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Background: Impaired diffusing capacity of the lung (DLCO) in the absence of post-bronchodilator (BD) airflow obstruction has been proposed as a marker of 'Pre-COPD'. However, the relationship between impaired DLCO and subsequent lung function decline and COPD incidence has not been examined in-depth., Methods: We conducted an observational study of adults aged between 40 and 70 years who were evaluated at a multi-centre lung function laboratory in Australia between 2014 and 2024. Adults referred with respiratory symptoms or a clinical suspicion of obstructive airways disease with follow-up spirometry obtained ≥12 months after the initial assessment were included. The relationship between impaired DLCO and subsequent lung function decline and COPD incidence was assessed among those with normal spirometry at baseline., Results: A total of 266 patients with a mean age of 53.2 (SD 12.8) years were evaluated after a median follow-up of 2.3 [IQR 1.5 to 3.3] years. We found no evidence of an association between impaired DLCO (below the lower limit of normal) and annualised rate of decline in post-BD FEV 1 (MD -0.1 % predicted per-year, 95%CI -1.3 to 1.2), FVC (-0.4 % predicted, 95%CI -1.6 to 0.8) or FEV 1 /FVC (-0.1 % per-year, 95%CI -0.1 to 0.1). The sensitivity of impaired DLCO for COPD incidence was 40 %, and specificity 82 %. Findings were similar in sub-samples limited to current and former smokers, and when impaired DLCO was defined as < 80 % predicted., Conclusion: Impaired DLCO was not an effective discriminator of lung function decline or COPD incidence in this real-world cohort., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Chronic respiratory tract infection by Pseudomonas aeruginosa is the hallmark of established lung disease in patients with cystic fibrosis (CF). Antibiotic therapy can usually only suppress but not eradicate infection. In recent years, pulmonary infection with non-tuberculous Mycobacteria (NTM) species has also been increasing. These patients are often colonised with multiple isolates and determination of clinical significance of each isolate is difficult. The clinical value of frequent routine susceptibility testing of individual isolates is unproven, particularly since a delay in susceptibility testing is inevitable when purification of multiple cultured isolates is required to test each isolate separately. From August 2019 until December 2020 we ceased routine susceptibility testing on P. aeruginosa respiratory tract isolates from patients with CF if a previous isolate from the patient had susceptibility testing performed. We found that the proportion of P. aeruginosa isolates that had susceptibility testing performed dropped from 97% to 11% as a result of this change in laboratory process. During this time, we also ceased routine culture for acid-fast bacilli if this had been performed within the previous 6 months. We present the cost and resource savings for these changes in laboratory process and assess for clinical impact measured as hospital admissions, length of stay in hospital and mortality., (Copyright © 2023 Royal College of Pathologists of Australasia. Published by Elsevier B.V. All rights reserved.)

A series of studies has reported weight gain in association with COVID-19 lockdowns; typically, this research has had short-term follow-up in populations that tended to gain weight. In this study, the effect of prolonged lockdowns on weight was assessed in a population of patients with chronic obstructive pulmonary disease. Before lockdown subjects gained an average of 0.022 kg per month; after lockdown this trend reversed with subjects losing weight at 0.032 kg per month, a trend that was highly significant (P < 0.001)., (© 2023 The Authors. Internal Medicine Journal published by John Wiley & Sons Australia, Ltd on behalf of Royal Australasian College of Physicians.)

Few studies have examined swallow of large liquid volumes representative of everyday drinking in COPD. Swallow by cup-drinking was evaluated in COPD using videofluoroscopy. Slower swallow was linked to aspiration indicating altered swallow habits in COPD. https://bit.ly/3wpdnO3., Competing Interests: Conflict of interest: L. Cvejic has nothing to disclose. Conflict of interest: N. Guiney has nothing to disclose. Conflict of interest: K.K. Lau has nothing to disclose. Conflict of interest: P. Finlay has nothing to disclose. Conflict of interest: K. Hamza has nothing to disclose. Conflict of interest: P. Leong is supported by the National Health and Medical Research Council Postgraduate Scholarship and the Royal Australasian College of Physicians, outside of this work. Views expressed do not necessarily reflect those of the funding bodies. Conflict of interest: M. MacDonald has nothing to disclose. Conflict of interest: P.T. King has nothing to disclose. Conflict of interest: P.G. Bardin has nothing to disclose., (Copyright ©The authors 2021.)

