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Funder: Cancer Research UK, Funder: Wellcome Trust, DNA methylation is aberrant in cancer, but the dynamics, regulatory role and clinical implications of such epigenetic changes are still poorly understood. Here, reduced representation bisulfite sequencing (RRBS) profiles of 1538 breast tumors and 244 normal breast tissues from the METABRIC cohort are reported, facilitating detailed analysis of DNA methylation within a rich context of genomic, transcriptional, and clinical data. Tumor methylation from immune and stromal signatures are deconvoluted leading to the discovery of a tumor replication-linked clock with genome-wide methylation loss in non-CpG island sites. Unexpectedly, methylation in most tumor CpG islands follows two replication-independent processes of gain (MG) or loss (ML) that we term epigenomic instability. Epigenomic instability is correlated with tumor grade and stage, TP53 mutations and poorer prognosis. After controlling for these global trans-acting trends, as well as for X-linked dosage compensation effects, cis-specific methylation and expression correlations are uncovered at hundreds of promoters and over a thousand distal elements. Some of these targeted known tumor suppressors and oncogenes. In conclusion, this study demonstrates that global epigenetic instability can erode cancer methylomes and expose them to localized methylation aberrations in-cis resulting in transcriptional changes seen in tumors.

Purpose To describe multiple ocular (and non-ocular) manifestations of disease that can present in a person who injects drugs (PWID). We report a case of a patient consecutively presenting across multiple visits to an ambulatory eye care clinic as the initial point of contact for endogenous endophthalmitis, fungal keratitis, bacteremia, and psoas abscess with vertebral osteomyelitis within a matter of weeks. Observations A 51-year-old male with past medical history of alcohol use disorder and injection drug use was initially seen in an eye clinic three days after suffering vision loss in the left eye associated with floaters, photophobia, and eye pain. After initial workup and treatment for panuveitis, endogenous endophthalmitis was suspected. A pars plana vitrectomy was performed, and intravitreal medications were given. A pathogen was never isolated from vitreous samples. Two weeks later, the patient presented with complaints of pain, blurry vision, and foreign body sensation in his opposite (right) eye. Examination revealed a corneal ulcer later identified as a Paecliomyces fungal infection. Two weeks after this, he developed fever, chills, and right-sided flank pain radiating to his testicles. Following evaluation by the emergency department and subsequent hospitalization after bacteremia was noted, he was found to have a right-sided psoas abscess with lumbar vertebral osteomyelitis. Fluid was drained, cultured, and grew methicillin-sensitive Staphylococcus aureus (MSSA). At his last visit, his best-corrected visual acuity was 20/20 OS and 20/30 OD despite central corneal scarring. It was only after hospitalization that he affirmed recent injection drug use, despite being queried about it through the course of his infections. Conclusions and importance Injection drug use is an increasingly common concern for all healthcare providers as the opioid crisis in the United States remains widespread. This case highlights multiple potential infectious processes which may impact persons who inject drugs when seen by eye care providers. It also describes difficulties in caring for people who inject drugs who may not provide critical and timely information relating to their injection drug use and/or may delay care even when faced with potentially vision- and/or life-threatening conditions.

Background: Recent studies have demonstrated that women with early stage ER-positive (ER+) and HER2-negative (HER2-) breast cancer have a persistent risk of recurrence and cancer related death up to 20 years post diagnosis, highlighting the chronic nature of ER+ breast cancer and critical need to identify tumor characteristics that are more predictive of risk of recurrence than standard clinical covariates. However, progress in delineating the dynamics of breast cancer relapse and biomarkers of late recurrence has been hindered by the lack of large cohorts with long-term clinical follow-up and molecular information. Methods: We report the results of a cohort of 3,240 breast cancer patients from the United Kingdom and Canada with 20 years of follow-up (median 9.75 years), including 1,980 with accompanying molecular data from the primary breast tumor. Information for each patient on loco-regional recurrence (LR), distant recurrence (DR), and site(s) of metastases was collected. We developed a non-homogenous Markov chain model that accounted for different clinical endpoints and timescales, as well as competing risks of mortality and the distinct baseline hazards that characterize different molecular subgroups. This approach enabled robust analysis of the spatio-temporal dynamics of breast cancer recurrence across the clinical subgroups, PAM50 subgroups and the integrative clusters, while also enabling individual risk of relapse predictions. Results: We employed our multistate model to compute the probability of experiencing a LR or DR, as well as the baseline transition probabilities from surgery, LR or DR at various time intervals for average individuals in each of the clinical/molecular subgroups. These analyses reveal four late-recurring ER+ (predominantly HER2-) subgroups, together accounting for 26% of all ER+ tumors, with high (median 42-55%) risk of recurrence up to 20 years post-diagnosis. Each of these four subgroups maps to one of the Integrative Clusters, defined based on genomic copy number alterations and gene expression, and is enriched for a characteristic copy number amplification events: 11q13 (CCND1, RSF1), 8p12 (FGFR1, ZNF703), 17q23 (RPS6KB1) and 8q24 (MYC). These four molecular subgroups are superior in predicting late DR than standard clinical variables. Conclusions: A detailed understanding of the rates and routes of metastasis and their variability across the distinct molecular subtypes is essential for devising personalized approaches to breast cancer care. We describe a molecularly characterized breast cancer cohort with long-term clinical follow-up and a statistical modeling framework, enabling delineation of the dynamics of breast cancer recurrence at unprecedented resolution. These analyses reveal four late recurring ER+ subgroups and accompanying biomarkers that collectively define the quarter of ER+ cases at highest risk of recurrence. Our findings highlight opportunities for improved patient stratification and biomarker-driven clinical trials directed at the subset of breast cancer patients with persistent risk of recurrence. Citation Format: Curtis C, Rueda OM, Sammut S-J, Chin S-F, Caswell-Jin JL, Seoane JA, Callari M, Batra R, Pereira B, Bruna A, Ali HR, Provenzano E, Liu B, Parisien M, Gillett C, McKinney S, Green A, Murphy L, Purushotham A, Ellis I, Pharoah P, Rueda C, Aparicio S, Caldas C. Dynamics of breast cancer relapse reveal molecularly defined late recurring ER-positive subgroups: Results from the METABRIC study [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr GS3-06.

The United States has experienced a dramatic rise in opioid and injection drug use over the past 2 decades. A public health emergency was declared in 2017 and subsequently, there have been several new reports on the rise of endogenous endophthalmitis specifically associated with injection drug use. The purpose of this review is to provide a current perspective of the ocular harms posed by injection drug use.The opioid epidemic has prompted several new studies from New England, one of the US regions most heavily affected, that examine the trends and characteristics of injection drug use-associated endogenous endophthalmitis. Patients may delay seeking care and may be infected with a variety of rare and atypical microbes, and as a result clinical appearance may vary widely. Injection drug use also leads to embolic phenomena such as talc retinopathy and septic emboli from endocarditis. HIV is highly associated with injection drug use and although HAART has drastically reduced the morbidity and mortality of HIV-associated infections, a variety of ocular disease may accompany an immunocompromised patient.Healthcare providers must remain vigilant in the recognition of injection drug use patients with vision loss and ocular inflammation to ensure prompt medical and/or surgical treatment.

