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We describe the clinical features and treatment outcome of a patient with combined central retinal vein occlusion and cilioretinal artery occlusion. A 52-year-old female presented to our clinic with decreased vision in the right eye for 4 days. Visual acuity and intraocular pressure were count fingers at 2&1/2M and 14 mm Hg in the right and 20/20 and 16 mm Hg in the left eye, respectively. Funduscopic exam and optical coherence tomography (OCT) of the right eye confirmed the diagnosis of concurrent cilioretinal artery occlusion and central retinal vein occlusion with segmental macular pallor in the territory of the cilioretinal artery, corresponding marked inner retina thickening on OCT and signs of vein occlusion. The patient received an intravitreal injection of bevacizumab and at 1-month follow-up, vision improved to 20/30 with corresponding anatomical improvement. It is very important to recognize combined central retinal vein occlusion and cilioretinal artery occlusion as they could be treated with intravitreal injections of anti-vascular endothelial growth factors with favorable treatment outcomes.

We report the case of a 35-year-old female with combined Chiari 1 malformation and basilar invagination, who presented with intermittent conjunctival chemosis and unilateral chorioretinal folds that were temporally correlated. She denied any flashes, floaters, eye redness, or pain. She also denied nausea or vomiting. Clinical exam and optical coherence tomography imaging revealed conjunctival chemosis and chorioretinal folds in the left eye. Subsequent magnetic resonance imaging of the brain and the orbits were consistent with combined Chiari 1 malformation and basilar invagination. The unilateral and intermittent chorioretinal folds and conjunctival chemosis presentation of combined Chiari 1 malformation and basilar invagination is unusual. To the best of our knowledge, this is the first case to be reported with this unique clinical presentation. It is most important to be aware that unilateral and intermittent chorioretinal folds associated with conjunctival chemosis may be signs of intracranial disease.

Introduction Peyronie’s disease (PD) is a fibroproliferative disorder of the tunica albuginea of the penis. Though the etiologies and potential mechanisms for PD remain understudied, known PD risk factors include family history, Dupuytren disease, diabetes mellitus, smoking, hypertension, and penile trauma. Endoscopic procedures have also been reported as a cause of PD. Although often referenced, current literature contains little evidence describing the potential association of endoscopic procedures with the development of PD. Objective To evaluate the association of endoscopic procedures and patient demographics in men with the development of Peyronie’s disease Methods Institutional review board approval was obtained, and a retrospective review was performed at a tertiary referral center of all patients with history of urologic endoscopy who were subsequently diagnosed with PD from January 2010 to January 2022. Electronic medical records were searched for ICD-9 and ICD-10 codes to identify unique records with a diagnosis of PD. Records were also identified by CPT codes for transurethral and percutaneous urologic endoscopic procedures. Endoscopic procedures were evaluated for the type of instrumentation and divided into 4 broad categories: diagnostic cystoscopy, urethral stricture manipulation, transurethral resection, and endoscopic treatment for urinary lithiasis. Records were evaluated for time to PD diagnosis following their procedure, presence of a post-operative urethral catheter, and demographic data. Results A total of 19,383 unique patients with endoscopy procedures and 629 unique patients with PD diagnosis were identified. 121 patients had a diagnosis of PD and history of endoscopy, of whom 50 patients (7.9%) were confirmed to have had endoscopy prior to PD diagnosis. The median age of PD diagnosis was 62. There was no increased association between PD and endoscopy in men with a diagnosis of diabetes (p = 0.5261), hypertension (p = 0.2256), or a history of smoking (p = 0.9398). The majority of PD diagnoses (54%, 27/50) were associated with cystoscopy performed supine (48.1%, p=0.0011), in a clinic (40.7%, p = 0.0001), and with flexible instrumentation (55.6%, p Conclusions Men with a diagnosis of PD and a history of prior urologic endoscopy are more likely to have undergone a simple, flexible cystoscopy in the clinic setting. There does not appear to be an association between the time to presentation of PD and the endoscopic procedure performed. Disclosure Any of the authors act as a consultant, employee or shareholder of an industry for: Endo Pharmaceuticals

