The organization of mental disorders into 16 DSM-IV and 10 ICD-10 chapters is complex and based on clinical presentation. We explored the feasibility of a more parsimonious meta-structure based on ...both risk factors and clinical factors.
Most DSM-IV disorders were allocated to one of five clusters as a starting premise. Teams of experts then reviewed the literature to determine within-cluster similarities on 11 predetermined validating criteria. Disorders were included and excluded as determined by the available data. These data are intended to inform the grouping of disorders in the DSM-V and ICD-11 processes.
The final clusters were neurocognitive (identified principally by neural substrate abnormalities), neurodevelopmental (identified principally by early and continuing cognitive deficits), psychosis (identified principally by clinical features and biomarkers for information processing deficits), emotional (identified principally by the temperamental antecedent of negative emotionality), and externalizing (identified principally by the temperamental antecedent of disinhibition).
Large groups of disorders were found to share risk factors and also clinical picture. There could be advantages for clinical practice, public administration and research from the adoption of such an organizing principle.
On the basis of historical data, patients with cancer of unknown primary (CUP) are generally assumed to have a dismal prognosis with overall survival of less than 1 year. Treatment is typically ...cytotoxic chemotherapy guided by histologic features and the pattern of metastatic spread. The purpose of this study was to provide a clinical and pathologic description of patients with CUP in the modern era, to define the frequency of clinically actionable molecular alterations in this population, to determine how molecular testing can alter therapeutic decisions, and to investigate novel uses of next-generation sequencing in the evaluation and treatment of patients with CUP.
Under Institutional Review Board approval, we identified all CUP patients evaluated at our institution over a recent 2-year period. We documented demographic information, clinical outcomes, pathologic evaluations, next-generation sequencing of available tumor tissue, use of targeted therapies, and clinical trial enrollment.
We identified 333 patients with a diagnosis of CUP evaluated at our institution from 1 January 2014 through 30 June 2016. Of these patients, 150 had targeted next-generation sequencing carried out on available tissue. Median overall survival in this cohort was 13 months. Forty-five of 150 (30%) patients had potentially targetable genomic alterations identified by tumor molecular profiling, and 15 of 150 (10%) received targeted therapies. Dominant mutation signatures were identified in 21 of 150 (14%), largely implicating exogenous mutagen exposures such as ultraviolet radiation and tobacco.
Patients with CUP represent a heterogeneous population, harboring a variety of potentially targetable alterations. Next-generation sequencing may provide an opportunity for CUP patients to benefit from novel personalized therapies.
Recent analyses of the excess of gamma-ray radiation emanating from the Galactic center (GC) region suggest an origin in a population of thousands of undetected millisecond pulsars (MSPs). We have ...conducted a search for pulsar candidates using new high-sensitivity, wide-field radio observations of the GC covering 5 deg2. We conducted the search at a low frequency of ∼320 MHz in order to take advantage of the very steep spectra typical of pulsars. Additional observations at 6 GHz of the most steep-spectrum, compact sources resulted in a list of seven candidate pulsars. No pulsations were detected for any of the candidates in a search conducted with the GBT at 1.5, 2, and 6 GHz, presumably due to severe temporal scattering in the GC region or along the line of sight. We discuss the implications of the nondetections on pulse period and distance estimates using two different models of the Galactic distribution of ionized gas. For our best candidate, C1748−2827, located 43′ from Sgr A*, we estimate that pulsations from a normal pulsar would have been detected up to a distance of ∼8 kpc and from an MSP up to ∼4.5 kpc.