The rates and routes of lethal systemic spread in breast cancer are poorly understood owing to a lack of molecularly characterized patient cohorts with long-term, detailed follow-up data. Long-term follow-up is especially important for those with oestrogen-receptor (ER)-positive breast cancers, which can recur up to two decades after initial diagnosis1–6. It is therefore essential to identify patients who have a high risk of late relapse7–9. Here we present a statistical framework that models distinct disease stages (locoregional recurrence, distant recurrence, breast-cancer-related death and death from other causes) and competing risks of mortality from breast cancer, while yielding individual risk-of-recurrence predictions. We apply this model to 3,240 patients with breast cancer, including 1,980 for whom molecular data are available, and delineate spatiotemporal patterns of relapse across different categories of molecular information (namely immunohistochemical subtypes; PAM50 subtypes, which are based on gene-expression patterns10,11; and integrative or IntClust subtypes, which are based on patterns of genomic copy-number alterations and gene expression12,13). We identify four late-recurring integrative subtypes, comprising about one quarter (26%) of tumours that are both positive for ER and negative for human epidermal growth factor receptor 2, each with characteristic tumour-driving alterations in genomic copy number and a high risk of recurrence (mean 47–62%) up to 20 years after diagnosis. We also define a subgroup of triple-negative breast cancers in which cancer rarely recurs after five years, and a separate subgroup in which patients remain at risk. Use of the integrative subtypes improves the prediction of late, distant relapse beyond what is possible with clinical covariates (nodal status, tumour size, tumour grade and immunohistochemical subtype). These findings highlight opportunities for improved patient stratification and biomarker-driven clinical trials. A statistical framework for breast-cancer recurrence uses long-term follow-up data and a knowledge of molecular subcategories to model distinct disease stages and to predict the risk of relapse.

Emergence of saprophytic fungi thriving in dead plant material and soil as opportunistic human pathogens is of great concern. Cladosporium species are environmental saprophytes reported to cause various superficial and invasive fungal infections worldwide. C. sphaerospermum, a predominantly indoor fungus has been reported from cases of meningitis, subcutaneous and pulmonary fungal infections in the past. Herein we report the first case of cerebral abscess due to C. sphaerospermum in an immunocompetent host who was successfully managed by combined medical and surgical therapy.

This medical record review study compares the clinical characteristics of endogenous endophthalmitis in patients with and without injection drug use.

Fluorescein angiography (FA) is an indispensable imaging modality in the diagnosis and management of patients with intermediate, posterior, and panuveitis. The pattern and type of retinovascular and chorioretinal involvement may be useful diagnostically and in the assessment of structural abnormalities associated with visual loss. Moreover, FA may provide a sensitive index with respect to extent of active inflammation and influence the threshold for treatment as well as monitoring the response to therapy. Finally, FA in combination with multimodal imaging provides not only expanded diagnostic and management capabilities but also may shed new light on our basic understanding of posterior segment inflammatory diseases.

Summary Objectives To describe whether body mass index (BMI) is a clinically meaningful predictor of patient reported outcomes following primary total hip replacement (THR) surgery. Design Combined data from prospective cohort studies. We obtained information from four cohorts of patients receiving primary THR for osteoarthritis: Exeter Primary Outcomes Study (EPOS) ( n = 1431); EUROHIP ( n = 1327); Elective Orthopaedic Centre ( n = 2832); and St. Helier ( n = 787). The exposure of interest was pre-operative BMI. Confounding variables included: age, sex, SF-36 mental health, comorbidities, fixed flexion, analgesic use, college education, OA in other joints, expectation of less pain, radiographic K&L grade, ASA grade, years of hip pain. The primary outcome was the Oxford Hip Score (OHS). Regression models describe the association of BMI on outcome adjusting for all confounders. Results For a 5-unit increase in BMI, the attained 12-month OHS decreases by 0.78 points 95%CI (0.27–1.28), P -value 0.001. Compared to people of normal BMI (20–25), those in the obese class II (BMI 35–40) would have a 12-month OHS that is 2.34 points lower. Although statistically significant this effect is small and not clinically meaningful in contrast to the substantial change in OHS seen across all BMI groupings. In obese class II patients achieved a 22.2 point change in OHS following surgery. Conclusions Patients achieved substantial change in OHS after THR across all BMI categories, which greatly outweighs the small difference in attained post-operative score. The findings suggest BMI should not present a barrier to access THR in terms of PROMs.

Objective Quantitative sensory testing (QST) and questionnaire-based assessments have been used to demonstrate features of neuropathic pain in subjects with musculoskeletal pain. However, their direct relationship has not been investigated in the community. The purpose of this study was to conduct an observational study to describe the characteristics of joint pain and to examine the relationship between QST measures and the PainDETECT Questionnaire (PD-Q). Methods Warm detection, heat pain, and mechanical pain thresholds as well as mechanical pain sensitivity over the sternum were determined and the PD-Q scores were calculated in a cross-sectional study of 462 participants in the Chingford Study. Comparisons were made between subjects with and those without joint pain. Logistic regression modeling was used to describe the association between neuropathic pain features, as determined by the PD-Q score, and each of the QST measures individually, adjusting for age, body mass index, and use of pain-modifying medications. Results A total of 66.2% of the subjects reported recent joint pain, with a median average pain severity of 5 of 10. There was increased sensitivity to painful stimuli in the group with pain as compared to the pain-free group, and this persisted after stratification by pain-modifying medication use. While only 6.7% of subjects had possible neuropathic pain features and 1.9% likely neuropathic pain features according to the standard PD-Q thresholds, features of neuropathic pain were common and were present in >50% of those reporting pain of at least moderate severity. Heat pain thresholds and mechanical pain sensitivity were significantly associated with features of neuropathic pain identified using the PD-Q, with an odds ratio (OR) of 0.88 (95% confidence interval [95% CI] 0.79–0.97; P = 0.011) and an OR of 1.24 (95% CI 1.04–1.48; P = 0.018), respectively. Conclusion QST measures and the PD-Q identified features of neuropathic pain in subjects in this community-based study, with significant overlap between the findings of the two techniques.

Objective:Genetic factors and abnormalities of joint morphology are important in the aetiology of hip osteoarthritis (OA). The extent to which genetic influences are manifest through joint morphology has undergone limited investigation. Using a cohort with an hereditary predisposition to end-stage hip OA and a control group with no inherited risk, we aimed to identify associations with abnormal joint morphology and clinical features.Design:One hundred and twenty-three individuals (mean age 52 years) with a family history of total hip arthroplasty (THA) (termed ‘sibkids’) were compared with 80 spouse controls. Morphology was assessed using standardised radiographs and cam, dysplasia, and pincer deformities defined. Regression modelling described the association of cohort with abnormal joint morphology, adjusting for confounders [age, gender, body mass index (BMI), OA, and osteophyte].Results:Sibkids had an odds ratio of 2.1 [95%confidence interval (CI) 1.3–3.5] for cam deformity. There were no differences in the prevalence of dysplasia or pincer deformities. In both groups, hips with cam deformities or dysplasia were more likely to have clinical features than normal hips [odds ratio (OR) 4.46 (1.8–11.3), and 4.40 (1.4–14.3) respectively]. Pincer deformity was associated with positive signs in the sibkids but not in the controls (OR 3.0; 1.1–8.2).Discussion:After adjustment for confounders that cause secondary morphological change, individuals with an hereditary predisposition to end-stage hip OA had a higher prevalence of morphological abnormalities associated with hip OA. Sibkids were more likely to demonstrate clinical features in the presence of pincer deformity, suggesting that the genes are acting not only through abnormal morphology but also through other factors that influence the prevalence of pain.

