Novel methodology to perform sulfur hexafluoride (SF6)-based multiple-breath wash-in and washout in infants using current commercially available equipment.

Multiple-breath inert gas washout (MBW) is ideally suited for early detection and monitoring of serious lung disease, such as cystic fibrosis, in infants and young children. Validated commercial options for the MBW technique are limited, and suitability of nitrogen (N2)-based MBW is of concern given the detrimental effect of exposure to pure O2 on infant breathing pattern. We propose novel methodology using commercially available N2 MBW equipment to facilitate 4% sulfur hexafluoride (SF6) multiple-breath inert gas wash-in and washout suitable for the infant age range. CO2, O2, and sidestream molar mass sensor signals were used to accurately calculate SF6 concentrations. An improved dynamic method for synchronization of gas and respiratory flow was developed to take into account variations in sidestream sample flow during MBW measurement. In vitro validation of triplicate functional residual capacity (FRC) assessments was undertaken under dry ambient conditions using lung models ranging from 90 to 267 ml, with tidal volumes of 28-79 ml, and respiratory rates 20-60 per minute. The relative mean (SD, 95% confidence interval) error of triplicate FRC determinations by washout was -0.26 (1.84, -3.86 to +3.35)% and by wash-in was 0.57 (2.66, -4.66 to +5.79)%. The standard deviations [mean (SD)] of percentage error among FRC triplicates were 1.40 (1.14) and 1.38 (1.32) for washout and wash-in, respectively. The novel methodology presented achieved FRC accuracy as outlined by current MBW consensus recommendations (95% of measurements within 5% accuracy). Further clinical evaluation is required, but this new technique, using existing commercially available equipment, has exciting potential for research and clinical use.

Genotyping of Pseudomonas aeruginosa reveals high diversity, stability over time and good outcome of eradication.

BACKGROUND: Genotyping of Pseudomonas aeruginosa (P.a) is used for surveillance at our CF clinic. METHODS: P.a from 1999 to 2012 were analysed, using pulsed-field gel electrophoresis (PFGE) and multiple-locus variable number of tandem repeats analysis (MLVA). RESULTS: Among 232 isolates from 104 patients, we identified 78 unique strains, of which 56 were isolated from individual patients. The B-clone was isolated from 13 patients and the camp transmission clone J-strains from 8 patients at the start of the study. There was no indication of transmission within the clinic. PFGE and MLVA clone identification was in 91% agreement. For patients who provided more than 2 P.a isolates, similar strains were identified over time for 45/49 chronically- and for 6/16 intermittently-colonized patients despite, periods of no detectable P.a after eradication therapy. CONCLUSIONS: Analyses revealed high genotypic diversity, acceptable outcome of eradication therapy and no indication of cross-infection at the CF centre.

Suppression of the molecular ultra-fast dissociation in bromomethane clusters.

We address the influence of clustering on the ultra-fast dissociation of bromomethane. Valence and core photo-electron spectroscopy, partial electron yield absorption, and resonant Auger spectroscopy have been used together with ab initio calculations to investigate the properties of the ultra-fast dissociation. The ratio of ultra-fast dissociation of molecules in clusters as compared to free molecules is determined to be significantly reduced. We propose partial delocalization of the excited electronic state as being responsible for this behavior.

Slow and fast lung compartments in cystic fibrosis measured by nitrogen multiple-breath washout.

Imaging studies describe significant ventilation defects across a wide range of cystic fibrosis (CF) related lung disease severity. These are unfortunately poorly reflected by phase III slope analysis-derived Scond and Sacin from multiple-breath washout (MBW). Methodology extending previous two-lung compartment model-based analysis is presented describing size and function of fast- and slow-ventilating lung compartments from nitrogen (N2) MBW and correlation to obstructive lung disease severity. In 37 CF subjects (forced expiratory volume in 1 s [FEV1] mean [SD] 84.8 [19.9] % predicted; abnormal lung clearance index [LCI] in 36/37, range 7.28-18.9) and 74 matched healthy controls, volume and specific ventilation of both fast and slowly ventilated lung compartments were derived from N2-based MBW with commercial equipment. In healthy controls lung emptying was characterized by a large compartment constituting 75.6 (8.4)% of functional residual capacity (FRC) with a specific ventilation (regional alveolar tidal volume/regional lung volume) of 13.9 (3.7)% and a small compartment with high specific ventilation (48.4 [15.7]%). In CF the slowly ventilated lung compartment constituted 51.9(9.1)% of FRC, with low specific ventilation of 5.3 (2.4)%. Specific ventilation of the slowly ventilated lung compartment showed stronger correlation with LCI (r2 = 0.70, P < 0.001) vs. Sacin (r2 = 0.44, P < 0.001) or Scond (no significant correlation). Overventilation of the fast lung compartment was no longer seen in severe CF lung disease. Magnitude and function of under- and overventilated lung volumes can be derived from routine N2 MBW in CF. Reported values agree with previous modelling-derived estimates of impaired ventilation and offer improved correlation to disease severity, compared with SnIII analysis.

