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The Black populations, often treated as ethnically homogenous, face a constant challenge in accessing and utilizing healthcare services. This study examines the intra-group differences in health-seeking behavior among diverse ethnic subgroups within Black communities. A cross-sectional analysis included 239 adults ≥18 years of age who self-identified as Black in the United States and Canada. Multiple logistic regression assessed the relationship between health-seeking behaviors and ethnic origin, controlling for selected social and health-related factors. The mean age of the participants was 38.6 years, 31% were male, and 20% were unemployed. Sixty-one percent reported a very good or excellent health status, and 59.7% were not receiving treatment for chronic conditions. Advancing age (OR = 1.05, CI: 1.01-1.09), female gender (OR = 3.09, CI: 1.47-6.47), and unemployment (OR = 3.46, CI: 1.35-8.90) were associated with favorable health-seeking behaviors. Compared with the participants with graduate degrees, individuals with high school diplomas or less (OR = 3.80, CI: 1.07-13.4) and bachelor's degrees (OR = 3.57, CI: 1.3-9.23) were more inclined to have engaged in favorable health-seeking behavior compared to those with graduate degrees. Across the Black communities in our sample, irrespective of ethnic origins or country of birth, determinants of health-seeking behavior were age, gender, employment status, and educational attainment.

Background & Aims: Texas has the highest age-adjusted incidence rate of hepatocellular carcinoma (HCC) in the United States. The Cancer Prevention and Research Institute of Texas has funded the Texas Collaborative Center for Hepatocellular Cancer (TeCH) to facilitate HCC research, education, and advocacy activities with the overall goal of reducing HCC mortality in Texas through coordination, collaboration, and advocacy., Methods: On September 17, 2022, TeCH co-sponsored a multi-stakeholder conference on HCC with the Baker Institute Center for Health and Biosciences. This conference was attended by HCC researchers, policy makers, payers, members from pharmaceutical industry and patient advocacy groups in and outside of Texas. This report summarizes the results of the conference., Results: The goal of this meeting was to identify different strategies for preventing HCC and evaluate their readiness for implementation., Conclusions: We call for a statewide (1) viral hepatitis elimination program; (2) program to increase nonalcoholic steatohepatitis and obesity awareness; (3) research program to develop health care models that integrate alcohol associated liver disease treatment and treatment for alcohol use disorder; and (4) demonstration projects to evaluate the effectiveness of identifying and linking patient with advanced fibrosis and cirrhosis to clinical care., (Copyright © 2023 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Prior work has found a negative priming effect for a sequence, and more purely time-based negative priming has also been identified. Although sequential effects have been reported with both visual and auditory stimuli, only visual stimuli have been used in experiments examining purely temporal negative priming. In this article, sequential and temporal negative priming are compared across modalities. Prime trials included random presentation of a target (auditory bird chirp or visual X), a non-target (auditory dog bark or visual O), and two neutral stimuli (auditory computer beeps or empty visual boxes). Probe trials included random presentation of the target and three neutral stimuli. Participants indicated the temporal location of the target. On 88% of the trials, participants ( N  = 119 in Experiment 1; N  = 65 in Experiment 2) indicated the location of the non-target stimulus from the prime trial. Results showed an increase in response time when the temporal location of the probe's target was the same as the location of the non-target stimulus from the prime trial, but this only occurred when the prime was presented more slowly. Experiment 2 tested, and falsified, the hypothesis that a fixed amount of time on the prime is necessary to bind features of the non-target stimulus with temporal and sequential positions. Together, these data show that sequential and temporal negative priming effects generalise across modality and that relative rather than fixed timing is critical. Implications for theories of negative priming are discussed.

Skyrmion-based devices have been proposed as a promising solution for low-energy data storage. These devices include racetrack or logic structures and require skyrmions to be confined in regions with dimensions comparable to the size of a single skyrmion. Here we examine skyrmions in FeGe device shapes using Lorentz transmission electron microscopy to reveal the consequences of skyrmion confinement in a device-like structure. Dumbbell-shaped elements were created by focused ion beam milling to provide regions where single skyrmions are confined adjacent to areas containing a skyrmion lattice. Simple block shapes of equivalent dimensions were also prepared to allow a direct comparison with skyrmion formation in a less complex, yet still confined, device geometry. The impact of applying a magnetic field and varying the temperature on the formation of skyrmions within the shapes was examined. This revealed that it is not just confinement within a small device structure that controls the position and number of skyrmions but that a complex device geometry changes the skyrmion behavior, including allowing skyrmions to form at lower applied magnetic fields than in simple shapes. The impact of edges in complex shapes is observed to be significant in changing the behavior of the magnetic textures formed. This could allow methods to be developed to control both the position and number of skyrmions within device structures., Competing Interests: The authors declare no competing financial interest., (© 2022 The Authors. Published by American Chemical Society.)