At 8 and 16 weeks post DMM surgery, there was more effector microglia expression in the DH, particularly at the L4 level of the spinal cord (Fig 1). Conclusions: The temporal correlation of fractalkine release with microglial activation suggests that fractalkine may contribute to microglial activation in the DH of the spinal cord. Microglial activation in the DH has been reported in murine mono-iodoacetate (MIA) arthritis as well as nerve injurymodels. Results from this study will help elucidate how pain signals propagate from the peripheral to the central nervous system in osteoarthritis.

Summary Objective Genetic factors are important in the aetiology of hip osteoarthritis (OA), but studies are limited by cross-sectional design and poor association with clinically important disease. Identifying cohorts with progressive OA will facilitate development of OA biomarkers. Using a middle-aged cohort with genetic predisposition to hip OA and a control group, we compared the prevalence of clinical and radiographic hip OA and incidence of progression over 5 years. Design 123 individuals (mean age 52 years) with a family history of total hip arthroplasty (THA) (‘sibkids') were compared with 80 (mean age 54 years) controls. The prevalence of radiographic OA [scored according to Kellgren & Lawrence (K&L)], clinical features, and incidence of clinical progression over a 5-year period were compared. A multivariate logistic regression model was used to adjust for confounders. Results Sibkids had odds ratios (ORs) of 2.7 [95% confidence interval (CI) 1.1–6.3, P = 0.02] for hip OA (K&L grade ≥2), 3.4 (1.4–8.4, P = 0.008) for clinical signs, and 2.1 (0.8–5.8, P = 0.14) for signs and symptoms. Over 5 years, sibkids had ORs of 4.7 (1.7–13.2, P = 0.003) for the development of signs, and 3.2 (1.0–10.3, P = 0.047) for the development of signs and symptoms. Discussion Compared to a control group and after adjustment for confounders, individuals with genetic predisposition to end-stage hip OA have higher prevalence of OA, clinical features, and progression. In addition to structural degeneration, the inherited risk may include predisposition to pain. Genetically-loaded cohorts are useful to develop hip OA biomarkers, as they develop progressive disease at a young age.

Introduction Breast cancer is a clinically and molecularly heterogeneous disease displaying distinct therapeutic responses. Although recent studies have explored the genomic and transcriptomic landscapes, the epigenetic architecture has received less attention. Material and methods An optimised Reduced Representation Bisulfite Sequencing (RRBS) protocol was used to profile the methylomes of 1482 primary breast tumours (and 237 matched adjacent normal tissues) from the METABRIC cohort. Existing copy number, mRNA/miRNA expression and gene panel mutation data from the same tumours, previously publishedCurtis et al, Nature 2012 was available. Results and discussions Noticeable epigenetic drift (both gain and loss of homogeneous DNA methylation patterns) was observed in breast tumours when compared to normal tissues, with markedly higher differences in late replicating genomic regions. The extent of epigenetic drift was also found to be highly heterogeneous between the breast tumours and was sharply correlated with the tumour’s mitotic index, indicating that epigenetic drift is largely a consequence of accumulation of passive cell division related errors. A novel algorithm called DMARC (Directed Methylation Altered Regions in Cancer) was developed that utilised the tumour-specific drift rates to discriminate between methylation alterations attained as a consequence of stochastic cell division errors (background) and those reflecting a more deterministic biological process (directed). Directed methylation alterations were significantly enriched for gene expression changes in breast cancer, compared to background alterations. By integrating with copy number and mutational profiles for these tumours, mutually exclusive patterns between DNA methylation and genomic aberrations were detected. This led to the identification of potential tumour suppressors and oncogenes, and revealed the deterministic nature of these epigenetic alterations. Finally, intra-tumoural methylation content was analysed to identify tumours associated with low epigenetic polymorphism implying a deterministic process vs. those with high polymorphism reflecting a stochastic process. Intra-tumoural heterogeneity as well as the extent of epiallelic burden were found to be prognostic, and revealed a distinction in the role of epiclonal dynamics in different breast cancer subtypes. Conclusion This constitutes the largest breast cancer methylome study, and has revealed the DNA methylation basis of inter-patient as well as intra-tumour heterogeneity in breast cancer.

Cyclic mechanical loads applied to the skeleton from habitual physical activity result in increased bone formation. These loads lead to dynamic pressure gradients and oscillatory flow of bone interstitial fluid, which, in turn, exposes cells resident in the bony matrix to oscillatory fluid shear stress. Dynamic fluid flow has previously been shown to be a potent anabolic stimulus for cultured osteoblasts. In this study, we used cDNA microarrays to examine early phase, broad-spectrum gene expression in MC3T3-E1 osteoblasts in response to physical stimulation. RNA was harvested at 30 min and 1 h post-stimulation. RNA was used for microarray hybridization as well as subsequent reverse transcription polymerase chain reaction (RT-PCR) validation of expression levels for selected genes. Microarray results were analysed by both functional and expression profile clustering. We identified a small number of genes at both the 30 min and 1 h timepoints that were either upregulated or downregulated with flow compared to no-flow control by twofold or more. From the group of genes upregulated at 30 min, we selected nine for RT-PCR confirmation. All were found to be upregulated by at least twofold. We identify a novel set of early response genes potentially involved in mediating the anabolic response of MC3T3 osteoblasts to flow, and provide functional groupings of these genes that may shed light on the relevant mechanosensory pathways involved.

It is well known that cyclic mechanical loading can produce an anabolic response in bone. In vivo studies have shown that the insertion of short-term recovery periods (10–15 s) into mechanical loading profiles led to an increased osteogenic response compared to continuous cyclic loading of bone. Although this is suggestive of temporal processing at the bone cell level, there is little evidence to support such a hypothesis. Therefore, the current study investigated the cellular mechanism of bone's response to rest inserted vs. continuous mechanical loading. Cell responses to rest inserted mechanical loading were quantified by applying oscillatory fluid flow (OFF) to osteoblastic cells and quantifying real-time intracellular calcium [Ca 2+ ] i , prostaglandin E 2 (PGE 2 ) release, and osteopontin (OPN) mRNA levels. Cells were exposed to OFF (1 Hz) at shear stresses of 1 and 2 Pa with rest periods of 5, 10, and 15 s inserted every 10 loading cycles. The insertion of 10 and 15 s rest periods into the flow profile resulted in multiple [Ca 2+ ] i responses by individual cells, increased [Ca 2+ ] i response magnitudes, and increased overall percent of cells responding compared to continuously loaded control groups. We determined the source of the multiple calcium responses to be from intracellular stores. In addition, rest inserted OFF led to similar levels of PGE 2 release and increased levels of relative OPN mRNA compared to cells exposed to continuous OFF. Our study suggests that the cellular mechanism of bone adaptation to rest inserted mechanical loading may involve modulation of intracellular levels of calcium (frequency, magnitude, percent of cells responding).