Lung clearance index: evidence for use in clinical trials in cystic fibrosis.

The ECFS-CTN Standardisation Committee has undertaken this review of lung clearance index as part of the group's work on evaluation of clinical endpoints with regard to their use in multicentre clinical trials in CF. The aims were 1) to review the literature on reliability, validity and responsiveness of LCI in patients with CF, 2) to gain consensus of the group on feasibility of LCI and 3) to gain consensus on answers to key questions regarding the promotion of LCI to surrogate endpoint status. It was concluded that LCI has an attractive feasibility and clinimetric properties profile and is particularly indicated for multicentre trials in young children with CF and patients with early or mild CF lung disease. This is the first article to collate the literature in this manner and support the use of LCI in clinical trials in CF.

Randomized, placebo-controlled trial of propranolol added to topiramate in chronic migraine.

OBJECTIVE: To assess the efficacy and safety of adding propranolol to topiramate in chronic migraine subjects inadequately controlled with topiramate alone. METHODS: This was a double-blind, placebo-controlled, randomized clinical trial conducted through the National Institute of Neurological Disorders and Stroke Clinical Research Collaboration, expected to randomize 250 chronic migraine subjects inadequately controlled (≥10 headaches/month) with topiramate (50-100 mg/day) to either propranolol LA (long acting) (240 mg/day) or placebo. Primary outcome was 28-day moderate to severe headache rate reduction at 6 months (weeks 16 to 24) compared with baseline (weeks -4 to 0). RESULTS: A planned interim analysis was performed after 48 sites randomized 171 subjects. The data and safety monitoring board recommended ending the trial after determining that it would be highly unlikely for the combination to result in a significant reduction in 28-day headache rate compared with topiramate alone if all 250 subjects were randomized. No safety concerns were identified. At study closure, 191 subjects were randomized. The 6-month reduction in moderate to severe 28-day headache rate and total 28-day headache rate for combination therapy vs topiramate alone was not significantly different: 4.0 vs 4.5 days (moderate to severe 28-day headache rate; p = 0.57) and 6.2 vs 6.1 days (total 28-day headache rate; p = 0.91). CONCLUSIONS: This study does not provide evidence that the addition of propranolol LA to topiramate adds benefit when chronic migraine is inadequately controlled with topiramate alone. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that propranolol LA, added to topiramate, is ineffective in chronic migraine patients who fail topiramate monotherapy.

Increased vitamin plasma levels in Swedish military personnel treated with nutrients prior to automatic weapon training.

Noise-induced hearing loss (NIHL) is a significant clinical, social, and economic issue. The development of novel therapeutic agents to reduce NIHL will potentially benefit multiple very large noise-exposed populations. Oxidative stress has been identified as a significant contributor to noise-induced sensory cell death and NIHL, and several antioxidant strategies have now been suggested for potential translation to human subjects. One such strategy is a combination of beta-carotene, vitamins C and E, and magnesium, which has shown promise for protection against NIHL in rodent models, and is being evaluated in a series of international human clinical trials using temporary (military gunfire, audio player use) and permanent (stamping factory, military airbase) threshold shift models (NCT00808470). The noise exposures used in the recently completed Swedish military gunfire study described in this report did not, on average, result in measurable changes in auditory function using conventional pure-tone thresholds and distortion product otoacoustic emission (DPOAE) amplitudes as metrics. However, analysis of the plasma samples confirmed significant elevations in the bloodstream 2 hours after oral consumption of active clinical supplies, indicating the dose is realistic. The plasma outcomes are encouraging, but clinical acceptance of any novel therapeutic critically depends on demonstration that the agent reduces noise-induced threshold shift in randomized, placebo-controlled, prospective human clinical trials. Although this noise insult did not induce hearing loss, the trial design and study protocol can be applied to other populations exposed to different noise insults.

Vitamin D deficiency as a risk factor for cystic fibrosis-related diabetes in the Scandinavian Cystic Fibrosis Nutritional Study.

