The phosphorylated neurofilament heavy subunit (pNF-H), a major structural component of motor axons, is a promising putative biomarker in amyotrophic lateral sclerosis (ALS) but has been studied ...mainly in CSF. We examined pNF-H concentrations in plasma, serum and CSF as a potential biomarker for disease progression and survival in ALS.
We measured pNF-H concentration by monoclonal sandwich ELISA in plasma (n=43), serum and CSF (n=20) in ALS patients collected at the Mayo Clinic Florida and Emory University. We included plasma from an ALS cohort (n=20) from an earlier pilot study in order to evaluate baseline pNF-H levels in relation to disease progression using the Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R), survival and anatomical region of ALS onset.
Higher pNF-H levels in plasma, serum and CSF showed evidence of association with faster decline in ALSFRS-R. There was evidence for a relationship of higher serum and plasma pNF-H levels with shorter survival, although evidence was weaker for CSF. pNF-H concentration in plasma (n=62) may be higher in patients with bulbar onset than in patients with spinal onset.
In ALS, increased pNF-H concentration in plasma, serum and CSF appears to be associated with faster disease progression. Factors affecting pNF-H levels or their detection in serum and plasma in relation to disease course may differ from those in CSF. Data raising the possibility that site of ALS onset (bulbar vs spinal) may influence pNF-H levels in peripheral blood seems noteworthy but requires confirmation. These data support further study of pNF-H in CSF, serum and plasma as a potential ALS biomarker.
We report the detection of pulsed gamma-ray emission from the fast millisecond pulsars (MSPs) B1937+21 (also known as J1939+2134) and B1957+20 (J1959+2048) using 18 months of survey data recorded by ...the Fermi Large Area Telescope and timing solutions based on radio observations conducted at the Westerbork and Nancay radio telescopes. In addition, we analyzed archival Rossi X-ray Timing Explorer and XMM-Newton X-ray data for the two MSPs, confirming the X-ray emission properties of PSR B1937+21 and finding evidence (~4 Delta *s) for pulsed emission from PSR B1957+20 for the first time. In both cases the gamma-ray emission profile is characterized by two peaks separated by half a rotation and are in close alignment with components observed in radio and X-rays. These two pulsars join PSRs J0034--0534 and J2214+3000 to form an emerging class of gamma-ray MSPs with phase-aligned peaks in different energy bands. The modeling of the radio and gamma-ray emission profiles suggests co-located emission regions in the outer magnetosphere.
ABSTRACT
We use spatially resolved spectroscopy of a distant giant gravitational arc to test orientation effects on Mg ii absorption equivalent width (EW) and covering fraction (〈κ〉) in the ...circumgalactic medium of a foreground star-forming galaxy (G1) at z ∼ 0.77. Forty-two spatially-binned arc positions uniformly sample impact parameters (D) to G1 between 10 and 30 kpc and azimuthal angles α between 30° and 90° (minor axis). We find an EW-D anticorrelation, akin to that observed statistically in quasar absorber studies, and an apparent correlation of both EW and 〈κ〉 with α, revealing a non-isotropic gas distribution. In line with our previous results on Mg ii kinematics suggesting the presence of outflows in G1, at minimum a simple 3D static double-cone model (to represent the trace of bipolar outflows) is required to recreate the EW spatial distribution. The D and α values probed by the arc cannot confirm the presence of a disc, but the data highly disfavour a disc alone. Our results support the interpretation that the EW-α correlation observed statistically using other extant probes is partly shaped by bipolar metal-rich winds.
