Early detection remains the most promising approach to improve long-term survival of patients with ovarian cancer. In a five-center case-control study, serum proteomic expressions were analyzed on ...153 patients with invasive epithelial ovarian cancer, 42 with other ovarian cancers, 166 with benign pelvic masses, and 142 healthy women. Data from patients with early stage ovarian cancer and healthy women at two centers were analyzed independently and the results cross-validated to discover potential biomarkers. The results were validated using the samples from two of the remaining centers. After protein identification, biomarkers for which an immunoassay was available were tested on samples from the fifth center, which included 41 healthy women, 41 patients with ovarian cancer, and 20 each with breast, colon, and prostate cancers. Three biomarkers were identified as follows: (a) apolipoprotein A1 (down-regulated in cancer); (b) a truncated form of transthyretin (down-regulated); and (c) a cleavage fragment of inter-alpha-trypsin inhibitor heavy chain H4 (up-regulated). In independent validation to detect early stage invasive epithelial ovarian cancer from healthy controls, the sensitivity of a multivariate model combining the three biomarkers and CA125 74% (95% CI, 52-90%) was higher than that of CA125 alone 65% (95% CI, 43-84%) at a matched specificity of 97% (95% CI, 89-100%). When compared at a fixed sensitivity of 83% (95% CI, 61-95%), the specificity of the model 94% (95% CI, 85-98%) was significantly better than that of CA125 alone 52% (95% CI, 39-65%). These biomarkers demonstrated the potential to improve the detection of early stage ovarian cancer.
Gas- and aerosol-phase measurements of oxidants, biogenic volatile organic compounds (BVOCs) and organic nitrates made during the Southern Oxidant and Aerosol Study (SOAS campaign, Summer 2013) in ...central Alabama show that a nitrate radical (NO3) reaction with monoterpenes leads to significant secondary aerosol formation. Cumulative losses of NO3 to terpenes are correlated with increase in gas- and aerosol-organic nitrate concentrations made during the campaign. Correlation of NO3 radical consumption to organic nitrate aerosol formation as measured by aerosol mass spectrometry and thermal dissociation laser-induced fluorescence suggests a molar yield of aerosol-phase monoterpene nitrates of 23-44 %. Compounds observed via chemical ionization mass spectrometry (CIMS) are correlated to predicted nitrate loss to BVOCs and show C10H17NO5, likely a hydroperoxy nitrate, is a major nitrate-oxidized terpene product being incorporated into aerosols. The comparable isoprene product C5H9NO5 was observed to contribute less than 1 % of the total organic nitrate in the aerosol phase and correlations show that it is principally a gas-phase product from nitrate oxidation of isoprene. Organic nitrates comprise between 30 and 45 % of the NOy budget during SOAS. Inorganic nitrates were also monitored and showed that during incidents of increased coarse-mode mineral dust, HNO3 uptake produced nitrate aerosol mass loading at a rate comparable to that of organic nitrate produced via NO3 + BVOCs.
Rationale
Recent clinical trials are reporting marked improvements in mental health outcomes with psychedelic drug-assisted psychotherapy.
Objectives
Here, we report on safety and efficacy outcomes ...for up to 6 months in an open-label trial of psilocybin for treatment-resistant depression.
Methods
Twenty patients (six females) with (mostly) severe, unipolar, treatment-resistant major depression received two oral doses of psilocybin (10 and 25 mg, 7 days apart) in a supportive setting. Depressive symptoms were assessed from 1 week to 6 months post-treatment, with the self-rated QIDS-SR16 as the primary outcome measure.
Results
Treatment was generally well tolerated. Relative to baseline, marked reductions in depressive symptoms were observed for the first 5 weeks post-treatment (Cohen’s
d
= 2.2 at week 1 and 2.3 at week 5, both
p
< 0.001); nine and four patients met the criteria for response and remission at week 5. Results remained positive at 3 and 6 months (Cohen’s
d
= 1.5 and 1.4, respectively, both
p
< 0.001). No patients sought conventional antidepressant treatment within 5 weeks of psilocybin. Reductions in depressive symptoms at 5 weeks were predicted by the quality of the acute psychedelic experience.