Funding Acknowledgements Type of funding sources: None. Introduction Social determinants of health (SDOH) are increasingly being recognized as critical, independent prognosticators in cardiovascular disease. Despite this, little is known about the role of SDOH in predicting outcomes following transcatheter aortic valve implantation (TAVI). Purpose To assess the value of adding census-derived SDOH in developing machine learning (ML) models for prediction of all-cause mortality in patients following TAVI. Methods A total of 398 patients, who underwent TAVI in 2019, were studied. Clinical, demographic, echocardiographic (echo) and census-derived SDOH data were collected. All-cause mortality at 1 year was the endpoint. A general linear ML model was fit with 100 iterations and a 70:30 training-test split. We compared the predictive performance of the model with and without adding SDOH. The SDOH included in the ML model were race (white vs. non-white), % zip code population as female, and zip code average yearly income less than $45,000. Results Baseline SDOH, demographic, clinical, and echo data are shown in Table 1. Following univariate and multivariate predictor analysis, the following input data were used for the ML model without the SDOH: post TAVI all-cause hospitalizations, history of outpatient hemodialysis, atrial fibrillation, heart failure with reduced ejection fraction, myocardial infarction, coronary artery disease and beta-blockers. The ML model with SDOH used the same input as well as the SDOH variables. The model with vs. without SDOH had a median AUC of 0.75 vs. 0.73 (p = 0.9957). Conclusions Despite not reaching statistical significance, our ML model provides a holistic picture of mortality predictors. Larger studies are needed to more assess the predictive value of SDOH post TAVI. Abstract Figure. Baseline patient characteristics Abstract Figure. ML Model: Area Under Curve

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.

Unlike early transcriptional responses to mitogens, later events are less well-characterized. Here, we identified delayed down-regulated genes (DDGs) in mammary cells after prolonged treatment with epidermal growth factor (EGF). The expression of these DDGs was low in mammary tumors and correlated with prognosis. The proteins encoded by several DDGs directly bind to and inactivate oncoproteins and might therefore act as tumor suppressors. The transcription factor teashirt zinc finger homeobox 2 (TSHZ2) is encoded by a DDG, and we found that overexpression of TSHZ2 inhibited tumor growth and metastasis and accelerated mammary gland development in mice. Although the gene TSHZ2 localizes to a locus (20q13.2) that is frequently amplified in breast cancer, we found that hypermethylation of its promoter correlated with down-regulation of TSHZ2 expression in patients. Yeast two-hybrid screens and protein-fragment complementation assays in mammalian cells indicated that TSHZ2 nucleated a multiprotein complex containing PRC1/Ase1, cyclin B1, and additional proteins that regulate cytokinesis. TSHZ2 increased the inhibitory phosphorylation of PRC1, a key driver of mitosis, mediated by cyclin-dependent kinases. Furthermore, similar to the tumor suppressive transcription factor p53, TSHZ2 inhibited transcription from the PRC1 promoter. By recognizing DDGs as a distinct group in the transcriptional response to EGF, our findings uncover a group of tumor suppressors and reveal a role for TSHZ2 in cell cycle regulation.

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.

Motivation Whole-genome bisulfite sequencing (WGBS) measures DNA methylation at base pair resolution resulting in large bedGraph like coverage files. Current options for processing such files are hindered by discrepancies in file format specification, speed, and memory requirements. Results We developed methrix, an R package, which provides a toolset for systematic analysis of large datasets. Core functionality of the package includes a comprehensive bedGraph or similar tab-separated text file reader—which summarizes methylation calls based on annotated reference indices, infers and collapses strands and handles uncovered reference CpG sites while facilitating a flexible input file format specification. Additional optimized functions for quality control filtering, subsetting and visualization allow user-friendly and effective processing of WGBS results. Easy integration with tools for differentially methylated region (DMR) calling and annotation further eases the analysis of genome-wide methylation data. Overall, methrix enriches established WGBS workflows by bringing together computational efficiency and versatile functionality. Availability and implementation Methrix is implemented as an R package, made available under MIT license at https://github.com/CompEpigen/methrix and can be installed from the Bioconductor repository. Supplementary information Supplementary data are available at Bioinformatics online.

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.

Using a flexible polarizable potential, the stable structures of H − (H 2 ) n (D 2 ) p clusters with fixed total size n + p = 32 have been investigated by means of path-integral molecular dynamics simulations as a function of composition. The most stable phase is found to be reverse core-shell, in which the heavier deuterium molecules reside outside. This result contrasts with neutral clusters, in which deuterium preferentially occupies internal sites. This purely quantum effect is interpreted to originate from the significant weakening of hydrogen covalent bonds in the vicinity of the ionic impurity and its lowering of zero-point energy that affects H 2 more than D 2 .

