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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.

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

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.

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.

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

We propose a new ion-trap geometry to carry out accurate measurements of the quadrupole shifts in the $^{171}$Yb-ion. This trap will produce nearly ideal harmonic potential where the quadrupole shifts due to the anharmonic components can be reduced by four orders of magnitude. This will be useful to reduce the uncertainties in the clock frequency measurements of the $6s~{^2}S_{1/2} \rightarrow 4f^{13} 6s^2 ~{^2}F_{7/2}$ and $6s~{^2}S_{1/2} \rightarrow 5d ~{^2}D_{3/2}$ transitions, from which we can deduce precise values of the quadrupole moments ($\Theta$s) of the $4f^{13} 6s^2 ~{^2}F_{7/2}$ and $5d ~{^2}D_{3/2}$ states. Moreover, it may be able to affirm validity of the measured $\Theta$ value of the $4f^{13} 6s^2 ~{^2}F_{7/2}$ state where three independent theoretical studies defer almost by one order in magnitude from the measurement. We also perform calculations of $\Theta$s using the relativistic coupled-cluster (RCC) method. We use these $\Theta$ values to estimate quadrupole shift that can be measured in our proposed ion trap experiment., Comment: 1 table, 5 figures