ABSTRACT We report on a search for radio transients at 340 MHz with the Jansky Very Large Array Low-band Ionosphere and Transient Experiment (VLITE). Between 2015 July 29 and September 27, operating ...in commensal mode, VLITE imaged approximately 2800 pointings covering 12,000 deg2 on the sky, sampling timescales ranging from tens of seconds to several hours on a daily basis. In addition, between 2015 February 25 and May 9, VLITE observed 55 epochs of roughly 2-4 hr each toward the COSMOS field. Using existing radio source catalogs, we have searched all of the daily VLITE images for transients, while for the COSMOS field we compared individual images and the summed image to search for new sources in repeated observations of the same field. The wide range of timescales makes VLITE sensitive to both coherent and incoherent transient source classes. No new transients are found, allowing us to set stringent upper limits on transients at milli-jansky levels and at low frequencies where comparatively few such surveys have been carried out to date. An all-sky isotropic surface density of bursting radio transients with similar rates, durations, and intensities as the unusual transient GCRT J1745−3009, discovered in wide-field monitoring toward the Galactic center, is ruled out with high confidence. The resulting non-detections allows us to argue that this is a coherent source, whose properties most resemble the growing class of nulling pulsars. We end with a discussion of the future prospects for the detection of transients by VLITE and other experiments.
Kinase fusions are rare and poorly characterized in breast cancer (BC). We aimed to characterize kinase fusions within a large cohort of advanced BC.
A total of 4854 patients with BC were analyzed by ...Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) targeted DNAseq and MSK-Fusion targeted RNAseq during the study time period.
Twenty-seven of 4854 (0.6%) patients harbored fusions: 11 FGFR (five FGFR2, three FGFR3, three FGFR1), five BRAF, four NTRK1, two RET, two ROS1, one ALK, one ERBB2, and one MET. A history of endocrine therapy was present in 15 (56%) of fusion-positive BC; eight of the 15 cases had available pre-treatment samples, of which six were fusion-negative. None of the fusion-positive BC samples harbored ESR1 hotspot mutations. Two patients with acquired LMNA-NTRK1 fusions and metastatic disease received larotrectinib and demonstrated clinical benefit.
Kinase fusions in BC are extremely rare, and appear to be enriched in hormone-resistant, metastatic carcinomas and mutually exclusive with ESR1 mutations. The present study expands the spectrum of genetic alterations activating mitogen-activated protein kinase (MAPK) signaling that can substitute for ESR1 mutations in this setting. Molecular testing at progression after endocrine therapy should include fusion testing, particularly in the absence of ESR1 hotspot alterations, in an effort to identify additional therapeutic options which may provide substantial clinical benefit.
•Kinase fusions in breast cancer are extremely rare.•Kinase fusions in breast cancer appear enriched in ESR1 wild-type metastases after progression on endocrine therapy.•Fusion testing of metastatic breast cancers upon progression after endocrine therapy may provide new therapeutic options.
We present a catalog of 9017 X-ray sources identified in Chandra observations of a 2°X 08 field around the Galactic center. This enlarges the number of known X-ray sources in the region by a factor ...of 2.5. The catalog incorporates all of the ACIS-I observations as of 2007 August, which total 2.25 Ms of exposure. At the distance to the Galactic center (8 kpc), we are sensitive to sources with luminosities of 4 X 1032 erg s-1 (0.5-8.0 keV; 90% confidence) over an area of 1 deg2, and up to an order of magnitude more sensitive in the deepest exposure (1.0 Ms) around Sgr A*. The positions of 60% of our sources are accurate to <1 '' (95% confidence), and 20% have positions accurate to <05. We search for variable sources, and find that 3% exhibit flux variations within an observation, and 10% exhibit variations from observation-to-observation. We also find one source, CXOUGC J174622.7 - 285218, with a periodic 1745 s signal (1.4% chance probability), which is probably a magnetically accreting cataclysmic variable. We compare the spatial distribution of X-ray sources to a model for the stellar distribution, and find 2.8s evidence for excesses in the numbers of X-ray sources in the region of recent star formation encompassed by the Arches, Quintuplet, and Galactic center star clusters. These excess sources are also seen in the luminosity distribution of the X-ray sources, which is flatter near the Arches and Quintuplet than elsewhere in the field. These excess point sources, along with a similar longitudinal asymmetry in the distribution of diffuse iron emission that has been reported by other authors, probably have their origin in the young stars that are prominent at l 01.