AIMS/HYPOTHESIS: Many cystic fibrosis patients are vitamin D-insufficient. Cystic fibrosis-related diabetes is a major complication of cystic fibrosis. The literature suggests that vitamin D might possess certain glucose-lowering properties. We aimed to assess the relationship between vitamin D and cystic fibrosis-related glucose intolerance. METHODS: We enrolled 898 cystic fibrosis patients from Sweden, Norway and Denmark. Vitamin D intake was assessed using a seven-day food record. Serum 25-hydroxyvitamin D (s25OHD) and HbA(1c) were measured, and an OGTT was carried out. Multiple linear and logistic regressions were used for HbA(1c) and cystic fibrosis-related diabetes/OGTT result as outcome variables, respectively. Each model was controlled for country, and for known cystic fibrosis-related diabetes risk factors: age, sex, genotype, liver dysfunction, long-term corticosteroid treatment, and lung and pancreatic function. RESULTS: Degree of vitamin D insufficiency (OR 1.36; p = 0.032) and s25OHD < 30 nmol/l (OR 1.79; p = 0.042) were significant risk factors for cystic fibrosis-related diabetes. Accordingly, HbA(1c) value was positively associated with s25OHD < 30 nmol/l and < 50 nmol/l, as well as with degree of vitamin D insufficiency (adjusted R (2) = 20.5% and p < 0.05 in all). In subgroup analyses, s25OHD < 30 nmol/l determined the HbA(1c) value in paediatric patients (adjusted R (2) = 20.2%; p = 0.017), but not in adults. CONCLUSIONS/INTERPRETATION: Vitamin D status is associated with HbA(1c) and diabetes in cystic fibrosis, particularly in children. The study justifies prospective studies on the proposed role of vitamin D deficiency in the pathophysiology of diabetes mellitus.

Large tunable Rashba spin splitting of a two-dimensional electron gas in Bi2Se3.

We report a Rashba spin splitting of a two-dimensional electron gas in the topological insulator Bi(2)Se(3) from angle-resolved photoemission spectroscopy. We further demonstrate its electrostatic control, and show that spin splittings can be achieved which are at least an order-of-magnitude larger than in other semiconductors. Together these results show promise for the miniaturization of spintronic devices to the nanoscale and their operation at room temperature.

Size of free neutral CO2 clusters from carbon 1s ionization energies.

Free neutral CO(2) clusters were produced by adiabatic expansion and characterized by carbon 1s (C1s) photoelectron spectroscopy using synchrotron radiation. The shift in C1s ionization energy (IE) between the cluster and the monomer, i.e., ΔIE = IE(cluster) - IE(monomer), was found to vary systematically with the experimental conditions. A functional relationship is established between the mean cluster size in the beam, , and ΔIE, in good agreement with theoretical calculations of shifts in ionization energy for model clusters. This makes it possible to use core-level photoelectron spectroscopy to monitor the mean cluster size and also to estimate from expansion conditions.

Inverse relation between vitamin D and serum total immunoglobulin G in the Scandinavian Cystic Fibrosis Nutritional Study.

BACKGROUND/OBJECTIVES: The hallmark of cystic fibrosis (CF) is chronic lung inflammation. The severity of lung disease is closely correlated with immunoglobulin G (IgG) levels. Beyond its contribution to the bone health, the importance of vitamin D has not been fully recognized owing to the lack of human studies providing evidence of its benefit. In the context of the recently described immunomodulatory functions of vitamin D, we aimed to assess the relationship between vitamin D and IgG levels. SUBJECTS/METHODS: Eight hundred and ninety-six CF patients were included (0.53-65.9 years) from seven centers in Denmark, Norway and Sweden. Serum 25-hydroxyvitamin D (25OHD) and total IgG were measured, spirometry was carried out and vitamin D intake data were gathered using a 7-day dietary food record. Multiple linear regression analyses were performed for IgG and forced expiratory volume in 1λs (FEV1) as dependent variables, and serum 25OHD, daily food and supplemented vitamin D sources of intake as independent variables. The model was controlled for age, gender, genotype, CF-related diabetes, season, infection/colonization status, long-term oral corticosteroid treatment, long-term treatment with macrolide antibiotics, pancreatic insufficient phenotype and body mass index z-score. RESULTS: Serum total IgG levels were negatively associated with serum 25OHD (adjusted R (2) = 0.376; beta = -0.02; P<0.001), supplemented vitamin D intake per kg bodyweight (adjusted R (2) = 0.375; beta = -0.82; P < 0.001) and total vitamin D intake per kg bodyweight (adjusted R (2) = 0.398; beta = -0.60; P = 0.002). Serum 25OHD was positively associated with FEV1 (adjusted R (2) = 0.308; beta = 0.0007; P = 0.025). CONCLUSIONS: Increasing vitamin D intake may positively modulate inflammation in CF. This study supports the proposed role of vitamin D in the immune system during infection and substantiates prospective studies.