Mechanical loading is an important regulator of bone formation and bone loss. Decreased osteoblast number and function are important cellular mechanisms by which mechanical disuse leads to decreased bone formation. Decreased osteoblast number may be a result of decreased osteoprogenitor proliferation, differentiation, or both. However, the effects of cellular level physical signals on osteoprogenitors are not well understood. In this study, we examined the effects of loading induced oscillatory fluid flow (OFF), a potent regulator of osteoblastic cell function, on marrow stromal cells (MSCs). MSCs subjected to OFF exhibited increased intracellular Ca2+ mobilization. In addition, MSCs exhibited increased proliferation and increased mRNA levels for osteopontin and osteocalcin genes. Collagen I and core binding factor 1 mRNA levels did not change. MSCs subjected to OFF also exhibited decreased alkaline phosphatase activity. These results suggest that MSCs are mechanosensitive and that Ca2+ may play a role in the signaling pathway.

The present study was designed to elucidate the mechanisms accounting for disruption of the normal function of the testis exposed to various levels of Pb. Three different doses of Pb (10, 50, 200mg Pb/kg body weight per d) were given orally to male Portan rats (groups 2, 3, 4). Zn (1mg Zn/kg body weight per d) was also given with Pb (50mg Pb/kg body weight per d) in group 5. Treatments continued for 3 months. Plasma luteinizing hormone and follicle-stimulating hormone concentrations were found to be decreased in Pb-exposed rats. This was in turn reflected in the appreciable decline in fertility status. In cell kinetic studies, significant declines in various cell populations (preleptotene, pachytene, young (step 7) spermatids and mature (step 19) spermatids) were seen. However, in group 5 after Zn supplementation, hormone levels, cell numbers and fertility status were found to be close to normal. It is concluded that Pb might act at maturation level to cause conspicuous degenerative changes in the testis; Zn supplementation protected against these effects.

Breast cancer is the most common cancer among women showing high clinical and molecular heterogeneity. Current clinical management causes patients overtreatment with implications on both patients’ quality of life and healthcare costs. Moreover, intrinsic or acquired tumor resistance to treatment leads to incurable metastatic progression in a significant proportion of patients. Consequently, there is an urgent need for better predictive biomarkers and a better understanding of the mechanisms driving response to treatment. As part of the METABRIC initiative, we fully molecularly characterized 2000 breast primary tumors, measuring gene expression, copy number aberration, somatic mutations and methylation. In addition, a biobank of breast cancer patient-derived tumor xenograft (PDTX) models (n=92) has been generated in our lab and a comprehensive molecular characterization was also obtained. We recently demonstrated that breast cancer PDTXs maintain originating cancers intra-tumor heterogeneity, hence representing a more relevant preclinical model than cell lines. An ex-vivo drug screening was performed in these models generating response data (IC50 and AUC) for 100 different drugs, including "best in class" PI3K, PARP and CDK4/6 inhibitors, novel biological and chemical inhibitors of HER2, ER, IGF1R and HER3, as well as standard of care agents. Here we derived signatures of pathway activation/disruption by integrating different data types in the METABRIC cohort. Their association with previous breast cancer classifications, as well as their prognostic significance was studied. The predictive power of these signatures was investigated in the PDTX cohort to identify novel pharmacogenomics associations. They were tested independently as well as in combination, to derive molecular predictors of response to treatment. We found known and novel associations between genomic/transcriptomic features and drug response. For example, our results confirmed the known association between estrogen receptor-related genes and response to tamoxifen treatment. We also identified markers of response to inhibitors of the PI3K/AKT/mTOR pathway. Selected findings were validated in clinical cohorts as well as in independent PDTX models. In conclusion, by integrating molecular data from large cohorts of clinical samples and PDTX we have generated a computational framework for the systematic identification of pharmacogenomics associations in breast cancer and to generate hypothesis for rational drug-drug combinations. Citation Format: Maurizio Callari, Rajbir N. Batra, Ankita Sati Batra, Wendy Greenwood, Suet-Feung Chin, Alejandra Bruna, Oscar M. Rueda, Carlos Caldas. Integrative analysis of molecular and drug response data from clinical samples and PDTXs to identify pharmacogenomic associations in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2991. doi:10.1158/1538-7445.AM2017-2991