Summary
Negative emotional outcomes (anxiety, depression and post‐traumatic stress) have been identified in patients discharged from intensive care. The aims of this prospective, longitudinal study ...were to assess levels of and changes in emotional outcome after intensive care, and to explore how these relate to objective and subjective indicators of the intensive care experience. Emotional outcome was assessed using the Hospital Anxiety and Depression and Impact of Event Scales. Anxiety (p = 0.046) and depression (p = 0.001) were reduced subsequently, but not avoidance (p = 0.340) or intrusion (p = 0.419). Most objective (age, gender, length of ICU and hospital stay) and subjective indicators (as measured by the Intensive Care Experience Questionnaire) of the intensive care experience were related to negative emotional outcome. Subjective interpretation of the intensive care experience emerged as a consistent predictor of adverse emotional outcome, in both the short‐ and the long‐term.
ABSTRACT
We present gravitational-arc tomography of the cool-warm enriched circumgalactic medium (CGM) of an isolated galaxy (‘G1’) at z ≈ 0.77. Combining VLT/MUSE adaptive-optics and Magellan/MagE ...echelle spectroscopy, we obtain partially resolved kinematics of Mg ii in absorption and O ii in emission. The unique arc configuration allows us to probe 42 spatially independent arc positions transverse to G1, plus four positions in front of it. The transverse positions cover G1’s minor and major axes at impact parameters of ≈10–30 and ≈60 kpc, respectively. We observe a direct kinematic connection between the cool-warm enriched CGM (traced by Mg ii) and the interstellar medium (traced by O ii). This provides strong evidence for the existence of an extended disc that co-rotates with the galaxy out to tens of kiloparsecs. The Mg ii velocity dispersion (σ ≈ 30–100 km s−1, depending on position) is of the same order as the modelled galaxy rotational velocity (vrot ≈ 80 km s−1), providing evidence for the presence of a turbulent and pressure-supported CGM component. We regard the absorption to be modulated by a galactic-scale outflow, as it offers a natural scenario for the observed line-of-sight dispersion and asymmetric profiles observed against both the arcs and the galaxy. An extended enriched co-rotating disc together with the signatures of a galactic outflow, are telltale signs of metal recycling in the z ∼ 1 CGM.
Background and purpose: Antidepressants, which raise the CNS concentrations of 5‐HT and noradrenaline, are frequently used in the treatment of chronic pain; however, it is not known if increasing ...CNS noradrenaline levels alone is sufficient for efficacy, in part resulting from a lack of small molecules with sufficient selectivity.
Experimental approach: In this report, we present the in vitro pharmacological and in vivo pharmacokinetic and pharmacological properties of the novel, orally available and CNS penetrant inhibitor of the noradrenaline transporter (NET), WAY‐318068 (1‐(1S,2R)‐1‐(3,5‐difluorophenyl)‐2‐hydroxy‐3‐(methylamino)propyl‐7‐fluoro‐3,3‐dimethyl‐1,3‐dihydro‐2H‐indol‐2‐one).
Key results: WAY‐318068 is a potent and effective inhibitor of the NET with a Ki of 8.7 nM in a binding assay, and an IC50 of 6.8 nM in an assay of transporter function, without significant binding to the dopamine transporter. Furthermore, the compound has only weak activity at the 5‐HT transporter, leading to a functional selectivity of greater than 2500‐fold. It is orally bioavailable with substantial quantities of the compound found in the CNS after oral dosing. As measured by microdialysis in rats, the compound causes a robust and significant increase in cortical noradrenaline levels without affecting 5‐HT. WAY‐318068 was effective in models of acute, visceral, inflammatory, osteoarthritic, neuropathic, diabetic and bone cancer pain, as well as in traditional models of depression at doses that do not cause motor deficits.
Conclusions and implications: Collectively, the present results support the conclusion that selectively increasing CNS levels of noradrenaline is sufficient for efficacy in models of depression and pain.
