197 Influence of inhalation mode on aerosol lung deposition in patients with cystic fibrosis PART 1: Pharmacokinetic data as representative of lung deposition

Objectives: To investigate the impact of two different inhalation flow maneuvers (TIM = slow and deep inhalation and TBM = normal tidal breathing) on aerosol lung deposition in patients with CF using pharmacokinetic parameters as a representation of lung deposition. Methods: Randomized, open-label, cross-over study. The study group consisted of 18 adult patients with a confirmed diagnosis of CF (genetic analysis). Each patient inhaled a tobramycin solution twice during separate study visits: once in TIM and the other time in TBM mode. Blood samples were collected in order to model tobramycin pharmacokinetics. Outcome measurements: Relative bioavailability (Frel) of tobramycin is defined as the ratio of AUCTIM to AUCTBM, in which the AUC represents the plasma concentration area under the curves. A ratio greater than 1 indicates higher lung deposition for TIM compared to TBM. Individual pharmacokinetic parameters were calculated and assimilated with patient tobramycin serum values using a computerized CF-based Bayesian population model (MW-Pharm, Mediware). Results: Frel was 1 or greater for all patients (mean = 1.55, sd = 0.39, 95%CI = 1.37-1.73). In addition, mean Frel was significant higher than the value of 1 (mean difference = 0.55,

Implications from Late-Time X-ray Detections of Optically Selected Tidal Disruption Events: State Changes, Unification, and Detection Rates

We present Chandra X-ray observations of four optically-selected tidal disruption events (TDEs) obtained 4-9 years after discovery. Three sources were detected with luminosities between 9X10^40 and 3X10^42 erg/s. The spectrum of PTF09axc is consistent with a power law of index 2.5+-0.1, whereas the spectrum of PTF09ge is very soft. The power law spectrum of PTF09axc and prior literature findings, provide evidence that TDEs transition from an early-time soft state to a late-time hard state many years after disruption. We propose that the time to peak luminosity for optical and X-ray emission may differ substantially in TDEs, with X-rays being produced or becoming observable later. This delay helps explain the differences in observed properties such as L_opt/L_ X of optically and X-ray selected TDEs. We update TDE rate predictions for the eROSITA instrument: it ranges from 3 per yr to 990 per yr, depending sensitively on the distribution of black hole spins and the time delay between disruption and peak X-ray brightness. We further predict an asymmetry in the number of retrograde and prograde disks in samples of optically and X-ray selected TDEs. The details of the observational biases can contribute to observed differences between optically and X-ray selected TDEs (with optically selected TDEs being fainter in X-rays for retrograde TDE disks).Comment: Accepted for publication to ApJ, 18 pages, 4 figure

Outcomes of patients with perforated colon cancer:A systematic review

Introduction: Perforated colon cancer (PCC) is a distinct clinical entity with implications for treatment and prognosis, however data on PCC seems scarce. The aim of this systematic review is to provide a comprehensive overview of the recent literature on clinical outcomes of PCC. Materials and methods: A systematic literature search of MEDLINE (PubMed), Embase, Cochrane library and Google scholar was performed. Studies describing intentionally curative treatment for patients with PCC since 2010 were included. The main outcome measures consisted of short-term surgical complications and long-term oncological outcomes. Results: Eleven retrospective cohort studies were included, comprising a total of 2696 PCC patients. In these studies, various entities of PCC were defined. Comparative studies showed that PCC patients as compared to non-PCC patients have an increased risk of 30-day mortality (8–33% vs 3–5%), increased post-operative complications (33–56% vs 22–28%), worse overall survival (36–40% vs 48–65%) and worse disease-free survival (34–43% vs 50–73%). Two studies distinguished free-perforations from contained perforations, revealing that free-perforation is associated with significantly higher 30-day mortality (19–26% vs 0–10%), lower overall survival (24–28% vs 42–64%) and lower disease-free survival (15% vs 53%) as compared to contained perforations. Conclusion: Data on PCC is scarce, with various PCC entities defined in the studies included. Heterogeneity of the study population, definition of PCC and outcome measures made pooling of the data impossible. In general, perforation, particularly free perforation, seems to be associated with a substantial negative effect on outcomes in colon cancer patients undergoing surgery. Better definition and description of the types of perforation in future studies is essential, as outcomes seem to differ between types of PCC and might require different treatment strategies.</p

WS14.5 Influence of breathing pattern on pulmonary aerosol deposition in patients with cystic fibrosis (CF): a pharmacokinetic approach