s / Osteoarthritis and Cartilage 22 (2014) S57–S489 S209 Purpose: Non-steroidal anti-inflammatory agents (NSAIDs) are commonly used to manage symptoms in patients with knee osteoarthritis (OA). While randomized controlled trials have demonstrated efficacy, real world effectiveness of these agents in long term studies is lacking. This study sought to estimate the effectiveness of NSAIDs on symptom management over 4 years among persons with radiographically confirmed OA. Marginal structural models, which take into consideration the likely dual role of indices of disease severity as confounders and intermediary variables, were compared to standard repeated-measure analyses. Methods: We identified NSAID naive participants with radiographic knee OA in the Osteoarthritis Initiative. Participants were evaluated over 4 years. NSAID users included those reporting any use of prescription medication use (i.e., either regular use or as-needed use) at each assessment. Outcome measures included WOMAC Pain, Stiffness and Physical Function. Beta coefficients derived from marginal structural models and generalized estimating equation models represented the average change in outcomemeasures attributed to long term NSAID use. Minimally important clinical differences were a priori set as at least 1.2 for pain, 0.5 for stiffness, and 4.1 for function. Results: Persons with radiographically confirmed OA with long term reports of prescription NSAIDS use experienced improvements in WOMAC Pain: -0.99 (95% Confidence Interval (CI): -2.38 to 0.4); WOMAC Stiffness: -0.64 (95% CI: -1.52 to 0.24); and WOMAC Function: -5.29 (95% CI: -9.7 to -0.89). In contrast, the analysis with generalized estimating equations yields an estimate of -0.03, -0.08 and 0.07 for difference in Pain, Stiffness and Function, respectively. Conclusions: When evaluated using marginal structural models, long term use of NSAIDs showed a modest trend towards relieving symptoms and a clinically significant improvement in function in patients with radiographically confirmed OA, whereas a standard regression models didn’t show such benefits. Studies on the treatment of OA using non-experimental data should consider using marginal structural models when evaluating the overall treatment effect from a timevarying treatment. 366 PATIENT REPORTED OUTCOMES FOLLOWING PRIMARY HIP REPLACEMENT SURGERY: DEVELOPMENT AND INTERNAL VALIDATION OF A PROGNOSTIC TOOL A. Judge yz, R.N. Batra y, D. Murray y, P.A. Dieppe x, M.T. Sanchez-Santos y, G. Thomas y, D. Beard y, M.K. Javaid yz, K. Dreinh€ ofer k{, K. Peter-G€ unther#, C. Cooper yz, N.K. Arden yz. yNIHR Musculoskeletal BioMed. Res. Unit, Univ. of Oxford, Oxford, United Kingdom; zMRC Lifecourse Epidemiology Unit, Univ. of Southampton, Southampton, United Kingdom; x Peninsula Coll. of Med. and Dentistry, Univ. of Plymouth, Plymouth, United Kingdom; k Inst. for Muskuloskeletal Rehabilitation, Charit e Univ.smedizin Berlin, Berlin, Germany; {Dept. of Orthopaedics, Traumatology and Sports Med., Med. Park Berlin Humboldtm€ uhle, Berlin, Germany; Dept. of Orthopaedic Surgery, Univ. Hosp. Carl Gustav Carus, Med. Faculty of the Technical Univ. of Dresden, Dresden, Germany Purpose: Although Total Hip Replacement (THR) is a successful surgical intervention, there are a minority of patients who do not achieve clinically meaningful improvement or whose symptoms get worse following surgery. The aim of this study was to develop a clinical risk prediction tool to predict patient reported outcomes following primary hip replacement surgery. Methods: We obtained data on two prospective cohorts of patients receiving primary THR for osteoarthritis: Exeter Primary Outcomes Study (n 1⁄4 1247); EUROHIP (n 1⁄4 845). The primary outcome was the Oxford Hip Score (OHS). Combining data from two large prospective cohort studies allowed us to take account of a wide and comprehensive range of both traditional and novel risk factors, including patient, radiographic and surgical predictors. Linear regression modelling was used to identify predictors of outcome. For internal validationwe used a combination of multiple imputation and bootstrapping with backward selection. Performance of the predictive model was assessed in terms of calibration and discrimination. Results: Of the radiographic variables pattern of OA was an important determinant of outcome. Those with superomedial, medial or concentric disease had worse outcomes than patients with a superolateral pattern of OA or no reduction in joint space. Arthritis in other joints, and previous surgery on other joints, were associated with worse outcomes. For surgical variables, a posterior surgical approach, and larger femoral component offset had better outcomes. For patient factors, worse preoperative pain/function, increasing age when over age 75, increasing BMI, lower levels of educational attainment and those with worse preoperative SF36 mental health scores, also had worse outcomes. These factors were operationalized into a clinical risk prediction tool. Calibration of the predicted 12-month post-operative OHS, and absolute change in OHS was good. The model showed good discriminatory ability with a bias corrected R-squared of 23.1%. We tested the ability of the model to identify patients with the worst possible outcomes following THR (defined as a change in OHS < 5-points of whom 89 (4.25%) patients met this criterion). Performance of the tool to identify patients with the worst outcomes was good (C-statistic 0.77 95%CI (0.72 to 0.82)). Conclusions: We have developed a clinical risk prediction tool that would provide information on the likely outcomes of hip replacement surgery. Following hip replacement the majority of patients do very well, and only a minority will not achieve clinically meaningful symptomatic change in OHS. The clinical tool performed well in terms of its calibration and discriminatory ability, and identification of those patients with the worst possible outcomes was good. The tool provides individualised risk prediction and allows patients to understand their expected outcomes of surgery – it has the potential to guide patientclinician decision-making. It will now undergo external validation in a new prospective cohort of patients. 367 COURSE OF PHYSICAL FUNCTIONING AND PAIN IN OSTEOARTHRITIS OF THE KNEE OR HIP: A SYSTEMATIC REVIEW M. de Rooij y, M. van der Leeden yz, A. H€ akkinen#x, W.F. Lems ky, L.D. Roorda y, C. Veenhof{, H.C. de Vet #, J. Dekker yy. yAmsterdam Rehabilitation Res. Ctr. j Reade, Amsterdam, Netherlands; zVU Univ. Med. Ctr., Dept. of Rehabilitation Med., Amsterdam, Netherlands; xDept. of Hlth. Sci., Univ. of Jyv€ askyl€ a and Jyv€ askyl€ a Central Hosp., Jyv€ askyl€ a, Finland; kVU Univ. Med. Ctr., Dept. of Rheumatology, Amsterdam, Netherlands; {Netherlands Inst. for Hlth. Services Res., Utrecht, Netherlands; VU Univ. Med. Ctr. EMGO Inst. for Hlth. and Care Res., Dept. of Epidemiology and Biostatistics, Amsterdam, Netherlands; yyVU Univ. Med. Ctr., Dept. of Psychiatry, Dept. of Rehabilitation Med., EMGO Inst., Amsterdam, Netherlands Purpose: (1) The aim of the study was to systematically summarize the literature from March 2005 to January 2013 on the course of physical functioning and pain in patients with OA of the knee or hip and (2) to provide an overview of prognostic factors of physical functioning and future pain for these patients. Methods: A search was conducted in PubMed, CINAHL, Embase and Psych-INFO in January 2013. Eligible studies were prospective cohort studies (minimum follow up was 6 months) that included participants with knee or hip OA diagnosed with radiographically and/or

OBJECTIVES: To identify patient characteristics and surgical factors associated with patient-reported outcomes over 5 years following primary total hip replacement (THR). DESIGN: Prospective cohort study. SETTING: Seven hospitals across England and Scotland. PARTICIPANTS: 1431 primary hip replacements for osteoarthritis. MAIN OUTCOME MEASURES: The Oxford Hip Score (OHS) was collected preoperatively and each year up to 5 years postoperatively. Repeated measures such as linear regression modelling are used to identify patient and surgical predictors of outcome and describe trends over time. RESULTS: The majority of patients demonstrated substantial improvement in pain/function in the first year after surgery-between 1 and 5 years follow-up, there was neither further improvement nor decline. The strongest determinant of attained postoperative OHS was the preoperative OHS-those with worse preoperative pain/function had worse postoperative pain/function. Other predictors with small but significant effects included: femoral component offset-women with an offset of 44 or more had better outcomes; age-compared to those aged 50-60, younger (age 60) had worse outcome, increasing body mass index (BMI), more coexisting diseases and worse Short Form 36 mental health (MH) was related to worse postoperative pain/function. Assessment of change in OHS between preoperative and postoperative assessments revealed that patients achieved substantial and clinically relevant symptomatic improvement (change), regardless of variation in these patient and surgical factors. CONCLUSIONS: Patients received substantial benefit from surgery, regardless of their preoperative assessments and surgical characteristics (baseline pain/function, age, BMI, comorbidities, MH and femoral component offset). Further research is needed to identify other factors that can improve our ability to identify patients at risk of poor outcomes from THR surgery.

To create a prognostic tool to quantify the 5-year cardiovascular (CV) risk in patients with newly diagnosed Wegener's granulomatosis (WG) and microscopic polyangiitis (MPA) without premorbid CV disease. We reviewed CV outcomes during the long-term followup of patients in the first 4 European Vasculitis Study Group (EUVAS) trials of WG and MPA. CV events were defined as CV death, stroke, myocardial infarction, coronary artery bypass graft, or percutaneous coronary intervention. Logistic regression was performed to create a model to predict the absolute risk of a CV event. The model was tested using the Wegener's Granulomatosis Etanercept Trial (WGET) cohort. Seventy-four (13.8%) of 535 patients with 5 years of followup from the EUVAS trials had at least 1 CV event: 33 (11.7%) of 281 WG versus 41 (16.1%) of 254 MPA. The independent determinants of CV outcomes were older age (odds ratio [OR] 1.45, 95% confidence interval [95% CI] 1.11-1.90), diastolic hypertension (OR 1.97, 95% CI 0.98-3.95), and positive proteinase 3 (PR3) antineutrophil cytoplasmic antibody (ANCA) status (OR 0.39, 95% CI 0.20-0.74). The model was validated using the WGET cohort (area under the receiver operating characteristic curve of 0.80). Within 5 years of diagnosis of WG or MPA, 14% of patients will have a CV event. We have constructed and validated a tool to quantify the risk of a CV event based on age, diastolic hypertension, and PR3 ANCA status in patients without prior CV disease. In patients with vasculitis, PR3 ANCA is associated with a reduced CV risk compared to myeloperoxidase ANCA or negative ANCA status. Copyright © 2011 by the American College of Rheumatology.