Supplying high voltage radio frequency (RF) is a critical part of ion trapping system due to impedance mismatching between RF source and the ion trap. A helical resonator has been constructed in order to deliver narrow bandwidth and high voltage RF to the ion trap for stable confinement of ions. The performances of the helical resonator have been studied for different capacitive load of the ion trap. Both the resonant frequency and quality factor of the resonator show strong dependence on external capacitive loads.

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.

Following the Civil War Congress passed the 14th amendment to the constitution. It granted citizenship to African Americans and forbade any state government from taking away life, liberty or property of any person without due process of law. However, the amendment benefited the corporations with little help to black Americans. Each time a state decided to curb the monopoly power of a business, the courts would step in and proclaim that the state flouted the due process clause. This collusion between the government and corporations has contributed to high rates of poverty in America, especially among African American communities.

The resonant frequency of a helical resonator, that efficiently delivers high voltage rf to an electrodynamic ion-trap, depends on capacitive and inductive loads. Estimation of these loads for the parts that are attached to the resonator are thus necessary for designing a resonator operating at a desired frequency. On the other hand, the trapped ion experiences a voltage induced by the capacitance resulting from the electrodes. This results to excess micromotion to the ion. Here, we estimate the capacitive and resistive loads arising from different parts of ourtrap.

We are developing a frequency standard based on the ultra-narrow electric octupole transition of the ytterbium-ion (171Yb+), which is in the optical wavelength region. In this article, we describe optimized design of our end-cap type Paul trap which will be used for trapping single ions for precision frequency metrology. Selection of the materials for fabricating different parts of the trap assembly is also described. Customized design of the ultra-high vacuum chamber, which houses the ion trap, oven producing ytterbium atomic beam, compensation electrodes and high numerical aperture fluorescence collection lens together with four pairs of optical viewports is lastly described.

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.

Traditional literature emphasizes the role of foreign capital, especially foreign direct investment (FDI) in explaining the high growth rates that many emerging economies have enjoyed during 1990s and 2000s. The present paper accepts this conventional wisdom but argues that the FDI has also created problems of urban sprawl and congestion that would not be so intense if economic development had primarily come from domestic sources. This is because the FDI is typically concentrated in urban areas that abound in manufacturing and it neglects the rural areas where agriculture predominates. The paper suggests that a small tax on foreign capital tends to mitigate the side effects of foreign investment.

It is well known that nations with high trade deficits normally have higher interest rates than those with surplus or balanced trade. However, such has not been the case with the USA, which has seen a relentless trade deficit since 1982. Its interest rates have been lower than those prevailing in many trade-surplus nations. Furthermore, these rates fell even as the trade shortfall shot up, generating an interest-rate paradox. This paper demonstrates that, unlike for other nations, the rising trade deficit itself became the cause of lower US interest rates, and this happened because of the world's strong interest in maintaining a high value of the dollar.

We construct a general equilibrium model of trade and show that an economy can experience technological progress and declining real wages provided that it is open to trade and import demand is sufficiently inelastic in both countries. This is a puzzling outcome so far as marginal productivity paradigm is concerned. In this context we demonstrate that new technology works differently in a closed vs an open economy. In an open economy, technical improvements may generate a fall in labor real earnings, but not in a closed economy. In addition, technical progress in manufacturing must increase manufacturing–service wage gap according to marginal productivity doctrine. We show that the opposite outcome can occur theoretically in an open economy—yet another seemingly puzzling labor market outcome.

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.

To develop and validate a clinical prediction model of patient-reported pain and function after undergoing total knee replacement (TKR). We used data of 1,649 patients from the Knee Arthroplasty Trial who received primary TKR across 34 centres in the UK. The external validation included 595 patients from Southampton University Hospital, and Nuffield Orthopaedic Centre (Oxford). The outcome was the Oxford Knee Score (OKS) 12-month after TKR. Pre-operative predictors including patient characteristics and clinical factors were considered. Bootstrap backward linear regression analysis was used. Low pre-operative OKS, living in poor areas, high body mass index, and patient-reported anxiety or depression were associated with worse outcome. The clinical factors associated with worse outcome were worse pre-operative physical status, presence of other conditions affecting mobility and previous knee arthroscopy. Presence of fixed flexion deformity and an absent or damaged pre-operative anterior cruciate ligament (compared with intact) were associated with better outcome. Discrimination and calibration statistics were satisfactory. External validation predicted 21.1% of the variance of outcome. This is the first clinical prediction model for predicting self-reported pain and function 12 months after TKR to be externally validated. It will help to inform to patients regarding expectations of the outcome after knee replacement surgery.