We report the prevalence of reduced levels of carbon monoxide transfer factor (TLCO) in middle-aged current or ex-smokers with normal spirometry. Spirometry and TLCO measurements were performed and we identified 391 subjects aged 40-60 years, with a significant smoking history and normal spirometry. In this group, 96 subjects (24%) had TLCO measuremements below the lower limit of normal when using the newly established Global Lung Initiative (GLI) reference equations. The measurement of TLCO should be considered as part of the standard assessment of smokers., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Rationale: Swallow may be compromised in COPD leading to aspiration and adverse respiratory consequences. However, prevalence and consequences of detectable aspiration in stable COPD are not known., Objectives: We tested the hypothesis that a significant number of patients with stable COPD will have detectable aspiration during swallow (prandial aspiration) and that they would experience more frequent severe acute exacerbations of COPD (AECOPD) over the subsequent 12 months., Methods: Patients (n=151) with verified and stable COPD of all severities were recruited at a tertiary care hospital. Videofluoroscopy was conducted to evaluate aspiration using Rosenbek's scale for penetration-aspiration during 100-mL cup drinking. AECOPD was documented as moderate (antibiotics and/or corticosteroid treatment) or severe (emergency department admission or hospitalisation) over the ensuing 12 months., Measurements and Main Results: Aspiration was observed in 30 out of 151 patients (19.9%, 18 males, 12 females; mean age 72.4 years). Patients with aspiration had more overall AECOPD events (3.03 versus 2 per patient; p=0.022) and severe AECOPD episodes (0.87 versus 0.39; p=0.032). Severe AECOPD occurred in more patients with aspiration (50% of patients versus 18.2%; OR 4.5, CI 1.9-10.5; p=0.001) and with silent aspiration (36.7% versus 18.2%; OR 2.6, CI 1.1-6.2; p=0.045). Aspiration was related to a shorter exacerbation-free period during the 12-month follow-up period (p=0.038)., Conclusions: Prandial aspiration is detectable in a subset of patients with COPD and was predictive of subsequent severe AECOPD. Studies to examine if the association is causal are essential to direct strategies aimed at prevention of aspiration and AECOPD., Competing Interests: Conflict of interest: L Cvejic has nothing to disclose. Conflict of interest: N. Guiney has nothing to disclose. Conflict of interest: T. Nicholson has nothing to disclose. Conflict of interest: K.K. Lau has nothing to disclose. Conflict of interest: P. Finlay has nothing to disclose. Conflict of interest: K. Hamza has nothing to disclose. Conflict of interest: C. Osadnik reports they were the recipient of a Lung Foundation Australia COPD Research Fellowship (2016–2018; AUD$160 000) and is the recipient of a Rebecca L. Cooper Medical Research Foundation Project Grant (2020–2021; AUD$100 000). Conflict of interest: P. Leong is supported by the National Health and Medical Research Council Postgraduate Scholarship and the Royal Australasian College of Physicians, outside of this work. Views expressed do not necessarily reflect those of the funding bodies. Conflict of interest: M. MacDonald has nothing to disclose. Conflict of interest: P.T. King has nothing to disclose. Conflict of interest: P.G. Bardin has nothing to disclose., (Copyright ©ERS 2021.)

Purpose: The STAKT study examined short-term exposure (4.5 days) to the oral selective pan-AKT inhibitor capivasertib (AZD5363) to determine if this drug can reach its therapeutic target in sufficient concentration to significantly modulate key biomarkers of the AKT pathway and tumor proliferation., Patients and Methods: STAKT was a two-stage, double-blind, randomized, placebo-controlled, "window-of-opportunity" study in patients with newly diagnosed ER + invasive breast cancer. Stage 1 assessed capivasertib 480 mg b.i.d. (recommended monotherapy dose) and placebo, and stage 2 assessed capivasertib 360 and 240 mg b.i.d. Primary endpoints were changes from baseline in AKT pathway markers pPRAS40, pGSK3β, and proliferation protein Ki67. Pharmacologic and pharmacodynamic properties were analyzed from blood sampling, and tolerability by adverse-event monitoring., Results: After 4.5 days' exposure, capivasertib 480 mg b.i.d. ( n = 17) produced significant decreases from baseline versus placebo ( n = 11) in pGSK3β (H-score absolute change: -55.3, P = 0.006) and pPRAS40 (-83.8, P < 0.0001), and a decrease in Ki67 (absolute change in percentage positive nuclei: -9.6%, P = 0.031). Significant changes also occurred in secondary signaling biomarker pS6 (-42.3, P = 0.004), while pAKT (and nuclear FOXO3a) also increased in accordance with capivasertib's mechanism (pAKT: 81.3, P = 0.005). At doses of 360 mg b.i.d. ( n = 5) and 240 mg b.i.d. ( n = 6), changes in primary and secondary biomarkers were also observed, albeit of smaller magnitude. Biomarker modulation was dose and concentration dependent, and no new safety signals were evident., Conclusions: Capivasertib 480 mg b.i.d. rapidly modulates key biomarkers of the AKT pathway and decreases proliferation marker Ki67, suggesting future potential as an effective therapy in AKT-dependent breast cancers., (©2019 American Association for Cancer Research.)

From detailed spectroscopy of ^{110}Cd and ^{112}Cd following the β^{+}/electron-capture decay of ^{110,112}In and the β^{-} decay of ^{112}Ag, very weak decay branches from nonyrast states are observed. The transition rates determined from the measured branching ratios and level lifetimes obtained with the Doppler-shift attenuation method following inelastic neutron scattering reveal collective enhancements that are suggestive of a series of rotational bands. In ^{110}Cd, a γ band built on the shape-coexisting intruder configuration is suggested. For ^{112}Cd, the 2^{+} and 3^{+} intruder γ-band members are suggested, the 0&#95;{3}^{+} band is extended to spin 4^{+}, and the 0&#95;{4}^{+} band is identified. The results are interpreted using beyond-mean-field calculations employing the symmetry conserving configuration mixing method with the Gogny D1S energy density functional and with the suggestion that the Cd isotopes exhibit multiple shape coexistence.

ZIP7, a member of the ZIP family of zinc importers, resides on the endoplasmic reticulum membrane and transports zinc from intracellular stores to the cytoplasm after activation by CK2 phosphorylation on two serine residues (S275 and S276). ZIP7 is known to be required for the growth of anti-hormone resistant breast cancer models, especially those with acquired tamoxifen resistance developed from MCF-7. Using our new pS 275 S 276 ZIP7 antibody which only recognises activated ZIP7 (pZIP7), we have demonstrated that the hyperactivation of ZIP7 is prevalent in tamoxifen-resistant breast cancer cells. This evidence suggests that pZIP7 might have potential as a biomarker of acquired resistance to such anti-hormones in breast cancer, a current unmet clinical need. In this regard, we have also developed a new immunohistochemical assay for pZIP7 which allowed pZIP7 to be tested on a small clinical series of breast cancer tissues confirming its prevalence in such tumours and relationship to a variety of clinicopathological parameters and biomarkers previously associated with endocrine resistant phenotypes, notably increased activated MAPK signalling, expression of ErbB2, CD71 and the proto-oncogene c-Fos, as well as with increased tumour grade.