OBJECTIVE: Assessment of disease activity in vasculitis can be achieved using the BVAS, a clinical checklist of relevant symptoms, signs and features of active disease. The aim of this study was to revalidate the BVAS version 3 (BVAS v. 3) in a cohort of patients with systemic vasculitis. METHODS: A total of 238 patients with vasculitis from seven countries in Europe were evaluated at a single time point. Spearman's correlation coefficients were calculated between BVAS v. 3 scores, vasculitis activity index (VAI), physician's global assessment (PGA), the physician's treatment decision, CRP and the vasculitis damage index (VDI) to demonstrate that the BVAS v. 3 measures disease activity. RESULTS: WG (63%), Churg-Strauss syndrome (9%) and microscopic polyangiitis (9%) were the most common diagnoses. The BVAS v. 3 showed convergent validity with the VAI [ρ = 0.82 (95% CI 0.77, 0.85)], PGA [ρ = 0.85 (95% CI 0.81, 0.88)] and the physician's treatment decision [ρ = 0.54 (95% CI 0.44, 0.62)]. There was little or no correlation between BVAS v. 3 and the CRP level [ρ = 0.18 (95% CI 0.05, 0.30)] or with the VDI [ρ = -0.10 (95% CI 0.22, 0.03)]. The inter-observer reliability was very high with an intra-class correlation coefficient (ICC) of 0.996 (95% CI 0.990, 0.998) for the total BVAS v. 3 score. CONCLUSION: The BVAS v. 3 has been evaluated in a large cohort of patients with vasculitis and the important properties of the tool revalidated. This study increases the utility of the BVAS v. 3 in different populations of patients with systemic vasculitis.

ObjectiveTo determine whether neuromyelitis optica (NMO) immunoglobulin (IgG) antibody status in NMO/Devic’s disease patients followed prospectively is persistent or can change relative to the clinical status and/or response to therapy.DesignA cross-sectional group of patients with NMO, relapsing extensive longitudinal transverse myelitis (RLETM) or optico-spinal multiple sclerosis (OSMS) were evaluated for the presence of NMO IgG antibodies. Repeated evaluation was made in all NMO/RLETM patients and in a subgroup of OSMS patients.SettingBaird Multiple Sclerosis Center, Buffalo, New York, an academic multiple sclerosis center.ResultsOut of a consecutive cohort of 38 patients evaluated for the presence of NMO IgG, 12 had NMO and 26 had OSMS. Five of the 12 NMO/RLETM patients were NMO IgG positive at the time of their initial evaluation. Four of these patients were repeatedly tested for NMO IgG: two of these became negative and two remained positive. One patient who was initially negative became positive during an acute event and again became negative during the stable disease phase following treatment. A positive test result was associated with active disease, whereas a negative NMO IgG result was consistently found in stable, long-term treated patients. None of the OSMS patients were positive for NMO IgG even during acute attacks.ConclusionsNMO IgG antibodies are associated with active NMO/RLETM. A well-controlled stable disease usually under effective immunosuppressive therapy can transform the NMO IgG to a negative status. Repeated NMO IgG testing should be considered as a useful biological marker for monitoring NMO/RLETM disease and or response to therapy.

PURPOSE: To study the modulatory effects of Salmonella lipid associated protein - lipopolysaccharides (LAP-LPS) on murine macrophages as the intracellular survival within the host macrophages is an important feature for a number of gram-negative pathogens like S.typhi. METHODS: Macrophage functions were studied in two groups of mice immunized with either LPS or LAP-LPS. RESULTS: Comparison of protective efficacy of mice preimmunized with LPS based preparations, against challenge infectious doses, showed higher protection in LAP-LPS complex immunized mice group as compared to the mice group immunized with LPS alone. Aggregation of S.typhi cells was lesser with intestinal mucus extracted from LAP-LPS immunized mice as compared to LPS immunized challenged group. A significant increase in the number of macrophages in LAP-LPS immunized mice was also observed in comparison to control and LPS immunized mice groups. Nitric oxide (NO) and superoxide dismutase (SOD) production were also more in macrophages derived from LAP-LPS immunized mice group. Phagocytic uptake studies showed that there was enhanced uptake of bacteria in the LAP-LPS immunized animals in comparison to LPS immunized and controls. Similar trend was observed in intracellular killing of bacteria by the macrophages. CONCLUSIONS: The results indicated the involvement of protein moiety in LAP on modulation of effects of LPS on macrophages.