Conclusions
Although limited conclusions can be drawn about treatment efficacy from open-label trials, tolerability was good, effect sizes large and symptom improvements appeared rapidly after just two psilocybin treatment sessions and remained significant 6 months post-treatment in a treatment-resistant cohort. Psilocybin represents a promising paradigm for unresponsive depression that warrants further research in double-blind randomised control trials.
Myotonic dystrophy types 1 (DM1) and 2 (DM2/proximal myotonic myopathy PROMM) are dominantly inherited disorders with unusual multisystemic clinical features. The authors have characterized the ...clinical and molecular features of DM2/PROMM, which is caused by a CCTG repeat expansion in intron 1 of the zinc finger protein 9 (ZNF9) gene.
Three-hundred and seventy-nine individuals from 133 DM2/PROMM families were evaluated genetically, and in 234 individuals clinical and molecular features were compared.
Among affected individuals 90% had electrical myotonia, 82% weakness, 61% cataracts, 23% diabetes, and 19% cardiac involvement. Because of the repeat tract's unprecedented size (mean approximately 5,000 CCTGs) and somatic instability, expansions were detectable by Southern analysis in only 80% of known carriers. The authors developed a repeat assay that increased the molecular detection rate to 99%. Only 30% of the positive samples had single sizeable expansions by Southern analysis, and 70% showed multiple bands or smears. Among the 101 individuals with single expansions, repeat size did not correlate with age at disease onset. Affected offspring had markedly shorter expansions than their affected parents, with a mean size difference of -17 kb (-4,250 CCTGs).
DM2 is present in a large number of families of northern European ancestry. Clinically, DM2 resembles adult-onset DM1, with myotonia, muscular dystrophy, cataracts, diabetes, testicular failure, hypogammaglobulinemia, and cardiac conduction defects. An important distinction is the lack of a congenital form of DM2. The clinical and molecular parallels between DM1 and DM2 indicate that the multisystemic features common to both diseases are caused by CUG or CCUG expansions expressed at the RNA level.
Background. Melioidosis is a tropical infectious disease associated with significant mortality. Most deaths occur early and are caused by fulminant sepsis. Methods. In this randomized, ...placebo-controlled trial, we assessed the efficacy of lenograstim (granulocyte colony-stimulating factor G-CSF, 263 µg per day administered intravenously) in ceftazidime-treated patients with severe sepsis caused by suspected melioidosis in Thailand. Results. Over a 27-month period, 60 patients were enrolled to receive either G-CSF (30 patients, 18 of whom had culture-confirmed melioidosis) or placebo (30 patients, 23 of whom had culture-confirmed melioidosis). Mortality rates were similar in both groups (G-CSF group, 70%; placebo group, 87%; risk ratio, 0.81; 95% confidence interval, 0.61–1.06; P = .2), including among patients with confirmed melioidosis (83% vs. 96%; P = .3). The duration of survival was longer for patients who received G-CSF than for patients who received placebo (33 h vs. 18.6 h; hazard ratio, 0.56; 95% confidence interval, 0.31–1.00; P = .05). Conclusions. Receipt of G-CSF is associated with a longer duration of survival but is not associated with a mortality benefit in patients with severe sepsis who are suspected of having melioidosis in Thailand. We hypothesize that G-CSF may “buy time” for severely septic patients, but survival is more likely to be improved by management of associated metabolic abnormalities and organ dysfunction associated with severe sepsis.
In western Cambodia, malaria parasites clear slowly from the blood after treatment with artemisinin derivatives, but it is unclear whether this results from parasite, host, or other factors specific ...to this population. We measured heritability of clearance rate by evaluating patients infected with identical or nonidentical parasite genotypes, using methods analogous to human twin studies. A substantial proportion (56%–58%) of the variation in clearance rate is explained by parasite genetics. This has 2 important implications: (1) selection with artemisinin derivatives will tend to drive resistance spread and (2) because heritability is high, the genes underlying parasite clearance rate may be identified by genome-wide association. Trial Registration. ClinicalTrials.gov identifier: NCT00493363; Current Controlled Trials identifier: ISRCTN15351875.