Background: Voice change is one of the earliest features of Parkinson's disease. However, quantitative studies of vocal fold dynamics which are needed to provide insight into disease biology, aid diagnosis, or track progression, are few., Methods: We therefore quantified arytenoid cartilage movements and glottic area during repeated phonation in 15 patients with Parkinson's disease (symptom duration < 6 years) and 19 controls, with 320-slice computerised tomography (CT). We related these measures to perceptual voice evaluations and spirometry. We hypothesised that Parkinson's disease patients have a smaller inter-arytenoid distance, a preserved or larger glottic area because vocal cord bowing has previously been reported, less variability in loudness, more voice dysdiadochokinesis and breathiness and a shortened phonation time because of arytenoid hypokinesis relative to glottic area., Results: Inter-arytenoid distance in Parkinson's disease patients was moderately smaller (Mdn = 0.106, IQR = 0.091-0.116) than in controls (Mdn = 0.132, IQR = 0.116-0.166) (W = 212, P = 0.015, r = -0.42), normalised for anatomical and other inter-subject variance, analysed with two-tailed Wilcoxon's rank sum test. This finding was confirmed in a linear mixed model analysis-Parkinson's disease significantly predicted a reduction in the dependent variable, inter-arytenoid distance (b = -0.87, SEb = 0.39, 95% CI [-1.66, -0.08], t(31) = -2.24, P = 0.032). There was no difference in glottic area. On perceptual voice evaluation, patients had more breathiness and dysdiadochokinesis, a shorter maximum phonation time, and less variability in loudness than controls. There was no difference in spirometry after adjustment for smoking history., Conclusions: As predicted, vocal fold adduction movements are reduced in Parkinson's disease on repeated phonation but glottic area is maintained. Some perceptual characteristics of Parkinsonian speech reflect these changes. We are the first to use 320-slice CT to study laryngeal motion. Our findings indicate how Parkinson's disease affects intrinsic laryngeal muscle position and excursion.

Background: Abnormal vocal cord movements can cause laryngeal extrathoracic airway obstruction (often called vocal cord dysfunction - VCD) leading to asthma-like symptoms. These aberrant movements are characteristically present during inspiration and termed paradoxical vocal cord movement (PVCM). We have reported PVCM in up to 40% of severe asthmatics, but it is not known if PVCM is detectable in all patients with asthma-like symptoms and if the condition is more often associated with abnormal lung function., Objective: We hypothesized that PVCM is frequently associated with asthma symptoms accompanied by airflow limitation. Studies examined whether PVCM is solely linked to experiencing asthma symptoms, or if PVCM is related to airflow limitation and/or other disease characteristics., Methods: Patients with asthma symptoms were recruited from general practice and severe asthma clinics (n = 155). Pulmonary function measurements were conducted, asthma control and Nijmegen (dysfunctional breathing) questionnaires were administered and skin prick testing was carried out. PVCM was quantified using dynamic 320-slice computerized tomography of the larynx. Groups were divided into patients with FEV 1 ≥ 80% predicted or FEV 1 < 80% predicted and FEV 1 /FVC < 0.7. ATS/ERS definitions of severity were also applied and evaluated. Detection of PVCM in the groups was compared and analyses performed to identify features associated with PVCM., Results: Overall (n = 155), PVCM was detected in 42 cases (27.1%). Patients with FEV 1 < 80% predicted had PVCM more often (25/68, 36.8%) than individuals with normal spirometry (17/87, 19.5%; P = 0.016). PVCM was associated with older age (P = 0.003) and with Nijmegen scores > 20 (P = 0.04). Patients with FEV 1 < 80% predicted plus Nijmegen scores > 20 were more likely to have PVCM (OR = 9.3, P = 0.02)., Conclusions and Clinical Relevance: Paradoxical vocal cord movement is more often associated with asthma symptoms accompanied by airflow limitation and dysfunctional breathing. Further studies are needed to determine whether PVCM is induced by dysfunctional breathing practices and/or airway obstruction. How PVCM links with symptomatic asthma and VCD also requires evaluation., (© 2016 John Wiley & Sons Ltd.)

Background: Dietary nitrate supplementation has been shown to decrease the oxygen cost of exercise and prolong exercise tolerance, as measured by sub-maximal exercise endurance distance and time at 85% V̇O2max, in both elite athletes and normal healthy subjects. Patients with chronic obstructive pulmonary disease (COPD) have reduced quality of life and ability to perform activities of daily living attributable to diminished exercise tolerance, and dietary nitrate may be able to ameliorate this., Methods: We performed a double-blind, computer-randomized placebo control crossover trial at a tertiary Australian hospital to investigate whether dietary nitrate supplementation as beetroot juice (BR) would augment submaximal exercise endurance in individuals with spirometrically confirmed stable moderate COPD. Volunteers underwent an incremental shuttle walk test to determine V̇O2max followed by a test dose of BR to establish safety in the study population. Participants performed an endurance shuttle walk test (ESWT) at 85% V̇O2max after randomization to either a 3 day wash-in of BR (4.8 mmol twice a day) or placebo (nitrate deplete BR), with a final dose on the morning of testing. They then crossed over after 4 day washout. Repeated measures two sided paired t-tests were employed., Results: 35 participants were recruited with 19 completing the trial. In the initial safety phase, we measured systolic blood pressure over four hours post first dose of BR, and found a mean 10 mmHg decrement maximal at 1 hour. One individual developed symptomatic postural hypotension and was excluded. The primary outcomes of ESWT distance and time to fatigue improved by 11% and 6% respectively; however these differences did not achieve statistical significance (p = 0.494 and 0.693 respectively)., Conclusions: Our study does not support a role for routine dietary nitrate supplementation for enhancement of exercise endurance in COPD., Trial Registration: Australia and New Zealand Clinical Trial Register: ACTRN12611001088932.

Laughter and humor therapy have been used in health care to achieve physiological and psychological health-related benefits. The application of these therapies to the dialysis context remains unclear. This paper reviews the evidence related to laughter and humor therapy as a medical therapy relevant to the dialysis patient population. Studies from other groups such as children, the elderly, and persons with mental health, cancer, and other chronic conditions are included to inform potential applications of laughter therapy to the dialysis population. Therapeutic interventions could range from humorous videos, stories, laughter clowns through to raucous simulated laughter and Laughter Yoga. The effect of laughter and humor on depression, anxiety, pain, immunity, fatigue, sleep quality, respiratory function and blood glucose may have applications to the dialysis context and require further research., (© 2014 Wiley Periodicals, Inc.)