Texas has the highest age-adjusted incidence rate of hepatocellular carcinoma (HCC) in the United States. To address cancer prevention and early detection through research, Cancer Prevention and Research Institute of Texas (CPRIT) has funded the Texas Collaborative Center for Hepatocellular Cancer (TeCH) to facilitate liver cancer research, education and advocacy activities. This paper describes the organizational structure, program measures, the actions completed and future plans of TeCH. This center is comprised of several cores and committees including the Administrative Core, Steering Committee, Data and Biospecimen Core, Scientific Committee, Clinical Network Committee, and the Community Outreach Committee. Each core and committee provide its own level of connectivity and necessary research support. We have developed and published a TeCH Framework, a conceptual model designed for improving primary and secondary prevention of HCC. TeCH and its committees facilitate connections and collaborations among HCC researchers and clinicians, healthcare leaders, biotechnology companies and the public to reduce liver cancer mortality in Texas by 2030., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Harrison, Kanwal, Asrani, Thrift, Amos, Jibaja-Weiss, Montealegre, Hwang, Singal and El-Serag.)

Background: Home oxygen therapy is prescribed for patients with advanced lung disease based on the criteria established in landmark trials in subjects with COPD. In clinical practice, its use has been extrapolated to other diseases, including interstitial lung disease (ILD). Patients with COPD and ILD experience a high symptom burden and require access to specialized multidisciplinary care. We aimed to evaluate the health-related outcomes and supportive care needs of patients with COPD and ILD receiving home oxygen therapy., Methods: This was a retrospective cohort study using the oxygen database of a quaternary metropolitan teaching hospital. Patients with a diagnosis of COPD or ILD who were prescribed home oxygen therapy between January 2012-December 2018 were identified. Demographic information, results of physiologic testing, comorbidities, hospitalizations, and mortality data were collected., Results: Three hundred and eighty-four subjects were included for analysis, of whom 56% were male. The median age was 75 y. The majority (59%) had a diagnosis of COPD. Long-term oxygen therapy (LTOT) was prescribed for 187 (48.7%), with no significant demographic differences between those with COPD or ILD. Another 187 were prescribed ambulatory oxygen alone, with 55 transitioning to LTOT during the study period. Most subjects (65.4%) were referred for pulmonary rehabilitation; however, palliative care referrals were generally low (22.9%). Referrals to other medical specialties and allied health were common (82%). Transplant-free survival after commencement of LTOT was poor, with 38% of subjects surviving at 5 y. The 5-y survival of subjects with ILD after commencing on LTOT was 10% compared to 52% for those with COPD. Multivariable Cox regression analyses showed that the only predictor of survival after commencing LTOT was the principal respiratory diagnosis., Conclusions: This study found that subjects prescribed LTOT had poor transplant-free survival after initiation, which was significantly worse for those with ILD compared to those with COPD. Despite their poor overall survival, worse than many cancers, only a minority were referred for palliative care input. Referrals to pulmonary rehabilitation were also suboptimal. This patient population had complex care needs requiring multidisciplinary management. Appropriate and early referrals to palliative care and improved care coordination for this complex group of patients are key areas for improvement in clinical practice., Competing Interests: Dr Khor discloses relationships with Air Liquide Healthcare, Boehringer Ingelheim, and Roche. Dr McDonald discloses relationships with Air Liquide Healthcare and Menarini. The remaining authors have disclosed no conflicts of interest., (Copyright © 2022 by Daedalus Enterprises.)

Magnetic skyrmions are topologically nontrivial particles with a potential application as information elements in future spintronic device architectures. While they are commonly portrayed as two dimensional objects, in reality magnetic skyrmions are thought to exist as elongated, tube-like objects extending through the thickness of the host material. The study of this skyrmion tube state (SkT) is vital for furthering the understanding of skyrmion formation and dynamics for future applications. However, direct experimental imaging of skyrmion tubes has yet to be reported. Here, we demonstrate the real-space observation of skyrmion tubes in a lamella of FeGe using resonant magnetic x-ray imaging and comparative micromagnetic simulations, confirming their extended structure. The formation of these structures at the edge of the sample highlights the importance of confinement and edge effects in the stabilisation of the SkT state, opening the door to further investigation into this unexplored dimension of the skyrmion spin texture.