Valence photoelectron spectroscopy of N2 and CO: recoil-induced rotational excitation, relative intensities, and atomic orbital composition of molecular orbitals.

Recoil-induced rotational excitation accompanying photoionization has been measured for the X, A, and B states of N(2)(+) and CO(+) over a range of photon energies from 60 to 900 eV. The mean recoil excitation increases linearly with the kinetic energy of the photoelectron, with slopes ranging from 0.73×10(-5) to 1.40×10(-5). These slopes are generally (but not completely) in accord with a simple model that treats the electrons as if they were emitted from isolated atoms. This treatment takes into account the atom from which the electron is emitted, the molecular-frame angular distribution of the electron, and the dependence of the photoelectron cross section on photon energy, on atomic identity, and on the type of atomic orbital from which the electron is ejected. These measurements thus provide a tool for investigating the atomic orbital composition of the molecular orbitals. Additional insight into this composition is obtained from the relative intensities of the various photolines in the spectrum and their variation with photon energy. Although there are some discrepancies between the predictions of the model and the observations, many of these can be understood qualitatively from a comparison of atomic and molecular wavefunctions. A quantum-mechanical treatment of recoil-induced excitation predicts an oscillatory variation with photon energy of the excitation. However, the predicted oscillations are small compared with the uncertainties in the data, and, as a result, the currently available results cannot provide confirmation of the quantum-mechanical theory.

Low levels of exhaled nitric oxide are associated with impaired lung function in cystic fibrosis.

Fraction of exhaled nitric oxide (FENO) is often reduced in cystic fibrosis (CF). FENO at different expiratory flows can provide an indication of the site of nitric oxide production. The aim of this study was to examine whether NO parameters are related to overall (FEV(1)) or peripheral (lung clearance index, LCI, measured by multiple breath SF(6) washout) airway function and systemic inflammation in CF. Secondary aim was to compare alveolar NO and bronchial NO flux calculated by two different mathematical models, a linear and a nonlinear method. Thirty-five healthy and 45 CF children were recruited. FENO at 50 ml/sec (FENO(50)) and bronchial NO flux were lower in CF than controls, 9.5 (2.7-38.8) (median (range)) versus 12.4 (5.2-40.1) ppb, P = 0.029, and 391 (97-1772) versus 578 (123-1993) (pl/sec), P = 0.036, respectively. No difference in alveolar NO was shown. The nonlinear method resulted in lower alveolar NO and higher bronchial flux, than the linear method, but the result was closely correlated in both groups. LCI was higher in CF than controls, 8.4 (6.5-12.9) versus 5.9 (5.1-7.8), P < 0.001. FENO(50) was negatively correlated with LCI (r = -0.43; P = 0.003) and positively correlated with FEV(1) (r = 0.42, P = 0.004) in CF. Alveolar NO correlated negatively with inflammatory markers: orosomucoid (r = -0.42, P = 0.005), platelets (r = -0.50, P < 0.001) and white blood cell count (r = -0.48, P = 0.001). In conclusion, FENO(50) and bronchial NO flux are reduced in young CF subjects and low FENO(50) is associated with overall and small airway obstruction. NO parameters derived from the different models were closely related but the values differed slightly.

The use, feasibility and psychometric properties of an individualised quality-of-life instrument: a systematic review of the SEIQoL-DW.

PURPOSE: To review published studies regarding the use, feasibility and psychometric performance of the schedule for the evaluation of individual quality of life-direct weighting (SEIQoL-DW) in clinical research. METHODS: Systematic literature review. Studies using the SEIQoL-DW were included if they were published in English and employed a quantitative design. A pre-defined checklist was used to analyse the reported results. RESULTS: Thirty-nine relevant articles were identified. The SEIQoL-DW has been included in studies relating to a variety of populations, including those who are severely ill. The results of convergent and discriminant validity support our hypotheses in which SEIQoL-DW was expected to correlate moderately to high with measures of global QoL, life satisfaction and mental health and weakly with measures of functional status and health. CONCLUSION: The SEIQoL-DW appears to be a feasible and valid instrument. The lack of association between the Index score and health, functional status, demographic and clinical parameters may be explained by the instrument's focus on global QoL and by that of the idiographic measurement approach reflecting the capacity of a patient to value domains other than health in life, despite having health problems. Nevertheless, continued psychometric evaluation in large populations with a longitudinal design is recommended.