Objective: It is not known how airway structure is altered during real-life acute asthma exacerbations. The aim of this study was to examine changes in airway structure during acute asthma exacerbations and at convalescence by using lung-volume controlled high resolution computerised tomography (HRCT)., Methods: Eight subjects with acute asthma exacerbation admitted to hospital were recruited. HRCT was performed within 72 h of admission (n = 8) and repeated after 8 weeks of convalescence (n = 7). Individual airways were carefully matched on acute and convalescent CT data sets for comparisons of airway parameters. A novel methodology was employed for standardisation of lung volumes to permit valid comparisons of lung imaging. Measurements of bronchial cross sectional airway area (Aa) and bronchial luminal area (Ai) for each matched airway were obtained using a validated program., Results: The airway wall thickness was analysed as wall area (WA) calculated as a percentage: WA% = WA/Aa × 100. Wilcoxon signed-rank testing was used to compare acute and convalescent asthma and Spearman's correlation to examine associations. Airway lumen (Ai) areas were similar in both acute and stable asthma phases (6.6 ± 3.1 mm(2) versus 7.2 ± 3.8 mm(2) p = 0.8). However, the airway wall was significantly thickened during acute asthma exacerbations compared to convalescence (62 ± 4% versus 55 ± 7%; p = 0.01). There was no correlation between airway structure dimensions and lung function measurements., Conclusions: This is the first study to demonstrate an increase in airway wall thickness during real-life acute asthma exacerbation. However, narrowing of the airway lumen area was variable and will require larger studies able to detect small differences. These results suggest that airway wall thickening linked to mucosal inflammation is likely to characterise acute asthma in vivo but that changes in the airway lumen accompanying bronchoconstriction may be more heterogeneous.

We report a precise determination of the (19)Ne half-life to be T(1/2)=17.262±0.007 s. This result disagrees with the most recent precision measurements and is important for placing bounds on predicted right-handed interactions that are absent in the current standard model. We are able to identify and disentangle two competing systematic effects that influence the accuracy of such measurements. Our findings prompt a reassessment of results from previous high-precision lifetime measurements that used similar equipment and methods.

NEWEST (Neoadjuvant Endocrine Therapy for Women with Estrogen-Sensitive Tumors) is the first study to compare biological and clinical activity of fulvestrant 500 versus 250 mg in the neoadjuvant breast cancer setting. We hypothesized that fulvestrant 500 mg may be superior to 250 mg in blocking estrogen receptor (ER) signaling and growth. A multicenter, randomized, open-label, Phase II study was performed to compare fulvestrant 500 mg (500 mg/month plus 500 mg on day 14 of month 1) versus fulvestrant 250 mg/month for 16 weeks prior to surgery in postmenopausal women with ER+ locally advanced breast cancer. Core biopsies at baseline, week 4, and surgery were assessed for biomarker changes. Primary endpoint: change in Ki67 labeling index (LI) from baseline to week 4 determined by automated computer imaging system (ACIS). Secondary endpoints: ER protein expression and function; progesterone receptor (PgR) expression; tumor response; tolerability. ER and PgR were examined retrospectively using the H score method. A total of 211 patients were randomized (fulvestrant 500 mg: n = 109; 250 mg: n = 102). At week 4, fulvestrant 500 mg resulted in greater reduction of Ki67 LI and ER expression versus 250 mg (-78.8 vs. -47.4% [p < 0.0001] and -25.0 vs. -13.5% [p = 0.0002], respectively [ACIS]); PgR suppression was not significantly different (-22.7 vs. -17.6; p = 0.5677). However, H score detected even greater suppression of ER (-50.3 vs. -13.7%; p < 0.0001) and greater PgR suppression (-80.5 vs. -46.3%; p = 0.0018) for fulvestrant 500 versus 250 mg. At week 16, tumor response rates were 22.9 and 20.6% for fulvestrant 500 and 250 mg, respectively, with considerable decline in all markers by both ACIS and H score. No detrimental effects on endometrial thickness or bone markers and no new safety concerns were identified. This provides the first evidence of greater biological activity for fulvestrant 500 versus 250 mg in depleting ER expression, function, and growth.

Mechanistic models of the spray drying and particle formation processes were used to conduct a formulation study with minimal use of material and time. A model microparticle vehicle suitable for respiratory delivery of biological pharmaceutical actives was designed. L-leucine was chosen as one of the excipients, because of its ability to enhance aerosol dispersibility. Trehalose was the second excipient. The spray drying process parameters used to manufacture the particles were calculated a priori. The kinetics of the particle formation process were assessed using a constant evaporation rate model. The experimental work was focused on the effect of increasing L-leucine mass fraction in the formulation, specifically its effect on leucine crystallinity in the microparticles, on powder density, and on powder dispersibility. Particle, powder and aerosol properties were assessed using analytical methods with minimal sample requirement, namely linear Raman spectroscopy, scanning electron microscopy, time-of-flight aerodynamic diameter measurements, and a new technique to determine compressed bulk density of the powder. The crystallinity of leucine in the microparticles was found to be correlated with a change in particle morphology, reduction in powder density, and improvement in dispersibility. It was demonstrated that the use of mechanistic models in combination with selected analytical techniques allows rapid formulation of microparticles for respiratory drug delivery using batch sizes of less than 80 mg., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Background and Objective: Swallowing is closely coordinated with breathing but in COPD altered synchronization may predispose patients to a breach of the upper airway protective mechanisms. However, aspiration during swallow has never been shown in COPD. We examined penetration of liquid material into the airway of patients with COPD and correlated it with breathing-swallow patterns., Methods: A case-control study was performed. Patients with COPD (n = 16) were matched with normal control subjects (n = 15). Sub-mandibular videofluoroscopy was carried out during swallow of graduated volumes of barium to detect penetration (contrast enters the airway and may contact vocal folds) and aspiration (contrast passes glottis). Respiration was monitored simultaneously to gauge synchronization. Hospitalization and mortality were assessed after 36 months., Results: Penetration/aspiration scores were higher in patients with COPD (3.3 ± 0.7 vs 1.6 ± 0.4 in healthy controls, P = 0.03; mean ± SE). Penetration with aspiration was observed in 4/16 patients with COPD versus 1/15 controls (P = 0.07). Penetration with or without aspiration was found in 6/16 patients (P = 0.04). Inspiration-swallow-expiration patterns were favoured in individuals with COPD (P = 0.02). Penetration/aspiration was associated with higher respiratory rates (P = 0.01), reduced hyoid elevation (P = 0.04), post-swallow larynx penetration (P = 0.05) and oxygen desaturation (P = 0.01). There was a trend for the penetration/aspiration group to have an adverse outcome., Conclusions: Upper airway protective mechanisms may be flawed in COPD, possibly through reduced coordination of breathing with swallowing. This abnormality may contribute to COPD morbidity in a subgroup of patients., (© 2011 The Authors. Respirology © 2011 Asian Pacific Society of Respirology.)