The intense research effort investigating magnetic skyrmions and their applications for spintronics has yielded reports of more exotic objects including the biskyrmion, which consists of a bound pair of counter-rotating vortices of magnetization. Biskyrmions have been identified only from transmission electron microscopy images and have not been observed by other techniques, nor seen in simulations carried out under realistic conditions. Here, quantitative Lorentz transmission electron microscopy, X-ray holography, and micromagnetic simulations are combined to search for biskyrmions in MnNiGa, a material in which they have been reported. Only type-I and type-II magnetic bubbles are found and images purported to show biskyrmions can be explained as type-II bubbles viewed at an angle to their axes. It is not the magnetization but the magnetic flux density resulting from this object that forms the counter-rotating vortices., (© 2019 The Authors. Published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Pronounced improvements in the understanding of semiconductor device performance are expected if electrostatic potential distributions can be measured quantitatively and reliably under working conditions with sufficient sensitivity and spatial resolution. Here, we employ off-axis electron holography to characterize an electrically-biased Si p-n junction by measuring its electrostatic potential, electric field and charge density distributions under working conditions. A comparison between experimental electron holographic phase images and images obtained using three-dimensional electrostatic potential simulations highlights several remaining challenges to quantitative analysis. Our results illustrate how the determination of reliable potential distributions from phase images of electrically biased devices requires electrostatic fringing fields, surface charges, specimen preparation damage and the effects of limited spatial resolution to be taken into account., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Major depressive disorder (MDD) is a serious public health burden and a leading cause of disability. Its pharmacotherapy is currently limited to modulators of monoamine neurotransmitters and second-generation antipsychotics. Recently, glutamatergic approaches for the treatment of MDD have increasingly received attention, and preclinical research suggests that metabotropic glutamate receptor 5 (mGlu5) inhibitors have antidepressant-like properties. Basimglurant (2-chloro-4-[1-(4-fluoro-phenyl)-2,5-dimethyl-1H-imidazol-4-ylethynyl]-pyridine) is a novel mGlu5 negative allosteric modulator currently in phase 2 clinical development for MDD and fragile X syndrome. Here, the comprehensive preclinical pharmacological profile of basimglurant is presented with a focus on its therapeutic potential for MDD and drug-like properties. Basimglurant is a potent, selective, and safe mGlu5 inhibitor with good oral bioavailability and long half-life supportive of once-daily administration, good brain penetration, and high in vivo potency. It has antidepressant properties that are corroborated by its functional magnetic imaging profile as well as anxiolytic-like and antinociceptive features. In electroencephalography recordings, basimglurant shows wake-promoting effects followed by increased delta power during subsequent non-rapid eye movement sleep. In microdialysis studies, basimglurant had no effect on monoamine transmitter levels in the frontal cortex or nucleus accumbens except for a moderate increase of accumbal dopamine, which is in line with its lack of pharmacological activity on monoamine reuptake transporters. These data taken together, basimglurant has favorable drug-like properties, a differentiated molecular mechanism of action, and antidepressant-like features that suggest the possibility of also addressing important comorbidities of MDD including anxiety and pain as well as daytime sleepiness and apathy or lethargy., (Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.)

Two-dimensional finite element simulations of electrostatic dopant potentials in parallel-sided semiconductor specimens that contain p-n junctions are used to assess the effect of the electrical state of the surface of a thin specimen on projected potentials measured using off-axis electron holography in the transmission electron microscope. For a specimen that is constrained to have an equipotential surface, the simulations show that the step in the projected potential across a p-n junction is always lower than would be predicted from the properties of the bulk device, but is relatively insensitive to the value of the surface state energy, especially for thicker specimens and higher dopant concentrations. The depletion width measured from the projected potential, however, has a complicated dependence on specimen thickness. The results of the simulations are of broader interest for understanding the influence of surfaces and interfaces on electrostatic potentials in nanoscale semiconductor devices., (© 2013 Elsevier B.V. All rights reserved.)

