The effect of Nickel hypersensitivity on the outcome of total knee arthroplasty and the value of skin patch testing: a systematic review.

BACKGROUND: To assess the Nickel sensitizing potential of total knee arthroplasty (TKA), explore the relationship between hypersensitivity and clinical outcomes, and evaluate the utility of skin patch testing pre- and/or postoperatively. MATERIALS AND METHODS: A literature search was performed through EMBASE, Medline and PubMed databases. Articles were screened independently by two investigators. The level of evidence of studies was assessed using the Oxford Centre for Evidence-Based Medicine Criteria and the quality evaluated using the Methodological Index for Non-randomized Studies and Cochrane risk-of-bias tools. RESULTS: Twenty studies met the eligibility criteria, reporting on 1354 knee arthroplasties. Studies included patients undergoing primary or revision TKA, pre- and/or postoperatively, and used patch testing to identify Nickel hypersensitivity. Prevalence of Nickel hypersensitivity ranged from 0% to 87.5%. One study compared the prevalence of Nickel hypersensitivity in the same patient group before and after surgery and noted newly positive patch test reactions in three patients (4.2%). Three studies reported lower prevalence of Nickel hypersensitivity in postoperative patients compared to preoperative ones. Seven studies suggested that hypersensitivity might cause adverse clinical outcomes, but six did not support any relationship. Seven studies recommended preoperative patch testing in patients with history of metal allergy, and nine concluded that testing may be valuable postoperatively. CONCLUSIONS: Patients undergoing TKA with no prior history of metal hypersensitivity do not seem to be at an increased risk of developing Nickel hypersensitivity, and there is conflicting evidence that patients with pre-existing hypersensitivity are more likely to experience adverse outcomes. Patch testing remains the most commonly used method for diagnosing hypersensitivity, and evidence suggests preoperative testing in patients with history of metal allergy to aid prosthesis selection, and postoperatively in patients with suspected hypersensitivity once common causes of implant failure have been excluded, since revision with hypoallergenic implants may alleviate symptoms.

An audit of mammographic screen detected lesions of uncertain malignant potential (B3) diagnosed on initial image guided needle biopsy: how has our practice changed over 10 years?

AIM: To review all cases of B3 lesion diagnosed at initial image-guided needle biopsy over two 5-year cohorts to identify upgrade rates to malignancy and the effect of changing guidance on the management of such lesions. MATERIALS AND METHODS: Data was collected retrospectively. Mammographic features, biopsy type and management were recorded for each lesion. Upgrade rates for each B3 histological category were quantified. Statistical analysis was performed using SPSS. RESULTS: There were 224 cases in 2005-2010 and 240 cases in 2010-2015. Mammographically 211 lesions were microcalcifications, 182 masses, 65 distortions and six asymmetric densities with no difference in the mammographic features in the two cohorts. Two hundred and eight 14 G core biopsies and 256 initial vacuum-assisted biopsies were performed. There was a statistically significant reduction in benign surgical biopsies and an increase in second-line vacuum biopsy/excision in the latter cohort, with no significant change in the upgrade rate. There was an overall 6% upgrade to invasive malignancy and 13% upgrade to ductal carcinoma in situ (DCIS). The upgrade rates for the following histological categories were atypical intraductal epithelial proliferation (AIDEP) 33.2% (21/63); classical (not pleomorphic) in situ lobular neoplasia (ISLN) 18.2% (6/33); flat epithelial hyperplasia (FEA) 21.7% (20/92); papilloma with atypia 53.8% (7/13), without atypia 12.1% (8/66); and radial scar/complex sclerosing lesion with atypia 16.7% (2/12), and without atypia 7.9% (6/76). CONCLUSION: Upgrade rates remain high for some histological categories even with first-line use of vacuum biopsy. Management of borderline lesions should be considered carefully in a multidisciplinary meeting. In many cases, the need for diagnostic surgical excision has been replaced by image-guided vacuum sampling.

Can digital breast tomosynthesis accurately predict whether circumscribed masses are benign or malignant in a screening population?