s / Osteoarthritis and Cartilage 20 (2012) S54–S296 S152 study ,using the cell culturing technology, was to observe what different results would come out from the MTTassay of the ATDC5 cell proliferation, whick had been cultured with different concentration E2. Methods: The 17-bestradiol we use was ordered from Sigma co. and the ATDC5 cell line was form the Riken cell bank. We culture the ATDC5 24 hours in the media with different concentration 17-bestradiol, then we test the OD value of the different cells in MTT assay to assume the proliferation of the ATDC5. Results: After culturing 24 hours in the media with different concentration 17-bestradiol, the proliferation of the ATDC5 in different concentration 17-bestradiol were different significantly, the higher of the concentration, the higher of the proliferation, as follows: beside the 10-11M against 0 M, the 10-10,10-9,10-8 and 10-7 M have significant difference in stimulating the proliferation of ATDC5 against 0 M. between the different concentration groups, only 10-8 M has significant difference against 10-11,10-10 M. Conclusions: First, 17-bestradiol has stimulation on the proliferation of ATDC5. Second, 10-8 M concentration of 17-bestradiol has the strongest stimulating effect than the other concentration of 17-bestradiol. Clinical Aspects / Outcomes 302 PRE-OPERATIVE BMI AS A PREDICTOR OF PATIENT REPORTED OUTCOMES OF PRIMARY HIP REPLACEMENT SURGERY: A COMBINED ANALYSIS OF 4 PROSPECTIVE COHORT STUDIES R.N. Batra , A. Judge , M.K. Javaid , G.E. Thomas , D. Beard , D. Murray , P. Dieppe , K. Drienhoefer , K. Peter-Geunther , R. Field , C. Cooper , N.K. Arden . NIHR BioMed. Res. Unit, Univ. of Oxford, Oxford, United Kingdom; MRC Lifecourse Epidemiology Unit, Univ. of Southampton, Southampton, United Kingdom; 3 Peninsula Coll. of Med. and Dentistry, Plymouth, United Kingdom; Charite Univ.smedizin Berlin, Dept. of Orthop., Traumatology and Sports Med., Berlin, Germany; Univ. Hosp. Carl Gustav Carus, Technical Univ. of Dresden, Dresden, Germany; 6 Elective Orthop. Ctr., Epsom, United Kingdom Purpose: Total hip replacement (THR) is a successful surgical intervention, providing relief from pain, increasingmobility and improving quality of life for majority of patients. Within the literature some, but not all studies, have found that obesity is associated with worse patient reported outcomes (PROMs) of THR, and there is increasing concern that obesity may be used as a barrier to accessing surgery. Methods: We obtained information from 4 prospective cohort studies of patients receiving primary THR for osteoarthritis (OA): Exeter Primary Outcomes Study (EPOS) (n1⁄41589); EUROHIP (n1⁄4908); South West London Elective Orthopaedic Centre (SWLEOC) (n1⁄41523); and St. Helier (n1⁄4799). The primary outcome was the 12 month Oxford Hip Score (OHS) which is used to assess pain and function.For the EUROHIP study, we imputed the OHS from WOMAC scores using truncated regression. Confounding variables included: age, sex, SF-36 mental health, comorbidities, fixed flexion, analgesic use, college education, OA in other joints, expectation of less pain, radiographic KL only age and sex were available in all 4 cohorts. Linear regression (ANCOVA) is used to describe the association of BMI on the 12 month OHS, adjusting for the pre-operative OHS. Multiple imputation methods were used to handle missing data. In order to combine data across the 4 studies we used two methodological approaches: a) Meta-Analysis For each study, separate models are built to describe the association of BMI on outcome. Models are adjusted only for age and sex in order to construct related hypotheses in each study. Fixed effects metaanalysis is used to combine the results; b) Combining studies Data from all 4 studies are combined using multiple imputation methods to impute data on missing confounders, allowing the association of BMI on outcome to be adjusted for all potential confounders. Results: a) Meta-Analysis Adjusting for age and sex, for a 5 unit increase in BMI, the 12 month OHS decreases by 0.81 95%CI (0.55 1.08) units (Figure 1); Ă b) Combining Studies Adjusting for age and sex alone, for a 5 unit increase in BMI, the 12 month OHS decreases by 0.72 (0.46 0.99) units. Adjusting for all potential confounders, the effect is attenuated to 0.51 (0.09 0.92). Hence, for each 5 unit increase in BMI, the difference in post-op OHS becomes larger and more important. For example, compared to people with a normal BMI (20 25), those in the morbidly obese group (BMI 35 40) would have a post-op OHS that is 1.53 units lower. However, there is a substantial improvement in OHS after THR across all BMI groups, which greatly outweighs any difference in post-op score (Figure 2).

Purpose: Establishing a population-based estimate for the lifetime risk of total hip and knee replacement (THR/TKR) is an important epidemiological development which will assist health service planners in assessing the future burden of lower limb arthroplasty. Methods:We used data from the U.K. General Practice Research Database (GPRD) which contains all the computerised records of 6.25m patients, and is representative of the population of the U.K. We collected data on all THRs and TKRs performed between 1991 and 2006, a total of over 27,000 THRs and 24,000 TKRs. We calculated incidence rates for THR/TKR under a Poisson model and combined these rates with mortality rates from the U.K Office for National Statistics (ONS) using a life-table framework. These estimates were then aggregated to produce a simple lifetime risk of THR and TKR by gender for age 50 and above. We also calculated the temporal trend in lifetime risk at age 50 by single calendar year from 1991 to 2006. Results: We estimated that at age 50 the mortality-adjusted lifetime risk of THR was 7.80% for females and 5.05% for males (TKR: 6.66% and 5.04% respectively). The risks of THR for females aged 50 was 54% greater for than for males (32% greater for TKR). The risk percentage decreases with increasing age for both THR and TKR in males and females. At age 80 the gender gap in risk of THR remains in favour of females (53% higher) but in TKR it is two-thirds of that at age 50 (females 21% higher). Between 1991 and 2006, the lifetime risk of THR rose from 3.89% to 10.41% for females and for males from 3.43% to 6.34%. Over the same period, for TKR the risk for females increased from 2.78% to 10.02% and for males from 1.57% to 7.39%.

Sequential lead accumulation and biochemical and histopathological changes were observed in rat testis and epididymis after oral administration at varied doses of lead (10, 50 and 200 mg kg(-1) body wt.) for 3 months and also following the concomitant administration of lead with zinc (1 mg kg(-1) body wt. +50 mg Pb kg(-1) body wt.). Accumulation of lead in both testis and epididymis increased with dose. The concomitant administration of zinc reduced the lead levels. Similarly, dose-related changes were seen in the activities of the enzymes alkaline phosphatase and Na(+)-K(+)-ATPase, which decreased with increased dose of lead. A significant improvement in the activities of these enzymes was seen in the groups given both lead and zinc. Histologically, discernible changes were noticed only at higher doses (50 and 200 mg kg(-1) body wt.), which included disorganization and disruption of spermatogenesis with accumulation of immature cells in lumen of tubule. At higher doses of lead, complete arrest of spermatogenesis was seen and a significant decrease in germ cell layer population was evident. Even in epididymis, the histoarchitecture was disrupted only at higher doses of lead both in the caput and corpus regions. The changes included damage of basement membrane, disorganization of epithelium and vacuolization of cells. The tubules were found almost empty, indicating arrest of spermatogenesis. However, with concomitant administration of lead and zinc both testis and epididymis presented a near-normal picture, indicating the protective role of zinc. Hence, the data indicate that the protective effect of zinc on lead toxicity was mediated largely by significant competition between lead and zinc or due to reduction of the available binding sites.

With increasing concerns about environmental pollution, the interaction of micronutrients with toxic metals is of great interest. The present study was designed to investigate testicular effects of lead following concomitant administration of zinc. Lead was administered orally as lead acetate (50 mg/kg b.w.) daily for 3 months to male Portan rats with or without zinc (1 mg/kg b.w. as zinc sulphate). The control group was given the same volume of distilled water. Endpoints included lead concentration in various body organs as well as in the reproductive system, including testicular subfractions; the testicular enzymes superoxide dismutase (SOD) and catalase; the marker enzyme delta-aminolevulinic acid dehydratase (delta-ALAD); and testicular histoarchitecture. The concentrations of lead in bone, kidney, prostate, testis, liver, epididymis, spleen, seminal vesicles, and blood were significantly higher in lead-treated rats. Lead deposition was reduced in animals that received supplemental zinc. There was a 30% reduction in lead deposition in the testis when zinc was coadministered. At the subcellular level, there was differential accumulation of lead; the nucleus preferentially took up the metal after lead treatment alone, while zinc coadministration shifted lead accumulation to the mitochondria. A significant decrease in delta-ALAD and in SOD activity was seen in the testis with lead treatment. Coadministration of zinc prevented these decreases, at least partially. Zinc coadministration did not prevent the inhibition of catalase observed with lead treatment. Histologically, the alterations in the testis with lead treatment alone were more pronounced compared to animals in which zinc was supplemented. Improvement in the inhibition of delta-ALAD and in the ubiquitous cellular enzyme SOD suggests less testicular tissue damage due to detoxification of free radicals. In conclusion, zinc supplementation ameliorates lead-induced testicular damage both at the cellular and subcellular level. The protective effect may be due to differential distribution of lead, either because of competition between lead and zinc or displacement of lead by zinc.

