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Excess copper in the liver is toxic in humans and other mammals, and may lead to acute or chronic hepatitis, steatohepatitis, acute liver failure, cirrhosis and death. Of the several human copper storage diseases that have been described, the molecular basis of only Wilson disease is understood with the discovery of the Wilson disease gene (ATP7B) in 1993. The therapeutic success using oral copper chelating agents and zinc therapy make Wilson disease one of the few treatable genetic metabolic liver diseases. In cases with a fulminant presentation or advanced disease at diagnosis, copper chelation is ineffective and liver transplantation may be lifesaving. Indian Childhood Cirrhosis (ICC) has been defined as a copper-storage disorder precipitated by increased copper intake which affects young children primarily of Indian descent, and which progresses to cirrhosis and death before age three to four years without treatment. Children from North America, Asia, Austria, Germany and other countries have been described with a similar condition, which has been termed idiopathic copper toxicosis (ICT). Several newer disorders of hepatic copper metabolism have been recently described.
OBJECTIVES/GOALS: Neuroblastoma (NB) is the most common extra-cranial solid tumor with outcomes varying from spontaneous regression to metastatic with high mortality rates. The tumor immune microenvironment (TIME) may play a significant role in this disease. In this study we analyze the TIME comparing high-risk (HR) and low-risk (LR) NBs using multiplex platforms. METHODS/STUDY POPULATION: Two tissue microarrays (TMAs) with 2mm cores were created from 41 patients treated at Columbia University Irving Medical Center. Five micron TMA slides were stained for Digital Spatial Profiling (DSP, nanoString) and multiplex immunofluorescence (mIF). For DSP, a 24-patient subset including 11 HR, 8 LR and 4 intermediate risk patients was analyzed for 34 proteins. Protein expression among risk groups was compared using Mann-Whitney t-test. For mIF, TMA FFPE slides were stained for DAPI, CD3, CD8, CD68, HLA-DR, PDL1 and Chromogranin A. Whole TMA cores were captured as 9 -20X multispectral images (MSIs) stitched into a 3x3 MSI using Vectra (Akoya). MSIs were processed with inForm and qualitative analysis performed comparing HR and LR tumors. RESULTS/ANTICIPATED RESULTS: With DSP, we find significantly more HLA-DR in HR compared to LR tumors (p = 0.016). When controlling for immune cells with CD45 we find HLA-DR/CD45 to be higher in HR than LR tumors (p = 0.026). We found increased PD1 and PDL1 expression in all groups without significant difference between LR and HR (p = 0.778 and p = 0.310, respectively). Preliminary analysis of mIF on 9 patients (4 HR and 5 LR) finds HR tumors appear to have more immune cells than LR tumors, specifically more CD3+CD8- T cells while total CD8+ cells may be similar. There may be less macrophages in the HR compared to LR tumors. Completion of image processing and quantitative analysis of mIF data is underway. DISCUSSION/SIGNIFICANCE OF IMPACT: Increased expression of immune markers in NB TIME correlates with higher risk, which is unlike many other tumors. We compared TIME in HR and LR NB using multiplex platforms, DSP and mIF. We find that HLA-DR is more expressed in HR NB while PD1 and PDL1 expression is consistently high and not different between risk groups. Further analysis is underway. CONFLICT OF INTEREST DESCRIPTION: Robyn D. Gartrell-Corrado received grant support from nanoString for Digital Spatial Profiling and received honoraria and travel support from Northwest Biotherapeutics and PerkinElmer, respectively.
Obsessive compulsive disorder (OCD) is observed at increased rates in first-degree relatives of probands with autism spectrum disorders (ASDs). In addition, OCD-like traits are observed in autism, and in Asperger syndrome. Furthermore, subjects with OCD may have traits that overlap with some aspects of higher functioning ASDs. These observations suggest that OCD and ASDs may share some genetic risk factors. In support of this, it has recently been suggested that both common and rare functional variants in the serotonin transporter (SLC6A4) may increase risk for OCD and/or ASD. We will review our large-scale analysis of common and rare functional variants SLC6A4 in ASDs and relate these results to studies of OCD. In parallel studies, we have carried our linkage analysis in families with ASDs, focusing on those with more severe OCD-like traits. These families demonstrated increased evidence for linkage to chromosomes 1, 6, and 19. Evidence for linkage to chromosomes 6 and 19 have been observed in other studies, which we will summarize. Finally, we have examined the evidence that common variants in the NrCAM, TPH1 and TPH2 genes are associated with ASDs, particularly in patients with more severe OCD-like traits, and these results will be summarized.