Biallelic inactivation of BRCA1 or BRCA2 is associated with a pattern of genome-wide mutations known as signature 3. By analyzing [sim]1, 000 breast cancer samples, we confirmed this association and established that germline nonsense and frameshift variants in PALB2, but not in ATM or CHEK2, can also give rise to the same signature. We were able to accurately classify missense BRCA1 or BRCA2 variants known to impair homologous recombination (HR) on the basis of this signature. Finally, we show that epigenetic silencing of RAD51C and BRCA1 by promoter methylation is strongly associated with signature 3 and, in our data set, was highly enriched in basal-like breast cancers in young individuals of African descent.

Background & Aims The guidelines of the European Society of Pediatric Gastroenterology, Hepatology, and Nutrition allow for diagnosis of celiac disease without biopsies in children with symptoms and levels of immunoglobulin A against tissue-transglutaminase (TGA-IgA) 10-fold or more the upper limit of normal (ULN), confirmed by detection of endomysium antibodies (EMA) and positivity for HLA-DQ2/DQ8. We performed a large, international prospective study to validate this approach. Methods We collected data from consecutive pediatric patients (18 years or younger) on a gluten-containing diet who tested positive for TGA-IgA from November 2011 through May 2014, seen at 33 pediatric gastroenterology units in 21 countries. Local centers recorded symptoms; measurements of total IgA, TGA, and EMA; and histopathology findings from duodenal biopsies. Children were considered to have malabsorption if they had chronic diarrhea, weight loss (or insufficient gain), growth failure, or anemia. We directly compared central findings from 16 antibody tests (8 for TGA-IgA, 1 for TGA-IgG, 6 for IgG against deamidated gliadin peptides, and 1 for EMA, from 5 different manufacturers), 2 HLA-DQ2/DQ8 tests from 2 manufacturers, and histopathology findings from the reference pathologist. Final diagnoses were based on local and central results. If all local and central results were concordant for celiac disease, cases were classified as proven celiac disease. Patients with only a low level of TGA-IgA (threefold or less the ULN) but no other results indicating celiac disease were classified as no celiac disease. Central histo-morphometry analyses were performed on all other biopsies and cases were carefully reviewed in a blinded manner. Inconclusive cases were regarded as not having celiac disease for calculation of diagnostic accuracy. The primary aim was to determine whether the nonbiopsy approach identifies children with celiac disease with a positive predictive value (PPV) above 99% in clinical practice. Secondary aims included comparing performance of different serological tests and to determine whether the suggested criteria can be simplified. Results Of 803 children recruited for the study, 96 were excluded due to incomplete data, low level of IgA, or poor-quality biopsies. In the remaining 707 children (65.1% girls; median age, 6.2 years), 645 were diagnosed with celiac disease, 46 were found not to have celiac disease, and 16 had inconclusive results. Findings from local laboratories of TGA-IgA 10-fold or more the ULN, a positive result from the test for EMA, and any symptom identified children with celiac disease (n = 399) with a PPV of 99.75 (95% confidence interval [CI], 98.61–99.99); the PPV was 100.00 (95% CI, 98.68–100.00) when only malabsorption symptoms were used instead of any symptom (n = 278). Inclusion of HLA analyses did not increase accuracy. Findings from central laboratories differed greatly for patients with lower levels of antibodies, but when levels of TGA-IgA were 10-fold or more the ULN, PPVs ranged from 99.63 (95% CI, 98.67–99.96) to 100.00 (95% CI, 99.23–100.00). Conclusions Children can be accurately diagnosed with celiac disease without biopsy analysis. Diagnosis based on level of TGA-IgA 10-fold or more the ULN, a positive result from the EMA tests in a second blood sample, and the presence of at least 1 symptom could avoid risks and costs of endoscopy for more than half the children with celiac disease worldwide. HLA analysis is not required for accurate diagnosis. Clinical Trial Registration no: DRKS00003555. © 2017 AGA Institute

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.