AIM: To evaluate whether digital breast tomosynthesis (DBT) can predict if circumscribed masses are benign or malignant by assessing margin sharpness. MATERIALS AND METHODS: Circumscribed masses were evaluated on co-registered two-dimensional digital mammography (2DDM) and DBT. Lesions were categorised as follows: category 1=visible sharp border 0-25% of the total margin; category 2 = 26-50% category 3= 51-75%, and category 4=76-100%. Changes in category between 2DDM and DBT were analysed; if the category was lower on DBT the change was negative, if higher the change was positive. RESULTS: Of 759 lesions, 121 masses classified as circumscribed on DBT were included; 25 were malignant and 96 benign. Of the benign lesions, 8/96 were within category 3 or 4 on 2DDM compared with 48/96 benign lesions within category 3 or 4 on DBT (Fisher's exact test p<0.000527). Forty-eight of 51 (94.1%) lesions categorised as 3 or 4 on DBT were benign and 65/67 (97.01%) of the positive category change group were benign. Lesions in category 1 on DBT had 45.4% chance of being malignant (20/44) compared with 22.72% (20/88) on 2DDM (chi-squared test p<0.001). Sixty-five of 67 (97.01%) lesions in the positive category change group were benign and 23/54 (42.6%) lesions with either no or negative category change were malignant. CONCLUSION: The present study demonstrates 97% accuracy in predicting circumscribed lesions as benign when using positive category change and 94% accuracy when >50% of the margin is sharply defined on DBT.

Host genetic factors associated with hepatocellular carcinoma in patients with hepatitis C virus infection: A systematic review.

Hepatitis C virus (HCV)-infected patients are at risk of developing hepatocellular carcinoma (HCC). Individuals at heightened risk could be targeted by intensive follow-up surveillance. We have conducted a systematic review of the literature to identify host genetic predisposition to HCC in HCV-infected patients. A comprehensive search of Medline and Embase databases was performed, and the strength of evidence of associations for each gene on development of HCC was evaluated. We identified 166 relevant studies, relating to 137 different genes, or combinations thereof. Seventeen genes were classified as having "good" evidence of an association, a significant association was observed for 37 genes but this finding had not yet been replicated, 56 genes had mixed or limited evidence of an association, and 27 genes showed no association. IFNL3/4, TNF-α and PNPLA3 genes had the most evidence of an association. There was, however, considerable heterogeneity in study design and data quality. In conclusion, we identified a number of genes with evidence of association with HCC, but also a need for more standardized approaches to address this clinically critical question. It is important to consider the underlying mechanism of these relationships and which are confounded by the presence of other HCC risk factors and response to therapy. We also identified many genes where the evidence of association is contradictory or requires replication, as well as a number where associations have been studied but no evidence found. These findings should help to direct future studies on host genetic predisposition to HCC in HCV-infected patients.

The role of canonical and non-canonical Hedgehog signaling in tumor progression in a mouse model of small cell lung cancer.

Hedgehog (Hh) signaling regulates cell fate and self-renewal in development and cancer. Canonical Hh signaling is mediated by Hh ligand binding to the receptor Patched (Ptch), which in turn activates Gli-mediated transcription through Smoothened (Smo), the molecular target of the Hh pathway inhibitors used as cancer therapeutics. Small cell lung cancer (SCLC) is a common, aggressive malignancy with universally poor prognosis. Although preclinical studies have shown that Hh inhibitors block the self-renewal capacity of SCLC cells, the lack of activating pathway mutations have cast doubt over the significance of these observations. In particular, the existence of autocrine, ligand-dependent Hh signaling in SCLC has been disputed. In a conditional Tp53;Rb1 mutant mouse model of SCLC, we now demonstrate a requirement for the Hh ligand Sonic Hedgehog (Shh) for the progression of SCLC. Conversely, we show that conditional Shh overexpression activates canonical Hh signaling in SCLC cells, and markedly accelerates tumor progression. When compared to mouse SCLC tumors expressing an activating, ligand-independent Smo mutant, tumors overexpressing Shh exhibited marked chromosomal instability and Smoothened-independent upregulation of Cyclin B1, a putative non-canonical arm of the Hh pathway. In turn, we show that overexpression of Cyclin B1 induces chromosomal instability in mouse embryonic fibroblasts lacking both Tp53 and Rb1. These results provide strong support for an autocrine, ligand-dependent model of Hh signaling in SCLC pathogenesis, and reveal a novel role for non-canonical Hh signaling through the induction of chromosomal instability.