Thanks to deep optical to near-IR imaging and spectroscopy, significant progress is made in characterizing the rest-frame UV to optical properties of galaxies in the early universe (z > 4. Surveys with Hubble, Spitzer, and ground-based facilities (Keck, Subaru, and VLT) provide spectroscopic and photometric redshifts, measurements of the spatial structure, stellar masses, and optical emission lines for large samples of galaxies. Recently, the Atacama Large (Sub) Millimeter Array (ALMA) has become a major player in pushing studies of high redshift galaxies to far-infrared wavelengths, hence making panchromatic surveys over many orders of frequencies possible. While past studies focused mostly on bright sub-millimeter galaxies, the sensitivity of ALMA now enables surveys like ALPINE, which focuses on measuring the gas and dust properties of a large sample of normal main-sequence galaxies at z > 4. Combining observations across different wavelengths into a single, panchromatic picture of galaxy formation and evolution is currently and in the future an important focus of the astronomical community.
The ALMA-ALPINE [CII] survey (A2C2S) aims at characterizing the properties of normal star-forming galaxies (SFGs) observed in the [CII]-158μm line in the period of rapid mass assembly at redshifts 4 < z < 6. Here we present the survey and the selection of 118 galaxies observed with ALMA, selected from large samples of galaxies with spectroscopic redshifts derived from UV-rest frame. The observed properties derived from the ALMA data are presented and discussed in terms of the overall detection rate in [CII] and far-IR continuum. The sample is representative of the SFG population at these redshifts. The overall detection rate is 61% down to a flux limit of 0.07 mJy. From a visual inspection of the [CII] data cubes together with the large wealth of ancillary data we find a surprisingly wide range of galaxy types, including 32.4% mergers, 25.7% extended and dispersion dominated, 13.5% rotating discs, and 16.2% compact, the remaining being too faint to be classified. ALPINE sets a reference sample for the gas distribution in normal star-forming galaxies at a key epoch in galaxy assembly, ideally suited for studies with future facilities like JWST and ELTs.
This paper closely studies Scotland v Canada to reveal the normative and substantive justice challenges facing immigration detainees across Canada. The Scotland decision at the Ontario Superior Court certified a habeas corpus writ as an individual remedy to release Mr. Ricardo Scotland from a pointless, seventeen-month incarceration. The decision frames Mr. Scotland’s detention as anomalous or divergent from an otherwise-functioning system. Against this view, this paper argues that access to habeas corpus cannot remedy the detention system’s scale of injustices. The paper contextualizes Mr. Scotland’s incarceration and the Superior Court decision against two primary claims: first, that the Canadian immigration and refugee determination system is arbitrarily biased against certain minoritized individuals, therefore transforming some people into detainable bodies; and second, that the global criminalization of migration trend has nested an arc of penal practices into Canadian policymaking and law, and this arc has seemingly normalized indefinite detention for some migrants. The paper concludes that restoration of access to habeas corpus cannot be understood as a substantive remedy to address the miscarriages of justice in the Canadian detention system.
The present study evaluates the use of multiple correspondence analysis (MCA), a type of exploratory factor analysis designed to reduce the dimensionality of large categorical data sets, in identifying behaviours associated with measures of overweight/obesity in Vanuatu, a rapidly modernizing Pacific Island country.
Starting with seventy-three true/false questions regarding a variety of behaviours, MCA identified twelve most significantly associated with modernization status and transformed the aggregate binary responses of participants to these twelve questions into a linear scale. Using this scale, individuals were separated into three modernization groups (tertiles) among which measures of body fat were compared and OR for overweight/obesity were computed.
Ni-Vanuatu adults (n 810) aged 20–85 years.
Among individuals in the tertile characterized by positive responses to most of or all the twelve modernization questions, weight and measures of body fat and the likelihood that measures of body fat were above the US 75th percentile were significantly greater compared with individuals in the tertiles characterized by mostly or partly negative responses.
