird populations, concern has been expressed regarding the potential for contamination of foodstuffs by mycotoxins, and the implications this might have for wildlife health. We investigated whether aflatoxin (AF) and ochratoxin A (OA) residues are present in foodstuffs sold for wild bird consumption at point of sale in Great Britain using high pressure liquid chromatography analyses. The hypothesis that production of these mycotoxins occurs in British climatic conditions, or under storage conditions after the point of sale, was tested under experimental conditions but was not proved by our study. While the majority of peanut samples were negative for AF residues, 10% (10/98) of samples at point of sale and 11% (13/119) of those across the storage and climate exposure treatment replicates contained AFB1 that exceeded the maximum permitted limit of 20 µg/kg. No significant difference was found in the detection of either mycotoxin between branded and non-branded products. The clinical significance, if any, of exposure of wild birds to mycotoxins requires further investigation. Nevertheless, the precautionary principle should be adopted and best practice steps to reduce the likelihood of wild bird exposure to mycotoxins are recommended.

'Loneliness in the city': examining socio-economics, loneliness and poor health in the North East of England.

OBJECTIVES: The aim of this study was to discover whether lower socio-economic status is associated with increased experiences of loneliness and isolation. The research subsequently determined whether this relationship impacted health inequalities. STUDY DESIGN: The study used a cross-sectional, self-reported survey collecting information on loneliness, isolation and poor health (n = 680). The survey was administered through Sunderland District Council in 2016-2017, and data were analysed at The University of Sunderland. METHODS: The study used a quantitative approach, and data were analysed using descriptive statistics, engaging in univariate, bivariate and multivariate levels of analysis. RESULTS: A number of significant findings emerged from the data analysis, linking lower socio-economic status to experiences of loneliness (P = 0.000) and social isolation (P = 0.000). When determining if social isolation and socio-economics had a detrimental impact on a person's health, no statistical association was discovered (P = 0.098). Yet, there was a significant relationship concerning socio-economic status, loneliness and poor health (P = 0.026). CONCLUSIONS: The authors have identified a number of associations within the data with reference to isolation, loneliness and poor health. Therefore, participants from a lower socio-economic group experienced disproportionately high levels of social isolation and emotional loneliness when compared with other socio-economic groups. The data also demonstrate that participants who experienced loneliness, and who were from a lower socio-economic background, were consistently more likely to report poor health than those from other socio-economic backgrounds.

Highly crosslinked polyethylene wear rates and acetabular component orientation: a minimum ten-year follow-up.

Aims: The aim of this study was to determine whether there is a difference in the rate of wear between acetabular components positioned within and outside the 'safe zones' of anteversion and inclination angle. Patients and Methods: We reviewed 100 hips in 94 patients who had undergone primary total hip arthroplasty (THA) at least ten years previously. Patients all had the same type of acetabular component with a bearing couple which consisted of a 28 mm cobalt-chromium head on a highly crosslinked polyethylene (HXLPE) liner. A supine radiostereometric analysis (RSA) examination was carried out which acquired anteroposterior (AP) and lateral paired images. Acetabular component anteversion and inclination angles were measured as well as total femoral head penetration, which was divided by the length of implantation to determine the rate of polyethylene wear. Results: The mean anteversion angle was 19.4° (-15.2° to 48°, sd 11.4°), the mean inclination angle 43.4° (27.3° to 60.5°, sd 6.6°), and the mean wear rate 0.055 mm/year (sd 0.060). Exactly half of the hips were positioned inside the 'safe zone'. There was no difference (median difference, 0.012 mm/year; p = 0.091) in the rate of wear between acetabular components located within or outside the 'safe zone'. When compared to acetabular components located inside the 'safe zone', the wear rate was no different for acetabular components that only achieved the target anteversion angle (median difference, 0.012 mm/year; p = 0.138), target inclination angle (median difference, 0.013 mm/year; p = 0.354), or neither target (median difference, 0.012 mm/year; p = 0.322). Conclusion: Placing the acetabular component within or outside the 'safe zone' did not alter the wear rate of HXLPE at long-term follow-up to a level that risked osteolysis. HXLPE appears to be a forgiving bearing material in terms of articular surface wear, but care must still be taken to position the acetabular component correctly so that the implant is stable. Cite this article: Bone Joint J 2018;100-B:891-7.