Host-Parasite Relationships and Life Histories of Trypanosomes in Australia.

Trypanosomes constitute a group of flagellate protozoan parasites responsible for a number of important, yet neglected, diseases in both humans and livestock. The most significantly studied include the causative agents of African sleeping sickness (Trypanosoma brucei) and Chagas disease (Trypanosoma cruzi) in humans. Much of our knowledge about trypanosome host-parasite relationships and life histories has come from these two human pathogens. Recent investigations into the diversity and life histories of wildlife trypanosomes in Australia highlight that there exists a great degree of biological and behavioural variation within and between trypanosomes. In addition, the genetic relationships between some Australian trypanosomes show that they are unexpectedly more closely related to species outside Australia than within it. These findings have led to a growing focus on the importance of understanding parasites occurring naturally in wildlife to (1) better document parasite biodiversity, (2) determine evolutionary relationships and degree of host specificity, (3) understand host-parasite interactions and the role of parasites in the natural ecosystem and (4) identify biosecurity issues of emerging disease in both wildlife and human populations. Here we review what is known about the diversity, life histories, host-parasite interactions and evolutionary relationships of trypanosomes in Australian wildlife. In this context, we focus upon the genetic proximity of key Australian species to the pathogenic T. cruzi and discuss similarities in their biology and behaviour that present a potential risk of human disease transmission by Australian vectors and wildlife.

The accuracy of digital breast tomosynthesis compared with coned compression magnification mammography in the assessment of abnormalities found on mammography.

AIM: To compare the diagnostic accuracy of the digital breast tomosynthesis (DBT) with coned compression magnification mammography (CCMM). MATERIALS AND METHODS: The study design included two reading sessions completed by seven experienced radiologists. In the first session, all readers read bilateral standard two-view mammograms and a CCMM view of the lesion before giving a combined score for assessment. In the second session, readers read bilateral standard two-view mammograms plus one-view DBT. The two reading sessions of the experiment were separated by at least 2 weeks to reduce the chance of reader memory of the images read in the previous session from influencing the performance in the subsequent session. RESULTS: Three hundred and fifty-four lesions were assessed and receiver-operative characteristic (ROC) analysis was used to evaluate the difference between the two modes. For standard two-view mammography plus CCMM, the area under the curve (AUC) was 0.87 [95% confidence interval (CI): 0.83-0.91] and for standard two-view mammography plus DBT the AUC was 0.93 (95% CI: 0.91-0.95). The difference between the AUCs was 0.06 with p-value of 0.0014. CONCLUSION: Two-view mammography with one-view DBT showed significantly improved accuracy compared to two-view mammography and CCMM in the assessment of mammographic abnormalities. These results show that DBT can be used effectively in the further evaluation of mammographic abnormalities found at screening and in symptomatic diagnostic practice.

A comparison of the accuracy of film-screen mammography, full-field digital mammography, and digital breast tomosynthesis.

AIM: To measure the change in diagnostic accuracy of conventional film-screen mammography and full-field digital mammography (FFDM) with the addition of digital breast tomosynthesis (DBT) in women recalled for assessment following routine screening. MATERIALS AND METHODS: Ethics approval for the study was granted. Women recalled for assessment following routine screening with screen-film mammography were invited to participate. Participants underwent bilateral, two-view FFDM and two-view DBT. Readers scored each lesion separately for probability of malignancy on screen-film mammography, FFDM, and then DBT. The scores were compared with the presence or absence of malignancy based on the final histopathology outcome. RESULTS: Seven hundred and thirty-eight women participated (93.2% recruitment rate). Following assessment 204 (26.8%) were diagnosed as malignant (147 invasive and 57 in-situ tumours), 286 (37.68%) as benign, and 269 (35.4%) as normal. The diagnostic accuracy was evaluated by using receiving operating characteristic (ROC) and measurement of area under the curve (AUC). The AUC values demonstrated a significant (p = 0.0001) improvement in the diagnostic accuracy with the addition of DBT combined with FFDM and film-screen mammography (AUC = 0.9671) when compared to FFDM plus film-screen mammography (AUC = 0.8949) and film-screen mammography alone (AUC = 0.7882). The effect was significantly greater for soft-tissue lesions [AUC was 0.9905 with the addition of DBT and AUC was 0.9201 for FFDM with film-screen mammography combined (p = 0.0001)] compared to microcalcification [with the addition of DBT (AUC = 0.7920) and for FFDM with film-screen mammography combined (AUC = 0.7843; p = 0.3182)]. CONCLUSION: The addition of DBT increases the accuracy of mammography compared to FFDM and film-screen mammography combined and film-screen mammography alone in the assessment of screen-detected soft-tissue mammographic abnormalities.