A high-precision half-life measurement for the superallowed β+ emitter 26Al(m) was performed at the TRIUMF-ISAC radioactive ion beam facility yielding T 1/2 6346.54 ± 0.46(stat) ± 0.60 (syst) ms, consistent with, but 2.5 times more precise than, the previous world average. The 26Al(m) half-life and ft value, 3037.53(61) s, are now the most precisely determined for any superallowed β decay. Combined with recent theoretical corrections for isospin-symmetry-breaking and radiative effects, the corrected Ft value for (26)Al(m), 3073.0(12) s, sets a new benchmark for the high-precision superallowed Fermi β-decay studies used to test the conserved vector current hypothesis and determine the V(ud) element of the Cabibbo-Kobayashi-Maskawa quark mixing matrix.

Activated Src kinase may contribute to the progression and spread of breast cancers and recent in vitro evidence suggests a role for Src in acquired endocrine resistance. The purpose of this study was to investigate whether modulation of Src activity in endocrine-sensitive and endocrine-resistant breast cancer cells directly affected their phenotype and sensitivity to 4-hydroxy Tamoxifen (tamoxifen) and to determine whether Src activity in breast cancer tissue affected patient outcome. Expression of constitutively active Src in ER-positive, endocrine-sensitive MCF7 breast cancer cells resulted in the development of an aggressive phenotype, akin to that previously observed in cell models of Tamoxifen resistance, and, significantly, attenuated their response to tamoxifen. Conversely, expression of dominant negative-Src in tamoxifen-resistant MCF7 cells resensitized them to tamoxifen. An exploratory immunohistochemical study of an archival primary breast tumor series (n = 75) with parallel clinicopathological data and in normal breast tissues (n = 19) revealed higher levels of activated Src in the cytoplasm (p < 0.01) and lower levels of nuclear Src (p < 0.01) in tumor tissue compared with normal tissue. Whereas elevated levels of activated-Src in the cytoplasm of tumors was significantly associated with reduced survival in ER+ patients (p = 0.031), elevated levels of activated Src within the nucleus appeared to associate with an improved hormonal response. Together these data are further suggestive of a role for Src in breast cancer where it may alter response to endocrine therapy.

Background and Objective: Mortality and morbidity in COPD have been related to reduced FEV1 as well as indices of body composition. Different techniques used to evaluate body composition may vary in accuracy, particularly in conditions with altered fluid balance such as COPD. We hypothesized that direct measurement of fat-free mass index (FFMI) by dual-energy X-ray absorptiometry (DEXA) would provide superior assessment of body composition in COPD., Methods: We measured body composition in 31 patients with COPD randomly selected from a teaching hospital clinic. To estimate total body water (TBW) and FFMI, skin-fold anthropometry, bioelectrical impedance analysis (BIA) with Schols and Lukaski equations as well as DEXA, total body potassium by whole-body gamma-counting (TBK) and in vivo neutron activation analysis were used. Combined body composition methods providing precise estimations of TBW were used for comparisons. Bland-Altman analyses, ANOVA and chi2-testing were used to examine data., Results: Mean BMI was 27.6 +/- 5.34 kg/m2 (mean +/- SD). Estimations of TBW were similar using Schols BIA or by using combined body composition methods. FFMI did not vary significantly between grades of COPD severity but was significantly different when assessed using DEXA and other methods. Calculated FFM hydration was significantly different from the fixed hydration factor used to calculate FFMI from BIA TBW (P < 0.05)., Conclusion: The Schols BIA method incorporates a fixed hydration factor that may lead to an erroneous estimation of FFMI with ensuing clinical implications. DEXA can be used to obtain accurate and comprehensive assessments of body composition and should be the preferred investigation in COPD.