The study indicates that MCA can be used to identify individuals or groups at risk for overweight/obesity, based on answers to simply-put questions. MCA therefore may be useful in areas where obtaining detailed information about modernization status is constrained by time, money or manpower.
Aripiprazole lauroxil (AL) is a long-acting injectable atypical antipsychotic that was evaluated for the treatment of schizophrenia in a randomized, placebo-controlled, Phase 3 study. Here, we present exploratory analyses of supportive efficacy endpoints.
Patients experiencing an acute exacerbation of schizophrenia received AL 441 mg intramuscularly (IM), AL 882 mg IM, or matching placebo IM monthly. Supportive endpoints included changes from baseline at subsequent time points in Clinical Global Impression-Severity (CGI-S) scale score; Positive and Negative Syndrome Scale (PANSS) Total score; PANSS Positive, Negative, and General Psychopathology subscale scores; PANSS Marder factors (post hoc); and PANSS responder rate. Overall response rate, based on PANSS Total score and Clinical Global Impression–Improvement (CGI-I) scale score, was also analyzed.
Of 622 patients who were randomized, 596 had ≥1 post-baseline PANSS score. Patients were markedly ill at baseline (mean PANSS Total scores 92–94). Compared with placebo, CGI-S scores; PANSS Positive, Negative, and General Psychopathology subscale scores; and PANSS Marder factors were all significantly (p<0.001) improved by Day 85 with both AL doses, with significantly lower scores starting from Day 8 in most instances. Treatment response rates were significantly (p<0.001) greater with both doses of AL vs placebo.
AL demonstrated robust efficacy on CGI-S score, PANSS subscale scores, PANSS Marder factors, and response rates. Study limitations included use of a fixed dose for initial oral aripiprazole and fixed monthly AL doses without the option to individualize the oral initiation dosing or injection frequency for efficacy, tolerability, or safety.
Anxiety disorders are common, and cognitive–behavioural therapy (CBT) is a first-line treatment. Candidate gene studies have suggested a genetic basis to treatment response, but findings have been inconsistent.
To perform the first genome-wide association study (GWAS) of psychological treatment response in children with anxiety disorders (n = 980).
Presence and severity of anxiety was assessed using semi-structured interview at baseline, on completion of treatment (post-treatment), and 3 to 12 months after treatment completion (follow-up). DNA was genotyped using the Illumina Human Core Exome-12v1.0 array. Linear mixed models were used to test associations between genetic variants and response (change in symptom severity) immediately post-treatment and at 6-month follow-up.
No variants passed a genome-wide significance threshold (P=5×10–8) in either analysis. Four variants met criteria for suggestive significance (P<5×10–6) in association with response post-treatment, and three variants in the 6-month follow-up analysis.
This is the first genome-wide therapygenetic study. It suggests no common variants of very high effect underlie response to CBT. Future investigations should maximise power to detect single-variant and polygenic effects by using larger, more homogeneous cohorts.
Background: The incidence of brain metastases is increasing with the development of improved systemic therapies with limited impact on intracranial disease. The purpose of this study was to determine if there is a threshold tumor size below which local control (LC) rates approach 100% after stereotactic radiosurgery (SRS). Methods: 200 patients with 1237 tumors were identified from a prospective registry of patients having undergone SRS between 2012-2014. Histology consisted predominantly of non-small cell lung cancer (NSCLC), melanoma and breast cancer. Results: The median tumor size was 6 mm in diameter or 70 mm3 and most commonly NSCLC. Thirty-three tumors had local progression at a median time of 8.8 months. The 1- and 2-year actuarial LC for all tumors were 97% and 93%. LC of 100% was seen for intracranial metastases less than 100 mm3 or 6 mm in diameter, independent of histology. Total tumor volume was an independent predictor of overall survival, after adjusting for age, KPS and extracranial disease status. Conclusions: SRS can achieve LC rates approaching 100% for subcentimeter metastases. The earlier detection and prompt treatment of small intracranial metastases may prevent the development of neurological symptoms, the need for surgical resection, and potentially improve overall survival. The results of this study would favour the implementation of routine staging MRIs.