Developing environment-specific water quality guidelines for suspended particulate matter.

It is generally well recognised that suspended particulate matter (SPM), from nano-scale particles to sand-sized sediments, can cause serious degradation of aquatic ecosystems. However, at present there is a poor understanding of the SPM conditions that water quality managers should aim to achieve in contrasting environments in order to support good ecological status. In this article, we analyse long-term SPM data collected from a wide range of reference-condition temperate environments in the UK (638 stream/river sites comprising 42 different ecosystem-types). One-way analysis of variance reveals that there is a statistically significant difference (p < 0.001) between the background SPM concentrations observed in contrasting ecosystems that are in reference condition (minimal anthropogenic disturbance). One of the 42 ecosystems studied had mean background concentrations of SPM in excess of the current European Union (EU) water quality guideline, despite being in reference condition. The implications of this finding are that the EU's current blanket water quality guideline (25 mg L(-1) for all environments) is inappropriate for this specific ecosystem-type which will be non-compliant with the guideline regardless of the intensity of land-use. The other 41 ecosystems studied had mean concentrations below the current EU water quality guideline. However, this does not necessarily mean that the guideline is appropriate for these ecosystems, as previous research has demonstrated that detrimental impacts can be experienced by some freshwater organisms, of all trophic levels, when exposed to concentrations below 25 mg L(-1). Therefore, it is suggested here that it is likely that some ecosystems, particularly those with mean concentrations in the 0.00-5.99 mg L(-1) range, require much lower guideline values in order to be effectively protected. We propose a model for predicting environment-specific water quality guidelines for SPM. In order to develop this model, the 638 reference condition sites were first classified into one of five mean background SPM ranges (0.00-5.99, 6.00-11.99, 12.00-17.99, 18.00-23.99 and >24.00 mg L(-1)). Stepwise Multiple Discriminant Analysis (MDA) of these ranges showed that a site's SPM range can be predicted as a function of: mean annual air temperature, mean annual precipitation, mean altitude of upstream catchment, distance from source, slope to source, channel width and depth, the percentage of catchment area comprised of clay, chalk, and hard rock solid geology, and the percentage of the catchment area comprised of blown sand as the surface (drift) material. The MDA technique, with cross-validation (Wilks-Lambda 0.358, p 0.000), can predict the correct or the next closest SPM range of a site in 90% of cases. This technique can also predict SPM range membership in a probabilistic manner, allowing for an estimate of uncertainty to be made in the allocation of a site to an environment-specific SPM range.

Host and parasite genomics, an Australasian perspective.

The last decade has seen rapid advances in the genetic technology that is allowing researchers to examine host-pathogen interactions at a whole organism level. The advent of 'affordable' post-genomic technology has opened up a world of proteomic, transcriptomic and metabolomic methodologies that have been utilized by research groups in the Australasian region to examine the hosts' response to parasitic infections. Significant contributions have been made to many areas of parasitic infections with particular strengths being in malaria vaccine development, genetic susceptibility to leishmaniasis, genomic and proteomic analysis of schistosomiasis and genetic determination of resistance to helminthes in domestic animals. This review highlights some of these studies that have made significant contributions to our knowledge of the pathogenesis of parasitic diseases with a particular emphasis placed on studies reported in the last couple of years.