Using a Heckscher–Ohlin model, this paper re-examines Robert Mundell's famous thesis that free trade and unimpeded capital mobility are perfect substitutes. Under very general conditions which, according to many economists, have caused international convergence of factor rewards, we show that in a polluted environment free trade is inferior to free international investment. This happens even though commodity prices and factor rewards are the same with both policies. The practical side of our thesis is that the world will be better off by reducing the volume of trade while removing all barriers to foreign direct investment that at present hamper the service industries.

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.

The purpose of this paper is to incorporate the currently mushrooming phenomenon of outsourcing into the standard two-sector, two-factor Heckscher–Ohlin model of international trade. We first show how outsourcing modifies a firm's production function, and then demonstrate that outsourcing generally raises the return to capital and lowers the real wage, although the nation's GDP rises in proportion to the value-added in the outsourcing industry. Furthermore, the output of the outsourcing sector may actually fall even though its unit cost goes down; the output of the other sector then rises. By contrast, employment in the outsourcing sector may actually rise.

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.

Outsourcing has become an increasingly contentious subject ever since N. Gregory Mankiw remarked in 2004 that outsourcing is just another way of doing international trade, and must be beneficial to the nation, including the workers. We construct a simple two-sector specific-factor model and explore the validity of Mankiw's remarks. We find his ideas are valid when the country does not produce any outsourced factor's work at home in that both the laborers and the nation benefit. But when some outsourced factor cum intermediate good is also produced at home, the nation still benefits but the workers may suffer.

We are developing the first optical frequency standard in India with single ytterbium ion (171Yb+), which is confined and laser cooled in an ion trap. This precision clock experiment needs to be automated for running it reliably and continuously over few days. For this we are developing a computer control systems. Some of its supporting hardware modules have already been designed and tested. In this article we describe scheme of our automation and control system.

We offer a new paradigm to understand the effects of trade on factor rewards. It utilizes the classical-Keynesian model, and shows that normally a country’s trade deficit hurts labor by lowering the real wage, but benefits the owners of capital. The effects of tariffs on factor rewards and employment are opposite to those of the trade deficit, which falls with a rise in the tariff rate. Countries with trade shortfalls unambiguously benefit from their tariffs, because laborers far outnumber capitalists, who suffer from the declining interest rate. Thus, tariffs lead to a rise in social welfare in trade-deficit countries.

In this paper we re-examine the contentious facts and issues and argue that the technology explanation of the entire real-wage controversy contradicts logic, common sense and history, whereas the trade explanation passes the severe test of rationality. Using a simple model we illustrate that in an open economy technical improvements may generate a fall in some or all types of real earnings, but not in a closed economy.

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.

This paper presents a framework which simplifies the task of developing, deploying, and managing complex, integrated, and standards-compliant eGovernance solutions. The framework enables development, configuration, integration, and management of solutions at a higher semantic level. It also provides commonly used services such as access to citizen and property records, access control and authentication services, public key infrastructure, and support for digital signatures. The ability to manage solutions at a higher semantic level enables administrators who are not proficient in programming to customize solutions in order to address specific needs of the different national, state, and local governments. This includes the ability to customize interfaces for multiple local languages used in government transactions and to customize workflows to conform to the organizational structure and policies to manage access to and retention of government records.

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.

The paper explains most, if not all, observations made by the empirical literature regarding the behavior of skilled and unskilled real wages in the United States, especially those since 1980. Generalizing the Stopler–Samuelson theorem, the authors show that the nontraded sector is critical to explaining the effects of changes in the price of traded goods on relative and absolute wages. Factor-intensities play their role as in the traditional Stolper–Samuelson model, but the output of the nontraded sector matters as well. Specifically, freer trade benefits capital and hurts both the skilled and unskilled labor if the import as well as the nontraded sectors contract. This is a new result to the literature on Stolper–Samuelson issues.

This paper modifies the simple classical model by introducing capacity utilization that varies across the course of the business cycle. By making the capacity usage a choice variable that turns out to be sensitive to changes in the price level, we show that the classical model loses its fundamental feature, namely the neutrality of money. In our generalized framework, a rise in money supply improves upon all the real variables if the economy suffers from excess capacity, as in recessions and depressions. We demonstrate that our model describes the various economic cross-currents during the Great Depression extremely well. Thus, monetary policy emerges with an activist role even in a generally classical setting.

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