Drugs that target the insulin-like growth factor-I receptor (IGF-IR) and/or insulin receptor (IR) are currently under investigation for a variety of malignancies including breast cancer. Although we have previously reported that IGF-IR expression in primary breast tumors is common, the activation status of this receptor has not been examined in relation to survival. Phosphorylated IGF-IR/IR (P-IGF-IR/IR) and its downstream signaling partner phospho-S6 (P-S6) were evaluated immunohistochemically in tumor tissue microarrays representing 438 cases of invasive breast cancer. P-IGF-IR/IR (n = 114; P = 0.046) and total levels of IR (n = 122; P = 0.009) were indicative of poor survival, whereas total IGF-IR (n = 112; P = 0.304) was not. P-IGF-IR/IR and P-S6 were coordinately expressed in primary breast tumors (likelihood ratio, 11.57; P = 6.70 x 10(-4)). Importantly, P-IGF-IR/IR was detected in all breast cancer subtypes (luminal, 48.1%; triple negative, 41.9%; and HER2, 64.3%). In vitro, the IGF-IR/IR inhibitor BMS-536924 decreased phospho-RSK and P-S6, and significantly suppressed the growth of breast cancer cell lines MCF-7, SUM149, and AU565 representing the luminal, triple negative, and HER2 subtypes, respectively, in monolayer and soft agar. BMS-536924 also inhibited growth in tamoxifen resistant MCF-7 Tam-R cells while having little effect on immortalized normal breast epithelial cells. Thus, we can determine which patients have the activated receptor and provide evidence that P-IGF-IR/IR is a prognostic factor for breast cancer. Beyond this, P-IGF-IR/IR could be a predictive marker for response to IGF-IR and/or IR-targeted therapies, as these inhibitors may be of benefit in all breast cancer subtypes including those with acquired resistance to tamoxifen.

The branching ratio for the superallowed beta(+) decay of (38)K(m) was measured at TRIUMF's ISAC radioactive ion beam facility. The M3 internal transition between the isomer and the ground state of (38)K(m) was observed with a branching ratio of 330(43) ppm. A search for the nonanalogue beta-decay branch to the first excited 0(+) state in (38)Ar was also performed and yielded an upper limit of < or =12 ppm at 90% C.L. These measurements lead to a revised superallowed branching ratio for (38)K(m) of 99.967(4)%, and increase the (38)K(m) ft value by its entire quoted uncertainty to ft=3052.1(10) s. Implications for tests of the nuclear-structure dependent corrections in superallowed beta decays and the extraction of the Cabibbo-Kobayashi-Maskawa matrix element V(ud) are discussed.

A high-precision branching ratio measurement for the superallowed beta+ decay of 62Ga was performed at the Isotope Separator and Accelerator radioactive ion beam facility. Nineteen gamma rays emitted following beta+ decay of 62Ga were identified, establishing the dominant superallowed branching ratio to be (99.861+/-0.011)%. Combined with recent half-life and Q-value measurements, this branching ratio yields a superallowed ft value of 3075.6+/-1.4 s for 62Ga decay. These results demonstrate the feasibility of high-precision superallowed branching ratio measurements in the A>or=62 mass region and provide the first stringent tests of the large isospin-symmetry-breaking effects predicted for these decays.

Aim: To compare grading of chronic obstructive pulmonary disease (COPD) using Australian guidelines Confirm diagnosis, Optimize function, Prevent deterioration, Develop a self-management plan and manage eXacerbations (COPD-X) versus Global initiative for Obstructive Lung Disease (GOLD) guidelines and to assess whether this is associated with differences in other health domains affected by COPD. Adult outpatients (n = 61) with COPD were studied using lung function measurements, six-minute walk test and body composition assessments. Subjects also completed self-rated dyspnoea scores and health-related quality-of-life scales. For each patient, COPD severity was graded using both COPD-X and GOLD guidelines, and results were collectively analysed. If significant discrepancies were observed, comparisons of other health domains were carried out. After grading severity using COPD-X and GOLD guidelines, significant discrepancies were noted. Of nine subjects with no disease (normal) based on COPD-X, seven were judged to be 'mild' according to GOLD. Similarly, 11 of 12 patients with mild disease (COPD-X) had 'moderate' disease judged by GOLD, and 9 of 23 with moderate severity (COPD-X) had 'severe' COPD using GOLD. Finally, 6 of 17 patients with COPD-X-rated severe disease had 'very severe' disease using the GOLD criteria. Among patients with COPD-X severe disease, those with GOLD discordant (very severe) severity had a poorer quality of life compared with those with GOLD concordant (severe) severity (P = 0.006). Similarly, there was also a trend towards lower six-minute walk test distance and greater subjective dyspnoea in GOLD very severe patients compared with GOLD severe patients. Significant discrepancies in grading of severity exist between Australian and international COPD guidelines. Current Australian guidelines for severity grading may not fully reflect the effect COPD has on other key domains of health.

Background: The paper presents a new robotic system for beating heart surgery. The final goal of this project is to develop a tele-operated system for the thoracoscopic treatment of patients with atrial fibrillation. The system consists of a robot that moves an innovative end-effector used to perform lines as in the Cox-Maze technique., Methods: The device is an electrode mesh that is introduced in the thorax through a trocar and is deployed inside the left atrium, where it can create selective ablation lines at any atrial region, using radio frequency. The current version of the umbrella has 22 electrodes. Using visual feedback from an ultrasound based navigation system, the surgeon can choose which electrodes on the mesh to activate. Once the umbrella is in contact with the endocardium of the left atrium, at the expected position, the surgeon activates the chosen electrodes sequentially. The umbrella can then be moved to another position., Results: In vitro and in vivo animal tests have been carried out in order to test and improve the instrument, the robotic system and the operative procedure., Conclusions: The performed trials proved the ability of the system to treat atrial fibrillation. More in vivo tests are currently being performed to make the robot and its device ready for clinical use., (Copyright 2006 John Wiley & Sons, Ltd.)

Aims: To identify the prevalence of post-traumatic psychological symptoms after maxillofacial trauma and prognostic factors related to poor outcome., Methods: Thirty-nine patients were assessed within 10 days of injury and 24 again 4-6 weeks later using five standardised self-report measures on each occasion and a short structured interview at the time of initial contact., Results: Specific post-traumatic psychological symptoms were present at initial assessment in 21 patients (54%), with 9 (41%) meeting diagnostic criteria for post-traumatic stress disorder at review 4-6 weeks later. Other psychiatric problems, such as anxiety and depression, were identified by the General Health Questionnaire and the Hospital Anxiety and Depression Scale. Characteristics associated with poorer outcome included: a previous history of psychological distress; fear of the unknown, and female sex., Conclusion: These findings highlight the adverse psychological effect of maxillofacial trauma both immediately after the event and 4-6 weeks after injury. Proper assessment of injured patients must include psychological aspects and further research is needed to identify the most appropriate response.