Inducible displacement of cemented tibial components ten years after total knee arthroplasty.

AIMS: The aim of this study was to evaluate the long-term inducible displacement of cemented tibial components ten years after total knee arthroplasty (TKA). PATIENTS AND METHODS: A total of 15 patients from a previously reported prospective trial of fixation using radiostereometric analysis (RSA) were examined at a mean of 11 years (10 to 11) postoperatively. Longitudinal supine RSA examinations were acquired at one week, one year, and two years postoperatively and at final follow-up. Weight-bearing RSA examinations were also undertaken with the operated lower limb in neutral and in maximum internal rotation positions. Maximum total point motion (MTPM) was calculated for the longitudinal and inducible displacement examinations (supine versus standing, standing versus internal rotation, and supine versus standing with internal rotation). RESULTS: All patients showed some inducible displacement. Two patients with radiolucent lines had greater mean standing-supine MTPM displacement (1.35; sd 0.38) compared with the remaining patients (0.68; sd 0.36). These two patients also had a greater mean longitudinal MTPM at ten years (0.64; sd 0.50) compared with the remaining patients (0.39; sd 0.13 mm). CONCLUSION: Small inducible displacements in well-fixed cemented tibial components were seen ten years postoperatively, of a similar magnitude to that which has been reported for well-fixed components one to two years postoperatively. Greater displacements were found in components with radiolucent lines. Cite this article: Bone Joint J 2018;100-B:170-5.

Genetic dissection of intraspecific variation in a male-specific sexual trait in Drosophila melanogaster.

An open question in evolutionary biology is the relationship between standing variation for a trait and the variation that leads to interspecific divergence. By identifying loci underlying phenotypic variation in intra- and interspecific crosses we can determine the extent to which polymorphism and divergence are controlled by the same genomic regions. Sexual traits provide abundant examples of morphological and behavioral diversity within and among species, and here we leverage variation in the Drosophila sex comb to address this question. The sex comb is an array of modified bristles or 'teeth' present on the male forelegs of several Drosophilid species. Males use the comb to grasp females during copulation, and ablation experiments have shown that males lacking comb teeth typically fail to mate. We measured tooth number in >700 genotypes derived from a multiparental advanced-intercross population, mapping three moderate-effect loci contributing to trait heritability. Two quantitative trait loci (QTLs) coincide with previously identified intra- and interspecific sex comb QTL, but such overlap can be explained by chance alone, in part because of the broad swathes of the genome implicated by earlier, low-resolution QTL scans. Our mapped QTL regions encompass 70-124 genes, but do not include those genes known to be involved in developmental specification of the comb. Nonetheless, we identified plausible candidates within all QTL intervals, and used RNA interference to validate effects at four loci. Notably, TweedleS expression knockdown substantially reduces tooth number. The genes we highlight are strong candidates to harbor segregating, functional variants contributing to sex comb tooth number.

Migration of a cemented fixed-bearing, polished titanium tibial baseplate (Genesis II) at ten years : a radiostereometric analysis.

AIMS: The purpose of the present study was to examine the long-term fixation of a cemented fixed-bearing polished titanium tibial baseplate (Genesis ll). PATIENTS AND METHODS: Patients enrolled in a previous two-year prospective trial (n = 35) were recalled at ten years. Available patients (n = 15) underwent radiostereometric analysis (RSA) imaging in a supine position using a conventional RSA protocol. Migration of the tibial component in all planes was compared between initial and ten-year follow-up. Outcome scores including the Knee Society Score, Western Ontario and McMaster Universities Arthritis Index, 12-item Short Form Health Survey, Forgotten Joint Score, and University of California, Los Angeles Activity Score were recorded. RESULTS: At ten years, the mean migration of the tibial component was less than 0.1 mm and 0.1° in all planes relative to the post-operative RSA exam. Maximum total point movement increased with time (p = 0.002) from 0.23 mm (sd 0.18) at six weeks to 0.42 mm (sd 0.20) at ten years. CONCLUSION: The low level of tibial baseplate migration found in the present study correlates to the low rate of revision for this implant as reported in individual studies and in joint replacement registries. TAKE HOME MESSAGE: Overall, the implant was found to be well fixed at ten years, supporting its continued clinical use and the predictive power of RSA for determining long-term fixation of implants. Cite this article: Bone Joint J 2016;98-B:616-21.

