Development of Prognosis in Palliative care Study (PiPS) predictor models to improve prognostication in advanced cancer: prospective cohort study

OBJECTIVE: To develop a novel prognostic indicator for use in patients with advanced cancer that is significantly better than clinicians' estimates of survival. DESIGN: Prospective multicentre observational cohort study. SETTING: 18 palliative care services in the UK (including hospices, hospital support teams, and community teams). PARTICIPANTS: 1018 patients with locally advanced or metastatic cancer, no longer being treated for cancer, and recently referred to palliative care services. MAIN OUTCOME MEASURES: Performance of a composite model to predict whether patients were likely to survive for "days" (0-13 days), "weeks" (14-55 days), or "months+" (>55 days), compared with actual survival and clinicians' predictions. RESULTS: On multivariate analysis, 11 core variables (pulse rate, general health status, mental test score, performance status, presence of anorexia, presence of any site of metastatic disease, presence of liver metastases, C reactive protein, white blood count, platelet count, and urea) independently predicted both two week and two month survival. Four variables had prognostic significance only for two week survival (dyspnoea, dysphagia, bone metastases, and alanine transaminase), and eight variables had prognostic significance only for two month survival (primary breast cancer, male genital cancer, tiredness, loss of weight, lymphocyte count, neutrophil count, alkaline phosphatase, and albumin). Separate prognostic models were created for patients without (PiPS-A) or with (PiPS-B) blood results. The area under the curve for all models varied between 0.79 and 0.86. Absolute agreement between actual survival and PiPS predictions was 57.3% (after correction for over-optimism). The median survival across the PiPS-A categories was 5, 33, and 92 days and survival across PiPS-B categories was 7, 32, and 100.5 days. All models performed as well as, or better than, clinicians' estimates of survival. CONCLUSIONS: In patients with advanced cancer no longer being treated, a combination of clinical and laboratory variables can reliably predict two week and two month survival

Type 2 solar radio events observed in the interplanetary medium. Part 1: General characteristics

Twelve type 2 solar radio events were observed in the 2 MHz to 30 kHz frequency range by the radio astronomy experiment on the ISEE-3 satellite over the period from September 1978 to December 1979. These data provide the most comprehensive sample of type 2 radio bursts observed at kilometer wavelengths. Dynamic spectra of a number of events are presented. Where possible, the 12 events were associated with an initiating flare, ground based radio data, the passage of a shock at the spacecraft, and the sudden commencement of a geomagnetic storm. The general characteristics of kilometric type 2 bursts are discussed

Recurrent cerebellar architecture solves the motor-error problem

Current views of cerebellar function have been heavily influenced by the models of Marr and Albus, who suggested that the climbing fibre input to the cerebellum acts as a teaching signal for motor learning. It is commonly assumed that this teaching signal must be motor error (the difference between actual and correct motor command), but this approach requires complex neural structures to estimate unobservable motor error from its observed sensory consequences. We have proposed elsewhere a recurrent decorrelation control architecture in which Marr-Albus models learn without requiring motor error. Here, we prove convergence for this architecture and demonstrate important advantages for the modular control of systems with multiple degrees of freedom. These results are illustrated by modelling adaptive plant compensation for the three-dimensional vestibular ocular reflex. This provides a functional role for recurrent cerebellar connectivity, which may be a generic anatomical feature of projections between regions of cerebral and cerebellar cortex

Photovoltaic Current Response of Mesoscopic Conductors to Quantized Cavity Modes

We extend the analysis of the effects of electromagnetic (EM) fields on mesoscopic conductors to include the effects of field quantization, motivated by recent experiments on circuit QED. We show that in general there is a photovoltaic (PV) current induced by quantized cavity modes at zero bias across the conductor. This current depends on the average photon occupation number and vanishes identically when it is equal to the average number of thermal electron-hole pairs. We analyze in detail the case of a chaotic quantum dot at temperature T_e in contact with a thermal EM field at temperature T_f, calculating the RMS size of the PV current as a function of the temperature difference, finding an effect ~pA.Comment: 4 pages, 2 figure

Radial Velocity along the Voyager 1 Trajectory: The Effect of Solar Cycle

As Voyager 1 and Voyager 2 are approaching the heliopause (HP)—the boundary between the solar wind (SW) and the local interstellar medium (LISM)—we expect new, unknown features of the heliospheric interface to be revealed. A seeming puzzle reported recently by Krimigis et al. concerns the unusually low, even negative, radial velocity components derived from the energetic ion distribution. Steady-state plasma models of the inner heliosheath (IHS) show that the radial velocity should not be equal to zero even at the surface of the HP. Here we demonstrate that the velocity distributions observed by Voyager 1 are consistent with time-dependent simulations of the SW-LISM interaction. In this Letter, we analyze the results from a numerical model of the large-scale heliosphere that includes solar cycle effects. Our simulations show that prolonged periods of low to negative radial velocity can exist in the IHS at substantial distances from the HP. It is also shown that Voyager 1 was more likely to observe such regions than Voyager 2