Traditionally there have been two main approaches to the balance of payment disequilibrium by a country--the absorption approach and the monetary approach. This paper develops an alternative framework focusing on a country’s domestic price level. The orthodox analysis fails to explain the persistence of trade deficits in the United States despite large and regular depreciation of the dollar, whereas a similar exchange depreciation in Mexico resulted in a quick turn around in its trade short fall. The paper shows that a trade imbalance can arise only if the general price level is not the same as the one consistent with balanced trade commercial policies--competitiveness and the production structure may be responsible for such price divergence.

Objective: To determine appropriate terminology for addressing women in pregnancy. Design: 100 women (aged 15–50) were asked to fill in a questionnaire using one of the six choices provided for addressing women in pregnancy. Setting: Antenatal clinic of a teaching hospital. Results: Preferences vary according to context but simple terms like mother-to-be and pregnant women were more popular than client, consumer and maternant. Conclusion: No single terminology for addressing women in pregnancy wins all round approval but simple softer terms like Mother-to-be please a vast majority.

Summary Objective Femoroacetabular Impingement (FAI) and Acetabular Dysplasia are common deformities, which have been implicated as a major cause of hip osteoarthritis (OA). We examined whether these subtle deformities of the hip are associated with the development of radiographic OA and total hip replacement (THR) in women. Design A population-based, longitudinal cohort of 1003 women underwent pelvis radiographs at years 2 and 20. Alpha Angle, Triangular Index Height, Lateral Centre Edge (LCE) angle and Extrusion Index were measured. An alpha angle of greater than 65° was defined as Cam-type FAI. Radiographic OA and the presence of a THR were then determined at 20 years. Results Cam-type FAI was significantly associated with the development of radiographic OA. Each degree increase in alpha angle above 65° was associated with an increase in risk of 5% (Odds Ratio (OR) 1.05 [95% confidence interval (CI) 1.01–1.09]) for radiographic OA and 4% (OR 1.04 [95% CI 1.00–1.08]) for THR. For Acetabular Dysplasia, each degree reduction in LCE angle below 28° was associated with an increase in risk of 13.0% (OR 0.87 [95% CI 0.78–0.96]) for radiographic OA and 18% (OR 0.82 [95% CI 0.75–0.89]) for THR. Conclusions This study demonstrates that Cam-type FAI and mild Acetabular Dysplasia are predictive of subsequent OA and THR in a large female population cohort. These are independent of age, BMI and joint space and significantly improve current predictive models of hip OA development.

s / Osteoarthritis and Cartilage 22 (2014) S57–S489 S412 high sensitive C-reactive protein (hsCRP), matrix metalloproteinase (MMP) mediated degradation of CRP (CRPM) and MMP-mediated collagen type I, II, and III degradation (C1M, C2M, and C3M, respectively). Statistical analyses were performed in IBM SPSS Statistics, version 19. One-way ANOVA was used to compare serological biomarkers and PPT measures and Fisher’s Least Significant Difference (LSD) post hoc test was applied. Results: Group B (BLOKS 1⁄4 2,3) had decreased PPTs compared to controls (p< 0.05, figure 1) and increased levels of C1M (p1⁄4 0.001), C2M (p 1⁄4 0.001) and hsCRP (p 1⁄4 0.023), but a lower level of C3M (p 1⁄4 0.033) compared to controls (Figure 2). Group A had increased levels of C1M (p 1⁄4 0.039), C2M (p1⁄4 0.001) and CRPM (p1⁄4 0.028) and lower level of C3M (p 1⁄4 0.019), but no difference was found in PPTs compared to controls. Dividing Group A into BLOKS 1⁄4 0, (n 1⁄4 16) and BLOKS 1⁄4 1 (n 1⁄4 22) revealed that patients with BLOKS 1⁄4 0 had decreased PPTs compared to patients with BLOKS 1⁄4 1 (p < 0.05, Figure 1). Interestingly, the level of PPTs of the BLOKS1⁄4 0 group was at the level of the group with BLOKS 2. There was no significant difference in the biomarker level in the differentiated Group A in any of the investigated markers (Figure 2). Conclusions: Patients with widespread synovitis have decreased PPTs and significantly increased levels of bone and cartilage degradation and inflammation. However, these patients had a decrease in synovial membrane degradation compared to controls. Dividing patients with localized synovitis into two groups based on the synovitis score identified subgroups with significantly different PPTs, but the same level of the biomarkers studied. This study illustrate that patients with different levels of sensitization have different profiles of tissue turnover and each constitute a specific group of severe KOA patients. 741 A CLINICAL TOOL FOR THE PREDICTION OF PATIENT-REPORTED OUTCOMES AFTER KNEE REPLACEMENT SURGERY M.T. Sanchez-Santos y, A. Judge yz, R.N. Batra y, D. Murray y, A. Price y, A.D. Liddle y, M.K. Javaid yz, C. Cooper yz, N.K. Arden yz. yNIHR Musculoskeletal BioMed. Res. Unit, Nuffield Dept. of Orthopaedics, Rheumatology and Musculoskeletal Sci., Univ. of Oxford, Oxford, United Kingdom; zMRC Lifecourse Epidemiology Unit, Univ. of Southampton, Southampton Gen. Hosp., Southampton, United Kingdom Purpose: To develop a clinical risk prediction tool to predict patientreported outcomes after undergoing primary total knee replacement (TKR) surgery. Methods:We used data from 1,649 patients from the Knee Arthroplasty Trial (KAT) who received primary TKR across 34 centres in the United Kingdom between July 1999 and January 2003. The main outcome was Oxford Knee Score (OKS) 12-months after surgery. A wide range of preoperative predictor variables including patient characteristics, clinical and surgical factors, were considered. Bootstrap backward linear regression analysis was used to identify risk factors of outcome. Results: Presence of a fixed flexion deformity, presence of varus/valgus deformity (compared with no deformity), and an absent preoperative ACL (compared with intact ACL) were associated with better OKS at 12 months. The clinical factors associated with worse post-operative OKS were worse ASA grade, presence of other conditions affecting mobility and previous knee surgery. Lower pre-operative OKS, living in poor areas, high BMI and worse SF-12 mental health score were also associated with worse outcome. Discrimination and calibration statistics were good. Patients’ characteristics explained 16.6% of the variability in outcome, when clinical variables were included 18.9% of the variance of outcome was explained, reaching 20.2% when surgical variables were added. Conclusions: The clinical risk tool will help to inform patients and clinicians regarding expectations of the outcome after knee replacement surgery, and may also provide useful information to support shared decision-making. External validation of the tool, to confirm its performance and validity, will be undertaken in a new prospective cohort of patients. 742 ASSOCIATION BETWEEN SYNOVITIS AND DEPRESSION IN PATIENTS WITH KNEE OSTEOARTHRITIS: A CROSS-SECTIONAL STUDY Y. Shimura y, H. Kurosawa y, M. Tsuchiya y, H. Kaneko z, L. Liu z, R. Sadatsuki z, A. Yusup z, S. Hada z, M. Kinoshita z, Y. Makino y, M. Sawa y, Y. Iwase y, K. Kaneko z, M. Ishijima z. y Juntendo Tokyo Koto Geriatric Med. Ctr., Tokyo, Japan; z Juntendo Univ. Graduate Sch. of Med.