Highly cross-linked polyethylene decreases the rate of revision of total hip arthroplasty compared with conventional polyethylene at 13 years' follow-up.

AIMS: The purpose of this study was to compare the long-term results of primary total hip arthroplasty (THA) in young patients using either a conventional (CPE) or a highly cross-linked (HXLPE) polyethylene liner in terms of functional outcome, incidence of osteolysis, radiological wear and rate of revision. METHODS: We included all patients between the ages of 45 and 65 years who, between January 2000 and December 2001, had undergone a primary THA for osteoarthritis at our hospital using a CPE or HXLPE acetabular liner and a 28 mm cobalt-chrome femoral head. From a total of 160 patients, 158 (177 hips) were available for review (CPE 89; XLPE 88). The mean age, body mass index (BMI) and follow-up in each group were: CPE: 56.8 years (46 to 65); 30.7 kg/m(2) (19 to 58); 13.2 years (2.1 to 14.7) and HXLPE: 55.6 years (45 to 65); BMI: 30 kg/m(2) (18 to 51); 13.1 years (5.7 to 14.4). RESULTS: The mean Harris hip score (HHS) at final follow-up was 89.3 for the CPE group and 90.9 for the HXLPE group (p = 0.078). Osteolysis was present around 15 acetabular (17%) and 16 femoral (18%) components in the CPE hips compared with none (0%) in the HXLPE hips. The mean radiological linear wear of the CPE liners was 0.11 mm/year compared with 0.035 mm/year for the HXLPE liners (p = 0.006). The cumulative implant survival, with revision for polyethylene wear as the endpoint, was 86% (95% confidence interval 78 to 94) in the CPE group and 100% in the HXLPE group at 13 years (numbers at risk at 13 years - CPE: 65, XLPE: 61). DISCUSSION: This study shows that HXLPE liners are associated with significantly less osteolysis and a lower rate of revision THA than CPE liners at long-term follow-up. TAKE HOME MESSAGE: The findings of this study highlight the clinical benefits of using HXLPE liners in THA and support the routine use of the material in order to improve implant longevity and to decrease the number of patients needing revision for aseptic osteolysis.

The obese patient: a problem of larger consequence.

Obesity is a worldwide epidemic that has both economic and health implications of enormous consequence. The obese patients tend to have earlier symptoms related to osteoarthritis, more peri-operative medical problems, higher rates of infection and more technical difficulties intra-operatively following hip and knee arthroplasty. Nevertheless, these patients have good long-term clinical outcomes and implant survival rates and are often some of the most satisfied patients after joint arthroplasty. Therefore, obese patients should not be denied surgery based on their weight alone.

Knee manipulation under anaesthetic following total knee arthroplasty: a matched cohort design.