The therapeutic effect of inhaled antibiotics on lung infection in CF patients is dependent on the aerosol deposition achieved in the lungs. Objectives: To evaluate the influence of two breathing patterns on pulmonary aerosol deposition using pharmacokinetic parameters as surrogate for deposition. Methods: In a randomized, open-label, crossover study pulmonary deposition in 18 adult CF patients is evaluated following inhalation of tobramycin aerosol using the I-neb nebulizer with TBM (Tidal Breathing Mode) and TIM (Target Inhalation Mode) breathing patterns. Breathing in TIM forced the patient to inhale in a slow and deep manner. According to their lung function, patients were categorized in subgroup 1, 2 or 3 corresponding to FEV1 predicted ≤59%, 60-79% or ≥80%. Blood samples were collected in order to model tobramycin pharmacokinetics. Results: Mean Cmax and AUC0-24hr were significantly increased for TIM compared to TBM. Inhalation in TIM also resulted in higher mean Cmax and AUC0-24hr for each subgroup. Mean bioavailability of TIM relative to TBM breathing pattern (Frel) was 1.53±0.41 and mean Frel in each subgroup was also significantly higher than 1. Subgroup category did not affect the results. Conclusion: Slow and deep inhalation of aerosolized tobramycin with the I-neb nebulizer resulted in an estimated 53% higher lung deposition compared to tidal breathing. This result was independent from lung function category, which suggests that regardless the disease state, slow and deep inhalation always results in higher pulmonary aerosol deposition compared to tidal breathing

Facilitating return to work through early specialist health-based interventions (FRESH): protocol for a feasibility randomised controlled trial

Background Over one million people sustain traumatic brain injury each year in the UK and more than 10 % of these are moderate or severe injuries, resulting in cognitive and psychological problems that affect the ability to work. Returning to work is a primary rehabilitation goal but fewer than half of traumatic brain injury survivors achieve this. Work is a recognised health service outcome, yet UK service provision varies widely and there is little robust evidence to inform rehabilitation practice. A single-centre cohort comparison suggested better work outcomes may be achieved through early occupational therapy targeted at job retention. This study aims to determine whether this intervention can be delivered in three new trauma centres and to conduct a feasibility, randomised controlled trial to determine whether its effects and cost effectiveness can be measured to inform a definitive trial. Methods/design Mixed methods study, including feasibility randomised controlled trial, embedded qualitative studies and feasibility economic evaluation will recruit 102 people with traumatic brain injury and their nominated carers from three English UK National Health Service (NHS) trauma centres. Participants will be randomised to receive either usual NHS rehabilitation or usual rehabilitation plus early specialist traumatic brain injury vocational rehabilitation delivered by an occupational therapist. The primary objective is to assess the feasibility of conducting a definitive trial; secondary objectives include measurement of protocol integrity (inclusion/exclusion criteria, intervention adherence, reasons for non-adherence) recruitment rate, the proportion of eligible patients recruited, reasons for non-recruitment, spectrum of TBI severity, proportion of and reasons for loss to follow-up, completeness of data collection, gains in face-to-face Vs postal data collection and the most appropriate methods of measuring primary outcomes (return to work, retention) to determine the sample size for a larger trial. Discussion To our knowledge, this is the first feasibility randomised controlled trial of a vocational rehabilitation health intervention specific to traumatic brain injury. The results will inform the design of a definitive trial

Generalized Boltzmann Equation for Lattice Gas Automata

In this paper, for the first time a theory is formulated that predicts velocity and spatial correlations between occupation numbers that occur in lattice gas automata violating semi-detailed balance. Starting from a coupled BBGKY hierarchy for the $n$-particle distribution functions, cluster expansion techniques are used to derive approximate kinetic equations. In zeroth approximation the standard nonlinear Boltzmann equation is obtained; the next approximation yields the ring kinetic equation, similar to that for hard sphere systems, describing the time evolution of pair correlations. As a quantitative test we calculate equal time correlation functions in equilibrium for two models that violate semi-detailed balance. One is a model of interacting random walkers on a line, the other one is a two-dimensional fluid type model on a triangular lattice. The numerical predictions agree very well with computer simulations.Comment: 31 pages LaTeX, 12 uuencoded tar-compressed Encapsulated PostScript figures (`psfig' macro), hardcopies available on request, 78kb + 52k

Cytokines and chemokines are detectable in swivel-derived exhaled breath condensate (SEBC): A pilot study in mechanically ventilated patients

Introduction. Exhaled breath condensate (EBC) is a noninvasive method to collect samples from the respiratory tract. Usually, a thermoelectric cooling module is required to collect sufficient EBC volume for analyses. In here, we assessed the feasibility of cytokine and chemokine detection in EBC collected directly from the ventilator circuit without the use of a cooling module: swivel-derived exhaled breath condensate (SEBC). Methods. SEBC was prospectively collected from the swivel adapter and stored at -80°C. The objective of this study was to detect cytokines and chemokines in SEBC with a multiplex immunoassay. Secondary outcomes were to assess the correlation between cytokine and chemokine concentrations in SEBC and mechanical ventilation parameters, systemic inflammation parameters, and hemodynamic parameters. Results. Twenty-nine SEBC samples were obtained from 13 ICU patients. IL-1β, IL-4, IL-8, and IL-17 were detected in more than 90% of SEBC samples, and significant correlations between multiple cytokines and chemokines were found. Several significant correlations were found between cytokines and chemokines in SEBC and mechanical ventilation parameters and serum lactate concentrations. Conclusion. This pilot study showed that it is feasible to detect cytokines and chemokines in SEBC samples obtained without a cooling module. Despite small sample size, correlations were found between cytokines and chemokines in SEBC and mechanical ventilation parameters, as well as serum lactate concentrations. This simple SEBC collection method provides the opportunity to collect EBC samples in large prospective ICU cohorts