Background: The role of the human camera holder during laparoscopic surgery keeps valuable personnel from other duties. EndoAssist is a robotic camera-holding device controlled by the operator's head movements. This study assesses its introduction into clinical practice., Method: Ninety-three patients undergoing laparoscopic cholecystectomy were randomized to have either the robotic (40) or a human (46) assistant. Seven patients converted to open operation were excluded. Six surgeons were evaluated. Operating time and subjective assessments were recorded. Learning curves were constructed., Results: The mean operating time was less using the robotic assistant (66 min) than with human assistance (74 min) (p < 0.05, two-tailed t-test). The learning curves for operating time showed that within three operations surgeons were trained in using the robot. The device was safe in use., Conclusion: The EndoAssist operating device is a significant asset in laparoscopic surgery and a suitable substitute for a human assistant. Surgeons became competent in the use of the robot within three operations. The robot offers stability and good control of the television image in laparoscopic surgery.

Radiotherapy given during treatment of oral and pharyngeal malignancy is frequently associated with colonization of the oral mucosa by Candida species. Treatment of these infections has included topical and systemic agents. In the present study 73 patients with oropharyngeal candidosis were treated with either amphotericin B (10 mg lozenges, four times daily for 14 days, 36 patients) or fluconazole (50 mg daily for 7 days, 37 patients). The yeasts most frequently isolated were C albicans and C glabrata. Clinical signs and symptoms showed improvement at end of treatment in 72% of patients who received amphotericin B compared with 92% of patients who received fluconazole. Mycological cure at end of treatment was achieved in 31% of the amphotericin B group and 46% of patients who received fluconazole. For both treatments the cure rate was less in denture wearers than in non denture wearers.

61 orthognathic surgery patients were studied (39% male, 61% female). It confirms that the group of patients we see in the West of Scotland are well adjusted psychologically and that the majority seek orthognathic surgery for aesthetic reasons. The degree of satisfaction is high (87%). Dissatisfaction is not related to sex, age or procedure. Patients who were dissatisfied tend to have higher neuroticism scores on the Eysenck Personality Inventory and those patients who had had unreal expectations of post surgical pain, numbness and swelling, were likely to express dissatisfaction with the outcome in the early stages. Several patients initially expressed some dissatisfaction with the outcome after 3 months then went on to increase their score and by 12 months became satisfied with the procedure. The authors outline the importance of adequate patient preparation prior to surgery and the use of printed literature is recommended.

The protein product of the bcl-2 gene is though to be involved in inhibition of apoptosis; it may therefore be important in the modulation of hormonal/anti-hormonal responsiveness exhibited by tumours. This study immunocytochemically investigates (i) relationships between bcl-2 protein expression in primary breast cancers and other markers of prognostic and therapeutic value and (ii) associations of the bcl-2 protein with breast cancer responsiveness to endocrine therapy. The bcl-2 protein was found within the tumour epithelial cell cytoplasm of 32/46 breast cancer specimens; inter-patient staining was heterogeneous. Immunostaining for steroid hormone receptors was strongly associated with that for the bcl-2 protein, and it is thus possible that this protein, like progesterone receptor, is under oestrogen regulation via oestrogen receptor. The protein was inversely related to 2 markers of endocrine insensitivity, epidermal growth factor receptor (EGFR) and c-erbB-2 oncoprotein, while no associations were observed with either transforming growth factor (TGF)-alpha or Ki-67 proliferative status. A highly significant relationship was observed between response to endocrine therapy and the presence of bcl-2 protein. Indeed, bcl-2 immunostaining proved to be a more accurate predictor of response than oestrogen receptor status. Patients with elevated bcl-2 immunostaining (particularly those who coexpressed high oestrogen receptor levels) appeared to derive the greatest benefit from endocrine therapy. Our results are paradoxical since it was expected that the bcl-2 protein would counteract the tumour inhibitory effects of endocrine therapies as it is thought to prevent programmed cell death.

Non-carbon dioxide greenhouse gases are considered in "Canada's National Report on Climate Change: Actions to Meet Commitments Under the United Nations Framework Convention on Climate Change". By including all major greenhouse gases and their anthropogenic sources and sinks using best available science, the Report provides a practical illustration of the "comprehensive approach" policy to implementing the Convention's requirements. In addition to carbon dioxide emissions from fossil fuel combustion, the Report includes information on other sources and sinks for carbon dioxide, and for methane and nitrous oxide. Other gases considered include polyflourocarbons, hydroflourocarbons, and the primary tropospheric ozone precursors, nitrogen oxides and volatile organic compounds. Current Global Warming Potential indices are used to compare and integrate the best estimates of climate change impacts of the major greenhouse gases. The presentation of emission data is intended to be transparent and comparable. The relative quality of the data for various gases and sources is indicated. The existence of environmental, economic, and other benefits to limiting emissions of all greenhouse gases, in addition to carbon dioxide, should be recognized. Continuing assessments and actions on non-carbon dioxide greenhouse gas emissions, both nationally and internationally, are suggested.

Anorganic bovine bone has been used in oral and maxillofacial surgery for several years. Its use has been limited to ridge augmentation. In this paper we have tried to evaluate its use in other settings within the speciality.

The expression of the epidermal growth factor receptor (EGF-R), c-erbB-2 protein product and Ki67 have been evaluated in 105 breast cancers of known responsiveness to endocrine therapy using immunohistochemistry. EGF-R staining was observed in 62 of the tumours and was significantly associated with elevated rates of cell proliferation (%Ki67 positive cells) and loss of hormone sensitivity. In contrast, c-erbB-2 expression was not correlated with cell proliferation rates and was less strongly related to hormone insensitivity. Subdivision of the EGF-R data according to c-erbB-2 measurements revealed an association between c-erbB-2 immunostaining and worsened patient outlook and hormone insensitivity in moderately EGF-R-positive tumours. c-erbB-2 immunostaining in highly EGF-R-positive tumours did not further contribute to the already poor prognosis of these patients. These data confirm the prognostic importance of EGF-R measurements in breast cancer and may infer a functional interaction between this protein and the c-erbB-2 protein product in the aberrant growth of a subset of breast tumours.