The purpose of this study was to compare clinical outcomes of total knee arthroplasty (TKA) after manipulation under anaesthesia (MUA) for post-operative stiffness with a matched cohort of TKA patients who did not requre MUA. In total 72 patients (mean age 59.8 years, 42 to 83) who underwent MUA following TKA were identified from our prospective database and compared with a matched cohort of patients who had undergone TKA without subsequent MUA. Patients were evaluated for range of movement (ROM) and clinical outcome scores (Western Ontario and McMaster Universities Arthritis Index, Short-Form Health Survey, and Knee Society Clinical Rating System) at a mean follow-up of 36.4 months (12 to 120). MUA took place at a mean of nine weeks (5 to 18) after TKA. In patients who required MUA, mean flexion deformity improved from 10° (0° to 25°) to 4.4° (0° to 15°) (p < 0.001), and mean range of flexion improved from 79.8° (65° to 95°) to 116° (80° to 130°) (p < 0.001). There were no statistically significant differences in ROM or functional outcome scores at three months, one year, or two years between those who required MUA and those who did not. There were no complications associated with manipulation. At most recent follow-up, patients requiring MUA achieved equivalent ROM and clinical outcome scores when compared with a matched control group. While other studies have focused on ROM after manipulation, the current study adds to current literature by supplementing this with functional outcome scores.

Metal ion levels after metal-on-metal total hip arthroplasty: a five-year, prospective randomized trial.

BACKGROUND: The U.S. Food and Drug Administration has requested post-market surveillance data, including data on metal ion levels, regarding metal-on-metal total hip arthroplasty. We performed a prospective, randomized study of metal ion levels in erythrocytes, serum, and whole blood at five years after 28 and 36-mm metal-on-metal and 28-mm metal-on-polyethylene total hip arthroplasty. METHODS: One hundred and five enrolled patients were randomized equally to the three bearing surface options and were blinded with regard to their treatment group. Metal ion measurements and clinical evaluations were performed at regular intervals. RESULTS: Cobalt and chromium ion levels in all blood sample types at the five-year time point were significantly lower in the metal-on-polyethylene group than in each of the two metal-on-metal groups (p < 0.001) with the exception of chromium in erythrocytes (p = 0.194). Cobalt in serum (p = 0.029) and erythrocytes (p = 0.002) showed significant increases from two to five years in the 36-mm metal-on-metal group; similar increases were not seen in the 28-mm metal-on-metal group. At five years, five patients in the 36-mm metal-on-metal group and none in the 28-mm metal-on-metal group had cobalt or chromium levels of >7 ppb. Correlations among levels in serum, erythrocyte, and whole blood were stronger for cobalt than for chromium. One patient in the 36-mm metal-on-metal group underwent revision because of an adverse local tissue reaction. CONCLUSIONS: The 36-mm metal-on-metal bearing underperformed the 28-mm metal-on-metal bearing with respect to metal ion levels. The authors are closely following all patients treated with metal-on-metal total hip arthroplasty.

The painful total hip replacement: diagnosis and deliverance.

Total hip replacement (THR) is a very common procedure undertaken in up to 285 000 Americans each year. Patient satisfaction with THR is very high, with improvements in general health, quality of life, and function while at the same time very cost effective. Although the majority of patients have a high degree of satisfaction with their THR, 27% experience some discomfort, and up to 6% experience severe chronic pain. Although it can be difficult to diagnose the cause of the pain in these patients, this clinical issue should be approached systematically and thoroughly. A detailed history and clinical examination can often provide the correct diagnosis and guide the appropriate selection of investigations, which will then serve to confirm the clinical diagnosis made.

Gastrocnemius flap reconstruction of soft-tissue defects following infected total knee replacement.

A soft-tissue defect over an infected total knee replacement (TKR) presents a difficult technical problem that can be treated with a gastrocnemius flap, which is rotated over the defect during the first-stage of a revision procedure. This facilitates wound healing and the safe introduction of a prosthesis at the second stage. We describe the outcome at a mean follow-up of 4.5 years (1 to 10) in 24 patients with an infected TKR who underwent this procedure. A total of 22 (92%) eventually obtained a satisfactory result. The mean Knee Society score improved from 53 pre-operatively to 103 at the latest follow-up (p < 0.001). The mean Western Ontario and McMaster Universities osteoarthritis index and Short-Form 12 score also improved significantly (p < 0.001). This form of treatment can be used reliably and safely to treat many of these complex cases where control of infection, retention of the components and acceptable functional recovery are the primary goals.

Outcomes and complications of total hip replacement in super-obese patients.