A dose dependence study of O(2) adsorbed on large Ar clusters.

An investigation of the behavior of O(2) molecules in and on O(2)-doped large (N approximately 8000) Ar host clusters has been performed by means of core and valence photoelectron spectroscopy. Data from pure O(2) and Ar clusters, as well as from O(2)-doped Ar clusters, are presented. The experimental data together with calculations of the binding energy shifts of oxygen molecular ions in and on the surface of a large host Ar cluster show that the diffusion behavior has a strong dependence on the doping pressure. We conclude that the oxygen molecules in the doped Ar host do not partake in band formation, since there is clear vibrational resolution in the spectral features stemming from screened O(2) (+) ions. This implies that valence photoelectron spectroscopy can be used to determine the geometrical structure of this and certain, similar, cluster systems.

Charge delocalization dynamics of ammonia in different hydrogen bonding environments: free clusters and in liquid water solution.

Valence and core level photoelectron spectra and Auger electron spectra of ammonia in pure clusters have been measured. The Auger electron spectra of gas-phase ammonia, pure ammonia clusters and ammonia in aqueous solution are compared and interpreted via ab initio calculations of the Auger spectrum of the ammonia monomer and dimer. The calculations reveal that the final two-hole valence states can be delocalized over both ammonia molecules. Features at energies pertaining to delocalized states involving one, or more, hydrogen bonding orbitals can be found in both the ammonia cluster Auger electron spectrum and in that of the liquid solvated molecule. The lower Coulombic repulsion between two delocalized valence final state holes gives higher kinetic energy of the Auger electrons which is also observed in the spectra. This decay path--specific to the condensed phase--is responsible for more than 5% of the total cluster Auger intensity. Moreover, this interpretation is also applicable to the solid phase since the same features have been observed, but not assigned, in the Auger spectrum of solid ammonia.

Testing the validity of a translated pharmaceutical therapy-related quality of life instrument, using qualitative 'think aloud' methodology.

BACKGROUND AND OBJECTIVE: In pharmacy practice, there is a need for valid and reliable instruments to study patient-reported outcomes. One potential candidate is a pharmaceutical therapy-related quality of life (PTRQoL) instrument. This study explored the face and content validity, including cognitive aspects of question answering of a PTRQoL instrument, translated from English to Swedish. METHOD: A sample of 16 customers at Swedish community pharmacies, was asked to fill in the PTRQoL instrument while constantly reporting how they reasoned. The resulting interviews and concurrent probing, were audio-taped, transcribed verbatim and analysed using constant comparison method. RESULTS AND DISCUSSION: The relation between the measurement and its theoretical underpinning was challenged. Respondents neglected to read the instructions, used response options in an unpredictable way, and varied in their interpretations of the items. CONCLUSION: The combination of 'think-aloud', retrospective probing and qualitative analysis informed on the validity of the PTRQoL instrument and was valuable in questionnaire development. The study also identified specific problems that could be relevant for other instruments probing patients' medicines-related attitudes and behaviour.

Follow-up of patients receiving a pharmaceutical care service in Sweden.

BACKGROUND: Pharmaceutical care (PC) services are increasingly provided in community pharmacies in the western world. Evaluations are often conducted as trials in highly controlled conditions measuring the efficacy of the service in terms of the economical, clinical and humanistic outcomes. Little is known about the real world provision of PC services and the factors associated with follow-up. OBJECTIVE: To characterize patients receiving a PC service, to explore factors associated with follow-up evaluations, and to describe the results of pharmacists' interventions. METHODS: A non-experimental, retrospective study using the Swedish national patient medication records data base. Patients receiving follow-up evaluations or one consultation within the service were compared using logistic regression. RESULTS: A total of 3298 patients received the PC service at 240 community pharmacies. Patient characteristics included: 66.3% female, mean age 71.1 years, mean number of prescription drugs used 10.5, with 86.2% of patients using >or=1 cardiovascular drugs. A quarter (25.8%) of patients had >or=1 drug-related problems, most commonly side effects. Follow-up evaluations were carried out for 46.6% of the patients, who were more likely to use a compliance aid. Patients receiving the PC service at pharmacies that had enrolled more than the mean number of patients (13.7) had twice as high a chance of receiving follow-up than those registered with pharmacies with fewer patients (i.e. below the mean) enrolled. Followed-up interventions led to a better perceived outcome in 46.3% of cases, no change in 48.5% and a worse outcome in 5.2%. CONCLUSIONS: This study demonstrates that the total number of patients enrolled in a PC service predicts whether follow-up evaluations will take place or not more than do patient characteristics.