Although auditory verbal hallucinations are often thought to denote mental illness, the majority of voice hearers do not satisfy the criteria for a psychiatric disorder. Here, we report the first ...functional imaging study of such nonclinical hallucinations in 7 healthy voice hearers comparing them with auditory imagery. The human voice area in the superior temporal sulcus was activated during both hallucinations and imagery. Other brain areas supporting both hallucinations and imagery included fronto temporal language areas in the left hemisphere and their contralateral homologues and the supplementary motor area (SMA). Hallucinations are critically distinguished from imagery by lack of voluntary control. We expected this difference to be reflected in the relative timing of prefrontal and sensory areas. Activity of the SMA indeed preceded that of auditory areas during imagery, whereas during hallucinations, the 2 processes occurred instantaneously. Voluntary control was thus represented in the relative timing of prefrontal and sensory activation, whereas the sense of reality of the sensory experience may be a product of the voice area activation. Our results reveal mechanisms of the generation of sensory experience in the absence of external stimulation and suggest new approaches to the investigation of the neurobiology of psychopathology.
Here, we present precise phase-connected pulse timing solutions for 16 γ-ray-selected pulsars recently discovered using the Large Area Telescope (LAT) on the Fermi Gamma-ray Space Telescope plus one ...very faint radio pulsar (PSR J1124–5916) that is more effectively timed with the LAT. We describe the analysis techniques including a maximum likelihood method for determining pulse times of arrival from unbinned photon data. A major result of this work is improved position determinations, which are crucial for multiwavelength follow-up. For most of the pulsars, we overlay the timing localizations on X-ray images from Swift and describe the status of X-ray counterpart associations. We report glitches measured in PSRs J0007+7303, J1124–5916, and J1813–1246. We analyze a new 20 ks Chandra ACIS observation of PSR J0633+0632 that reveals an arcminute-scale X-ray nebula extending to the south of the pulsar. We were also able to precisely localize the X-ray point source counterpart to the pulsar and find a spectrum that can be described by an absorbed blackbody or neutron star atmosphere with a hard power-law component. Another Chandra ACIS image of PSR J1732–3131 reveals a faint X-ray point source at a location consistent with the timing position of the pulsar. Finally, we present a compilation of new and archival searches for radio pulsations from each of the γ-ray-selected pulsars as well as a new Parkes radio observation of PSR J1124–5916 to establish the γ-ray to radio phase offset.
Chronic lymphocytic leukaemia (CLL) patients have an increased risk of other malignancies. This may be due to surveillance bias, treatment or immunosuppression.
Cohort study of 612 consecutively ...diagnosed CLL patients in a Canadian province, with comparisons to follicular lymphoma (FL) patients.
Treated CLL patients had a 1.7-fold increased risk of second cancers compared with untreated CLL patients. As compared with untreated FL patients, untreated CLL patients had a two-fold increased incidence of second malignancies.
Chronic lymphocytic leukaemia patients have an inherent predisposition to second cancers and the incidence is further increased by treatment.
Background
The number of surgeons entering fellowship training before independent practice is increasing. This may have a negative impact on surgeons in training. The impact of fellowship training on ...patient outcomes is not yet known. This review aimed to investigate the impact of fellowship training in surgery on patient outcomes.
Methods
A systematic review of the literature was conducted to identify studies exploring the structural and surgeon‐specific characteristics of fellowship training on patient outcomes. Data from these studies were extracted, synthesized and reported qualitatively, or quantitatively through meta‐analysis.
Results
Twenty‐three studies were included. The mortality rate for patients in centres with an affiliated fellowship programme was lower than that for centres without (odds ratio 0·86, 95 per cent c.i. 0·84 to 0·88), as was the rate of complications (odds ratio 0·90, 0·78 to 1·02). Surgeons without fellowship training converted more laparoscopic operations to open surgery than those with fellowship training (risk ratio (RR) 1·04, 95 per cent c.i. 1·03 to 1·05). Comparison of outcomes for senior surgeons versus current fellows showed no differences in rates of mortality (RR 1·00, 1·00 to 1·01), complications (RR 1·03, 0·98 to 1·08) or conversion to open surgery (RR 1·01, 1·00 to 1·01).
Conclusion
Fellowship training appears to have a positive impact on patient outcomes.
Fellowship training improves outcomes
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