The purpose of this study was to examine the complications and outcomes of total hip replacement (THR) in super-obese patients (body mass index (BMI) > 50 kg/m(2)) compared with class I obese (BMI 30 to 34.9 kg/m(2)) and normal-weight patients (BMI 18.5 to 24.9 kg/m(2)), as defined by the World Health Organization. A total of 39 THRs were performed in 30 super-obese patients with a mean age of 53 years (31 to 72), who were followed for a mean of 4.2 years (2.0 to 11.7). This group was matched with two cohorts of normal-weight and class I obese patients, each comprising 39 THRs in 39 patients. Statistical analysis was performed to determine differences among these groups with respect to complications and satisfaction based on the Western Ontario and McMaster Universities (WOMAC) osteoarthritis index, the Harris hip score (HHS) and the Short-Form (SF)-12 questionnaire. Super-obese patients experienced significantly longer hospital stays and higher rates of major complications and readmissions than normal-weight and class I obese patients. Although super-obese patients demonstrated reduced pre-operative and post-operative satisfaction scores, there was no significant difference in improvement, or change in the score, with respect to HHS or the WOMAC osteoarthritis index. Super-obese patients obtain similar satisfaction outcomes as class I obese and normal-weight patients with respect to improvement in their scores. However, they experience a significant increase in length of hospital stay and major complication and readmission rates.

The importance of perceived helplessness and emotional health in understanding the relationship among pain, function, and satisfaction following revision knee replacement surgery.

OBJECTIVE: Little is known about the relationships among pain, function, psychological variables like perceived helplessness and emotional health, and patient satisfaction in people with revision knee replacement surgery. We hypothesized that pain and function would have a direct association with satisfaction as well as an indirect association through patient perceptions of helplessness and emotional health. DESIGN: This longitudinal study included 145 participants undergoing revision knee replacement surgery. Demographic data and expectation of benefit from surgery were recorded prior to surgery. The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), the Arthritis Helplessness Scale (AHS) and the Mental Component Scale (MCS) of the SF-36 (emotional health) were collected prior to and 2 years post-surgery. Satisfaction was recorded 2 years post-surgery. Regression analyses were conducted to test for mediation effects of helplessness and MCS. RESULTS: Participants were on average 69 years old and 54% were women. Participants were satisfied with the results of the surgery (mean ± standard deviation (SD) = 70.42 ± 31.46). Less pain and functional disability were associated with increased patient satisfaction and, the effect of pain or function was also mediated through helplessness whereby more pain and disability were associated with perceptions of helplessness and helplessness was associated with lower satisfaction. MCS did not mediate the relationship of pain and function with satisfaction. CONCLUSION: Helplessness plays an important role in understanding patient satisfaction. Interventions aimed at improving patient outcome should target not only pain and function but also should address strategies to support people in managing following knee revision surgery to maximize satisfaction with outcome.

The influence of obesity on total joint arthroplasty.

Obesity is an epidemic across both the developed and developing nations that is possibly the most important current public health factor affecting the morbidity and mortality of the global population. Obese patients have the potential to pose several challenges for arthroplasty surgeons from the standpoint of the influence obesity has on osteoarthritic symptoms, their peri-operative medical management, the increased intra-operative technical demands on the surgeon, the intra- and post-operative complications, the long term outcomes of total hip and knee arthroplasty. Also, there is no consensus on the role the arthroplasty surgeon should have in facilitating weight loss for these patients, nor whether obesity should affect the access to arthroplasty procedures.

Hip and knee arthroplasty 2011: what's new, what's true, does it matter? Evidence based issues.

This conversation represents an attempt by several arthroplasty surgeons to critique several abstracts presented over the last year as well as to use them as a jumping off point for trying to figure out where they fit in into our current understanding of multiple issues in modern hip and knee arthroplasty.

Commissioning of a displacement-controlled knee wear simulator and exploration of some issues related to the lubricant.