Considerable interest is currently being shown in the use of information technology to assist in improving group process, particularly those associated with strategic planning. Three major approaches are developing to provide this support, and these are described in this article. In general, articles about Group DSS are overwhelmingly favourable to the approaches, although research findings suggest that some forms of Group DSS can have deleterious effects on the quality of meetings. These research findings are discussed.

Two hundred and fifty five patients undergoing treatment for oral cancer were studied. Tumour site, classification and treatment modality were recorded and an assessment of their ability to swallow was made postoperatively. Patients were graded into one of three groups depending on dietary consistency. Pre- and postoperative dental examinations were made and patients were weighted pre- and postoperatively. Postoperative functional problems are outlined. The results indicated that 21% of the sample reported difficulty with swallowing solid foods and 46% were limited to semi-solid or liquid diets postoperatively; 16% were unable to wear upper or lower dentures postoperatively and 15% of edentulous patients were able to wear an upper denture only; 65% of the patients who had surgery and radiotherapy were unable to regain their preoperative weight after 6 months. Patients with T1 tumours who did not progress to radiotherapy faired much better postoperatively and were more likely to return to normal diet and regain their preoperative weight.

Qualitative and semiquantitative assessments of oestrogen receptor and progesterone receptor positivity determined on previously immunocytochemically stained slides were performed by eight independent assessors. Concordance between assessments of steroid receptor status was good (24/25, 96%). Interassessor variations in estimates of positive immunostaining levels were high, varying by between 10 and 75% for individual slides. In 2 cases estimates for the same section ranged between 15% nuclei positive and 90% nuclei positive. Wide variations were also recorded for slides stained for progesterone receptors. Results using an assessment procedure combining staining intensity and percentage positivity estimates were also subject to marked discordance. A computerised image analysis system, also used to assess slides gave results similar to the mean manually determined percentage positivity values. It is suggested that quality control of steroid receptor immunocytochemical quantification be considered and that automated image analysis may represent an accurate and valid means of achieving this.

Frozen sections of breast tumor tissue have been stained using an immunoperoxidase [estrogen receptor (ER)-immunocytochemistry] kit incorporating a monoclonal antiserum [H222] to visualize nuclear human ERs. Quantitation of specific staining has been performed by manual procedures using optical microscopy and by a computer-assisted image analysis system (CAS 100). Initial investigations with a test panel of ER-immunocytochemistry-positive tumors revealed a good qualitative agreement between CAS and manual assessments. Reduced variance was, however, observed between quantified ER-immunocytochemistry results from four experienced investigators using the CAS analysis. An extended study confirmed the relationships between CAS and manual methods of assessment. These findings were evident when studies were scored either by assessment of the percentage of positively stained cells (n = 92; r = 0.919; P less than 0.01) or by H-score calculations (n = 92; r = 0.913; P less than 0.01). A good correlation was also found between CAS quantification and the results of an ER enzyme immunoassay of 48 primary breast cancer specimens (r = 0.715; P less than 0.05). In 49 cases it was possible to relate CAS-defined ER status and levels to the subsequent response of patients to endocrine therapy. ER was assessed on specimens obtained prior to commencement of treatments for recurrent breast cancer. Presuming the presence of ER to be a prerequisite for successful therapy, very good correlations between response and both status and levels of positivity were recorded. None of 16 patients with CAS-ER-negative tumors responded to treatment, while 16 of 33 (48.4%) CAS-ER-positive patients achieved an objective response according to International Union Against Cancer criteria. A relationship between response and the degree of CAS-ER positivity was obtained when the CAS score divisions of 0, 1-100, and greater than 100 (response rates, 0, 41, and 64%, respectively) were used. These data demonstrate that automated image analysis offers a reliable, reproducible procedure for quantifying ER in immunocytochemically stained sections. It has potential advantages over manual procedures, providing less opportunity for subjective influences in scoring sections. Future advances in software design should further reduce elements of subjectivity and increase both the speed and reliability of results. We anticipate image analysis becoming a valuable tool in investigations concerning, for example, the influence of heterogeneity of steroid receptor distribution on the rate of recurrence of breast cancer after mastectomy and in the clinical course of the disease.

One hundred and forty-seven patients with unstable fractures of the zygoma are discussed. Complications encountered during the treatment of such patients with antral packs and external pins are compared. These results are evaluated.

An estrogen receptor enzyme immunoassay kit (ER-EIA) has been evaluated in 70 human breast carcinomas against a routine cytoplasmic [3H]estradiol binding assay (ERU). A linear correlation between the ER-EIA and the ERU was observed for binding values up to 400 fmol/mg of cytosol protein. Above this value, the ERU underestimates the concentration of receptor. The ERU gave a lower number of estrogen receptor-positive tumors (50 of 70) than did the ER-EIA assay (59 of 70). In the ERU-negative ER-EIA-positive tumors, receptor values as determined by the ER-EIA assay all fell below 50 fmol/mg of protein (mean, 19.9 +/- 4.2 fmol/mg of protein). Application of an exchange procedure which estimates the total steroid binding capacity of the cytosol gave positive results in 7 of 9 ERU-negative ER-EIA-positive tumors (mean, 16.9 +/- 2.95 fmol/mg of protein). Subdivision of the binding data according to the menopausal status of the patient indicates low receptor values in premenopausal women by each assay. A correlation between the ER-EIA assay and the histological grade of tumors was observed; Grade I well-differentiated tumors were all positive, while Grade II and III tumors were 86% and 75% positive, respectively. No correlation between the ER-EIA assay and tumor lymph node stage or tumor size was observed.