The bacterial family Enterobacteriaceae is notable for its well studied human pathogens, including Salmonella, Yersinia, Shigella, and Escherichia spp. However, it also contains several plant ...pathogens. We report the genome sequence of a plant pathogenic enterobacterium, Erwinia carotovora subsp. atroseptica (Eca) strain SCRI1043, the causative agent of soft rot and blackleg potato diseases. Approximately 33% of Eca genes are not shared with sequenced enterobacterial human pathogens, including some predicted to facilitate unexpected metabolic traits, such as nitrogen fixation and opine catabolism. This proportion of genes also contains an overrepresentation of pathogenicity determinants, including possible horizontally acquired gene clusters for putative type IV secretion and polyketide phytotoxin synthesis. To investigate whether these gene clusters play a role in the disease process, an arrayed set of insertional mutants was generated, and mutations were identified. Plant bioassays showed that these mutants were significantly reduced in virulence, demonstrating both the presence of novel pathogenicity determinants in Eca, and the impact of functional genomics in expanding our understanding of phytopathogenicity in the Enterobacteriaceae.
ABSTRACT
From an on-going survey of the Galactic bulge, we have discovered a number of compact, steep spectrum radio sources. In this study, we have carried out more detailed observations for two of ...these sources, located 43 arcmin and 12${_{.}^{\circ}}$7 from the Galactic Centre. Both sources have a very steep spectrum (α ≃ − 3) and are compact, with upper limits on the angular size of 1–2 arcsec. Their flux densities appear to be relatively steady on time-scales of years, months, and hours, with no indications of rapid variability or transient behaviour. We detect significant circularly polarized emission from both sources, but only weak or upper limits on linear polarization. Neither source has a counterpart at other wavelengths and deep, high-frequency searches fail to find pulsations. We compare their source properties with other known compact, non-thermal source populations in the bulge (e.g. X-ray binaries, magnetars, the Burper, and cataclysmic variables). Our existing data support the hypothesis that they are scatter broadened millisecond or recycled pulsars, either at the bulge or along the line of sight. We also consider the possibility that they may be a new population of Galactic radio sources which share similar properties as pulsars but lack pulsations; a hypothesis that can be tested by future large-scale synoptic surveys.
This article investigates whether childhood abuse and neglect subtypes (i.e., physical, sexual, and emotional abuse, and physical and emotional neglect) differentially predict the severity of ...individual posttraumatic stress disorder (PTSD) symptom clusters and overall posttraumatic stress. Eighty‐nine patients admitted to the short‐term adolescent treatment unit of a psychiatric hospital completed a battery of psychological assessments. Findings of multiple regression analyses showed that emotional and sexual abuse rather than physical abuse, emotional neglect, or physical neglect is related to individual symptom cluster severity and overall posttraumatic stress. Results suggested that a greater level of specificity is necessary when assessing child abuse and posttraumatic stress because each level provides more specific information about how to intervene to reduce the risk of negative outcomes.
We report the results of a low frequency radio variability and slow transient search using archival observations from the Very Long Array. We selected six 325 MHz radio observations from the spring ...of 2006, each centered on the Spitzer-Space-Telescope Wide-area Infrared Extragalactic Survey (SWIRE) Deep Field: 1046+59. Observations were spaced between one day to three months, with a typical single-epoch peak flux sensitivity below 0.2 mJy beam super(-1) near the field pointing center. We describe the observation parameters, data post-processing, and search methodology used to identify variable and transient emission. Our search revealed multiple variable sources and the presence of one, day-scale transient event with no apparent astronomical counterpart. This detection implies a transient rate of 1 + or - 1 event per 6.5 deg super(2) per 72 observing hours in the direction of 1046+59 and an isotropic transient surface density capital sigma = 0.12 deg super(-2) at 95% confidence for sources with average peak flux density higher than 2.1 mJy over 12 hr.
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