Background: The purpose of the study was to evaluate the impact of BRAF inhibitors on survival outcomes in patients receiving stereotactic radiosurgery (SRS) for melanoma brain metastases. Methods: We prospectively collected treatment outcomes for 80 patients with melanoma brain metastases who underwent SRS. Thirty-five patients harbored the BRAF mutation (BRAF-M) and 45 patients did not (BRAF-WT). Results: The median overall survival from first SRS procedure was 11.2 months if treated with a BRAF inhibitor and 4.5 months for BRAF-WT. Actuarial survival rates for BRAF-M patients on an inhibitor were 54% and 41% at 6 and 12 months after radiosurgery, in contrast to 28% and 19% for BRAF-WT. Overall survival was extended for patients on a BRAF inhibitor if initiated at or after the first SRS. The local control rate did not differ based on BRAF status and was over 90%. Patients with higher KPS, fewer treated metastases, controlled systemic disease, RPA class 1 and BRAF-M patients had extended overall survival. Conclusions: Patients with BRAF-M treated with both SRS and BRAF inhibitors, at or after SRS, have increased overall survival. As patients live longer due to more effective systemic and local therapies, close surveillance and early management of intracranial disease with SRS will become increasingly important.
We previously reported an association between 5HTTLPR genotype and
outcome following cognitive–behavioural therapy (CBT) in child anxiety
(Cohort 1). Children homozygous for the low-expression short-allele
showed more positive outcomes. Other similar studies have produced mixed
results, with most reporting no association between genotype and CBT
To replicate the association between 5HTTLPR and CBT outcome in child
anxiety from the Genes for Treatment study (GxT Cohort 2,
n = 829).
Logistic and linear mixed effects models were used to examine the
relationship between 5HTTLPR and CBT outcomes. Mega-analyses using both
cohorts were performed.
There was no significant effect of 5HTTLPR on CBT outcomes in Cohort 2.
Mega-analyses identified a significant association between 5HTTLPR and
remission from all anxiety disorders at follow-up (odds ratio 0.45,
P = 0.014), but not primary anxiety disorder
The association between 5HTTLPR genotype and CBT outcome did not
replicate. Short-allele homozygotes showed more positive treatment
outcomes, but with small, non-significant effects. Future studies would
benefit from utilising whole genome approaches and large, homogenous
We are analysing late-time (older than about 150 d past explosion) optical spectra of Type II-Plateau (IIP) supernovae (SNe), which are H-rich SNe that come from red supergiant (RSG) progenitors. The dataset includes nearly 100 spectra of about 40 objects, making this the largest sample of SN IIP nebular spectra ever investigated. Quantitative criteria from within the spectra themselves are employed to determine if an observation is truly nebular, and thus should be included in the study. We present the temporal evolution of the fluxes, shapes, and velocities of various emission lines (see, for example, Fig. 1). These measured values are also compared to photometric data in order to search for correlations that can allow us to gain insight into the diversity of RSG progenitors and learn more about the details of the explosion itself.
Trans-oesophageal echocardiographic imaging is valuable in the pre- and post-operative evaluation of children and adults with CHD; however, the frequency by which trans-oesophageal echocardiography guides the intra-operative course of patients is unknown.
We retrospectively reviewed 1748 intra-operative trans-oesophageal echocardiograms performed between 1 October, 2005 and 31 December, 2010, and found 99 cases (5.7%) that required return to bypass, based in part upon the intra-operative echocardiographic findings.
The diagnoses most commonly requiring further repair and subsequent imaging were mitral valve disease (20.9%), tricuspid valve disease (16.0%), atrioventricular canal defects (12.0%), and pulmonary valve disease (14.1%). The vast majority of those requiring immediate return to bypass benefited by avoiding subsequent operations and longer lengths of hospital stay. A total of 14 patients (0.8%) who received routine imaging required further surgical repair within 1 week, usually due to disease that developed over ensuing days. Patients who had second post-operative trans-oesophageal echocardiograms in the operating room rarely required re-operations, confirming the benefit of routine intra-operative imaging.
This study represents a large single institutional review of intra-operative trans-oesophageal echocardiography, and confirms its applicability in the surgical repair of patients with CHD. Routine imaging accurately identifies patients requiring further intervention, does not confer additional risk of mortality or prolonged length of hospital stay, and prevents subsequent operations and associated sequelae in a substantial subset of patients. This study demonstrates the utility of echocardiography in intra-operative monitoring of surgical repair and highlights patients who are most likely to require return to bypass, as well as the co-morbidities of such manipulations.