A six-station displacement-controlled knee simulator with separately controlled left (L) and right (R) banks (three wear implants per bank) was commissioned for a total of three million cycles (Mc) following ISO 14243-3. A commissioning protocol was applied to compare the polyethylene wear among the six wear stations by exchanging the implants between wear stations. Changes in lubricant characteristics during wear testing, such as polypeptide degradation, low-molecular-weight polypeptide concentration, and possible microbial contamination were also assessed. The total mean wear rate for the implants was 23.60 +/- 1.96 mm3/Mc and this was of a similar magnitude to the mean wear rate for the same implant tested under similar conditions by DePuy Orthopaedics Inc. (Warsaw, IN). Repeated run-in wear was observed when the implants were exchanged between wear stations, suggesting that implants should be subjected to the same wear station throughout the duration of a wear test. The total polypeptide degradation for the implants measured 30.53 +/- 3.96 percent; the low-molecular-weight polypeptide concentration of the "used" lubricant for implants (0.131 +/- 0.012 g/L) was 3.3 times greater than the mean polypeptide concentration of the fresh, "unused" lubricant (0.039 +/- 0.004 g/L). This increase in low-molecular weight polypeptide concentration was suggested to be attributable to protein shear in the articulation of the implant, the circulation of the lubricant, and some proteolytic activity. Sodium azide was ineffective in maintaining a sterile environment for wear testing as a single, highly motile Gram-negative micro-organism was identified in the lubricant from wear tests.

Mass gain behaviour of tibial polyethylene inserts during soak testing.

Fluid adsorption and the associated mass gain behaviour in tibial inserts of total knee replacements was investigated in polyethylene (PE) manufactured from extruded GUR 1050 resin. Repeatedly removing the PE inserts from the soak fluid for gravimetric assessment (including cleaning, desiccation, and weighing) increased the mass gain. Soaking PE inserts for 46 days or 92 days seemed to give about the same mass gain. PE inserts that were soaked at 37 degrees C gained more mass than PE inserts soaked at room-temperature. Gas-plasma sterilized PE inserts gained less mass than gamma-in-air sterilized PE inserts. No statistically significant differences were detected in mass gain between PE inserts that were of 10mm and 14mm thickness. The mass gain of PE inserts was higher in protein-rich soak fluid compared with low-ion distilled water. Prior to knee simulator wear testing, tibial PE inserts should be conditioned in the same medium and under the same test conditions (gravimetric assessment frequency, fluid protein content, and fluid temperature). This approach would help improve the accuracy and precision of the gravimetrically determined PE wear rate during knee simulator wear testing.

Genetic and metabolic determinants of nutritional phenotype in an insect-bacterial symbiosis.

The pervasive influence of resident microorganisms on the phenotype of their hosts is exemplified by the intracellular bacterium Buchnera aphidicola, which provides its aphid partner with essential amino acids (EAAs). We investigated variation in the dietary requirement for EAAs among four pea aphid (Acyrthosiphon pisum) clones. Buchnera-derived nitrogen contributed to the synthesis of all EAAs for which aphid clones required a dietary supply, and to none of the EAAs for which all four clones had no dietary requirement, suggesting that low total dietary nitrogen may select for reduced synthesis of certain EAAs in some aphid clones. The sequenced Buchnera genomes showed that the EAA nutritional phenotype (i.e. the profile of dietary EAAs required by the aphid) cannot be attributed to sequence variation of Buchnera genes coding EAA biosynthetic enzymes. Metabolic modelling by flux balance analysis demonstrated that EAA output from Buchnera can be determined precisely by the flux of host metabolic precursors to Buchnera. Specifically, the four EAA nutritional phenotypes could be reproduced by metabolic models with unique profiles of host inputs, dominated by variation in supply of aspartate, homocysteine and glutamate. This suggests that the nutritional phenotype of the symbiosis is determined principally by host metabolism and transporter genes that regulate nutrient supply to Buchnera. Intraspecific variation in the nutritional phenotype of symbioses is expected to mediate partitioning of plant resources among aphid genotypes, potentially promoting the genetic subdivision of aphid populations. In this way, microbial symbioses may play an important role in the evolutionary diversification of phytophagous insects.