We present timing solutions for four pulsars discovered in the Green Bank Northern Celestial Cap survey. All four pulsars are isolated with spin periods between 0.26 and 1.84 s. PSR J0038−2501 has a ...0.26 s period and a period derivative of 7.6 × 10−19 s s−1, which is unusually low for isolated pulsars with similar periods. This low period derivative may be simply an extreme value for an isolated pulsar or it could indicate an unusual evolution path for PSR J0038−2501, such as a disrupted recycled pulsar from a binary system or an orphaned central compact object (CCO). Correcting the observed spin-down rate for the Shklovskii effect suggests that this pulsar may have an unusually low space velocity, which is consistent with expectations for DRPs. There is no X-ray emission detected from PSR J0038−2501 in an archival Swift observation, which suggests that it is not a young orphaned CCO. The high dispersion measure of PSR J1949+3426 suggests a distance of 12.3 kpc. This distance indicates that PSR J1949+3426 is among the most distant 7% of Galactic field pulsars, and is one of the most luminous pulsars.
We report the discovery of 76 new T dwarfs from the UKIRT Infrared Deep Sky Survey (UKIDSS) Large Area Survey (LAS). Near-infrared broad- and narrow-band photometry and spectroscopy are presented for ...the new objects, along with Wide-field Infrared Survey Explorer (WISE) and warm-Spitzer photometry. Proper motions for 128 UKIDSS T dwarfs are presented from a new two epoch LAS proper motion catalogue. We use these motions to identify two new benchmark systems: LHS 6176AB, a T8p+M4 pair and HD 118865AB, a T5.5+F8 pair. Using age constraints from the primaries and evolutionary models to constrain the radii, we have estimated their physical properties from their bolometric luminosity. We compare the colours and properties of known benchmark T dwarfs to the latest model atmospheres and draw two principal conclusions. First, it appears that the H − 4.5 and J − W2 colours are more sensitive to metallicity than has previously been recognized, such that differences in metallicity may dominate over differences in T
eff when considering relative properties of cool objects using these colours. Secondly, the previously noted apparent dominance of young objects in the late-T dwarf sample is no longer apparent when using the new model grids and the expanded sample of late-T dwarfs and benchmarks. This is supported by the apparently similar distribution of late-T dwarfs and earlier type T dwarfs on reduced proper motion diagrams that we present. Finally, we present updated space densities for the late-T dwarfs, and compare our values to simulation predictions and those from WISE.
The putative virulence and antimicrobial resistance gene contents of extended spectrum β-lactamase (ESBL)-positive E. coli (n=629) isolated between 2005 and 2009 from humans, animals and animal food ...products in Germany, The Netherlands and the UK were compared using a microarray approach to test the suitability of this approach with regard to determining their similarities. A selection of isolates (n=313) were also analysed by multilocus sequence typing (MLST). Isolates harbouring bla(CTX-M-group-1) dominated (66%, n=418) and originated from both animals and cases of human infections in all three countries; 23% (n=144) of all isolates contained both bla(CTX-M-group-1) and bla(OXA-1-like) genes, predominantly from humans (n=127) and UK cattle (n=15). The antimicrobial resistance and virulence gene profiles of this collection of isolates were highly diverse. A substantial number of human isolates (32%, n=87) did not share more than 40% similarity (based on the Jaccard coefficient) with animal isolates. A further 43% of human isolates from the three countries (n=117) were at least 40% similar to each other and to five isolates from UK cattle and one each from Dutch chicken meat and a German dog; the members of this group usually harboured genes such as mph(A), mrx, aac(6')-Ib, catB3, bla(OXA-1-like) and bla(CTX-M-group-1). forty-four per cent of the MLST-typed isolates in this group belonged to ST131 (n=18) and 22% to ST405 (n=9), all from humans. Among animal isolates subjected to MLST (n=258), only 1.2% (n=3) were more than 70% similar to human isolates in gene profiles and shared the same MLST clonal complex with the corresponding human isolates. The results suggest that minimising human-to-human transmission is essential to control the spread of ESBL-positive E. coli in humans.
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