Andreev reflection eigenvalue density in mesoscopic conductors

The energy-dependent Andreev reflection eigenvalues determine the transport properties of normal-superconducting systems. We evaluate the eigenvalue density to get an insight into formation of resonant electron-hole transport channels. The circuit-theory-like method developed can be applied to any generic mesoscopic conductor or combinations thereof. We present the results for experimentally relevant cases of a diffusive wire and a double tunnel junction.Comment: 5 pages, 3 figure

Conductance of a Mott Quantum Wire

We consider transport through a one-dimensional conductor subject to an external periodic potential and connected to non-interacting leads (a "Mott quantum wire"). For the case of a strong periodic potential, the conductance is shown to jump from zero, for the chemical potential lying within the Mott-Hubbard gap, to the non-interacting value of 2e^2/h, as soon as the chemical potential crosses the gap edge. This behavior is strikingly different from that of an optical conductivity, which varies continuously with the carrier concentration. For the case of a weak potential, the perturbative correction to the conductance due to Umklapp scattering is absent away from half-filling.Comment: 4 pages, RevTex, 1 ps figure included; published versio

Quantum chaos in a deformable billiard: Applications to quantum dots

We perform a detailed numerical study of energy-level and wavefunction statistics of a deformable quantum billiard focusing on properties relevant to semiconductor quantum dots. We consider the family of Robnik billiards generated by simple conformal maps of the unit disk; the shape of this family of billiards may be varied continuously at fixed area by tuning the parameters of the map. The classical dynamics of these billiards is well-understood and this allows us to study the quantum properties of subfamilies which span the transition from integrability to chaos as well as families at approximately constant degree of chaoticity (Kolmogorov entropy). In the regime of hard chaos we find that the statistical properties of interest are well-described by random-matrix theory and completely insensitive to the particular shape of the dot. However in the nearly-integrable regime non-universal behavior is found. Specifically, the level-width distribution is well-described by the predicted $\chi^2$ distribution both in the presence and absence of magnetic flux when the system is fully chaotic; however it departs substantially from this behavior in the mixed regime. The chaotic behavior corroborates the previously predicted behavior of the peak-height distribution for deformed quantum dots. We also investigate the energy-level correlation functions which are found to agree well with the behavior calculated for quasi-zero-dimensional disordered systems.Comment: 25 pages (revtex 3.0). 16 figures are available by mail or fax upon request at [email protected]

Mu‐opioid antagonists for opioid‐induced bowel dysfunction in people with cancer and people receiving palliative care

BACKGROUND: Opioid-induced bowel dysfunction (OIBD) is characterised by constipation, incomplete evacuation, bloating, and gastric reflux. It is one of the major adverse events of treatment for pain in cancer and in palliative care, resulting in increased morbidity and reduced quality of life. This is an update of two Cochrane reviews. One was published in 2011, Issue 1 on laxatives and methylnaltrexone for the management of constipation in people receiving palliative care; this was updated in 2015 and excluded methylnaltrexone. The other was published in 2008, Issue 4 on mu-opioid antagonists (MOA) for OIBD. In this updated review, we only included trials on MOA (including methylnaltrexone) for OIBD in people with cancer and people receiving palliative care. OBJECTIVES: To assess the effectiveness and safety of MOA for OIBD in people with cancer and people receiving palliative care. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials, MEDLINE, Embase, CINAHL, and Web of Science to August 2017. We also searched clinical trial registries and regulatory websites. We contacted manufacturers of MOA to identify further data. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that assessed the effectiveness and safety of MOA for OIBD in people with cancer and people at a palliative stage irrespective of the type of terminal disease they experienced. DATA COLLECTION AND ANALYSIS: Two review authors assessed risk of bias and extracted data. The appropriateness of combining data from the trials depended upon sufficient homogeneity across the trials. Our primary outcomes were laxation, impact on pain relief, and adverse events. Impact on pain relief was a primary outcome because a possible adverse effect of MOAs is a reduction in pain relief from opioids. We assessed the evidence on these outcomes using GRADE. MAIN RESULTS: We identified four new trials for this update, bringing the total number included in this review to eight. In total, 1022 men and women with cancer irrespective of stage or at a palliative care stage of any disease were randomised across the trials. The MOAs evaluated were oral naldemedine and naloxone (alone or in combination with oxycodone), and subcutaneous methylnaltrexone. The trials compared with MOA with a placebo or with the active intervention administered at different doses or in combination with other drugs. The trial of naldemedine and the two of naloxone in combination with oxycodone were in people with cancer irrespective of disease stage. The trial on naloxone alone was in people with advanced cancer. The four trials on methylnaltrexone were undertaken in palliative care where most participants had cancer. All trials were vulnerable to biases; four were at a high risk as they involved a sample of fewer than 50 participants per arm. In the trial of naldemedine compared to placebo in 225 participants, there were more spontaneous laxations over the two-week treatment for the intervention group (risk ratio (RR) 1.93, 95% confidence intervals (CI) 1.36 to 2.74; moderate-quality evidence). In comparison with higher doses, lower doses resulted in fewer spontaneous laxations (0.1 mg versus 0.2 mg: RR 0.73, 95% CI 0.55 to 0.95; 0.1 mg versus 0.4 mg: RR 0.69, 95% CI 0.53 to 0.89; moderate-quality evidence). There was moderate-quality evidence that naldemedine had no effect on opiate withdrawal. There were five serious adverse events. All were in people taking naldemedine (low-quality evidence). There was an increase in the occurrence of other (non-serious) adverse events in the naldemedine groups (RR 1.36, 95% CI 1.04 to 1.79, moderate-quality evidence). The most common adverse event was diarrhoea. The trials on naloxone taken either on its own, or in combination with oxycodone (an opioid) compared to oxycodone only did not evaluate laxation response over the first two weeks of administration. There was very low-quality evidence that naloxone alone, and moderate-quality evidence that oxycodone/naloxone, had no effect on analgesia. There was low-quality evidence that oxycodone/naloxone did not increase the risk of serious adverse events and moderate-quality evidence that it did not increase risk of adverse events. In combined analysis of two trials of 287 participants, we found methylnaltrexone compared to placebo induced more laxations within 24 hours (RR 2.77, 95% CI 1.91 to 4.04. I² = 0%; moderate-quality evidence). In combined analysis, we found methylnaltrexone induced more laxation responses over two weeks (RR 9.98, 95% CI 4.96 to 20.09. I² = 0%; moderate-quality evidence). The proportion of participants who had a rescue-free laxation response within 24 hours of the first dose was 59.1% in the methylnaltrexone arms and 19.1% in the placebo arm. There was moderate-quality evidence that the rate of opioid withdrawal was not affected. Methylnaltrexone did not increase the likelihood of a serious adverse event; there were fewer in the intervention arm (RR 0.59, 95% CI 0.38 to 0.93; I² = 0%; moderate-quality evidence). There was no difference in the proportion of participants experiencing an adverse event (RR 1.17, 95% CI 0.94 to 1.45; I² = 74%; low-quality evidence). Methylnaltrexone increased the likelihood of abdominal pain and flatulence. Two trials compared differing methylnaltrexone schedules of higher doses with lower doses. For early laxation, there was low-quality evidence of no clear difference between doses on analgesia and adverse events. Both trials measured laxation response within 24 hours of first dose (trial one: RR 0.82, 95% CI 0.41 to 1.66; trial two: RR 1.07, 95% CI 0.81 to 1.42). AUTHOR'S CONCLUSIONS: In this update, the conclusions for naldemedine are new. There is moderate-quality evidence to suggest that, taken orally, naldemedine improves bowel function over two weeks in people with cancer and OIBD but increases the risk of adverse events. The conclusions on naloxone and methylnaltrexone have not changed. The trials on naloxone did not assess laxation at 24 hours or over two weeks. There is moderate-quality evidence that methylnaltrexone improves bowel function in people receiving palliative care in the short term and over two weeks, and low-quality evidence that it does not increase adverse events. There is a need for more trials including more evaluation of adverse events. None of the current trials evaluated effects in children

Formation of a "Cluster Molecule" (C20)2 and its thermal stability

The possible formation of a "cluster molecule" (C20)2 from two single C20 fullerenes is studied by the tight-binding method. Several (C20)2 isomers in which C20 fullerenes are bound by strong covalent forces and retain their identity are found; actually, these C20 fullerenes play the role of "atoms" in the "cluster molecule". The so-called open-[2+2] isomer has a minimum energy. Its formation path and thermal stability at T = 2000 - 4000 K are analyzed in detail. This isomer loses its molecular structure due to either the decay of one of C20 fullerenes or the coalescence of two C20 fullerenes into a C40 cluster. The energy barriers for the metastable open-[2+2] configuration are calculated to be U = 2 - 5 eV.Comment: 21 pages, 8 figure