A novel tertiary amine series of potent muscarinic M(3) receptor antagonists are described that exhibit potential as inhaled long-acting bronchodilators for the treatment of chronic obstructive pulmonary disease. Geminal dimethyl functionality present in this series of compounds confers very long dissociative half-life (slow off-rate) from the M(3) receptor that mediates very long-lasting smooth muscle relaxation in guinea pig tracheal strips. Optimization of pharmacokinetic properties was achieved by combining rapid oxidative clearance with targeted introduction of a phenolic moiety to secure rapid glucuronidation. Together, these attributes minimize systemic exposure following inhalation, mitigate potential drug-drug interactions, and reduce systemically mediated adverse events. Compound 47 (PF-3635659) is identified as a Phase II clinical candidate from this series with in vivo duration of action studies confirming its potential for once-daily use in humans.

New N-(1,2-diphenylethyl)piperazines 6 are disclosed as dual serotonin and noradrenaline reuptake inhibitors (SNRI) which may have potential in treating stress urinary incontinence (SUI). In this Letter, we present new data for SNRI PF-526014 (4) including performance in a canine in vivo model of SUI, cardiovascular assessment, pharmacokinetics in dog and determination of the primary routes of metabolism in vitro. Starting from 4, detailed structure activity relationships established that potent dual SNRIs could be achieved by appropriate substitution of the phenyl rings (6: R; R(1)) combined with a preferred stereochemistry. From this set of compounds, piperazine (-)-6a was identified as a potent and selective dual SNRI with improved metabolic stability and reduced ion channel activity when compared to 4. Based on this profile, (-)-6a was selected for further evaluation in a preclinical model of SUI., (Copyright 2010 Elsevier Ltd. All rights reserved.)

The structure-activity relationship and the synthesis of novel N-[(3S)-pyrrolidin-3-yl]benzamides as dual serotonin and noradrenaline monoamine reuptake inhibitors (SNRI) is described. Preferred compound 9 aka PF-184,298 is a potent SNRI with good selectivity over dopamine reuptake inhibition (DRI), good in vitro metabolic stability, weak CYP inhibition and drug-like physicochemical properties consistent with CNS target space. Evaluation in an in vivo preclinical model of stress urinary incontinence showed 9 significantly increased urethral tone at free plasma concentrations consistent with its in vitro primary pharmacology.

Focused Ion beam (FIB) prepared GaAs p-n junctions have been examined using off-axis electron holography. Initial analysis of the holograms reveals an experimentally determined built-in potential in the junctions that is significantly smaller than predicted from theory. In this paper we show that through combinations of in situ annealing and in situ biasing of the specimens, by varying the intensity of the incident electron beam, and by modifying the FIB operating parameters, we can develop an improved understanding of phenomena such as the electrically 'inactive' thickness and subsequently recover the predicted value of the built-in potential of the junctions. PACS numbers: 85.30.De.

Electron tomography and electron holography experiments have been combined to investigate the 3D electrostatic potential distribution in semiconductor devices. The experimental procedure for the acquisition and data reconstruction of holographic tilt series of silicon p-n junction specimens is described. A quantitative analysis of the experimental results from specimens of two different thicknesses is presented, revealing the 3D electrostatic potential variations arising from the presence of surfaces and damage generated by focused ion beam (FIB) sample preparation. Close to bulk-like properties are measured in the centre of the tomographic reconstruction of the specimen, revealing higher electrically active dopant concentrations compared to the measurements obtained at the specimen surfaces. A comparison of the experimental results from the different thickness specimens has revealed a 'critical' thickness for this specimen preparation method of 350nm that is required for this device structure to retain 'bulk'-like properties in the centre of the membrane.

The need to determine the electrical properties of semiconductor junctions with high spatial resolution is as pressing now as ever. One technique that offers the possibility of quantitative high-resolution mapping of two- and three-dimensional electrostatic potential distributions is off-axis electron holography. In this study, we review some of the issues associated with interpreting phase shifts measured using off-axis electron holography, and we describe how a quantitative determination of the dopant-related electrostatic potential can be achieved for device structures. Issues that include the presence of surface "dead" layers, external electrostatic fringing fields, variations in specimen thickness and dynamical diffraction are discussed, and their impact on the quantification of results obtained using off-axis electron holography is examined.

The nontuberculous mycobacteria (NTM) exhibit heterogeneous pathogenicity in humans. Articles on known and potential human factors capable of producing susceptibility to NTM lung disease (NTMLD) were identified by a systematic search of the medical literature, and are reviewed in the present study. Patients with pre-existing structural lung disease are known to be at risk of NTMLD. Other susceptible groups have become recognised since the 1980s, in particular middle-aged nonsmokers without previous lung disease (a group including those with Lady Windermere syndrome) and patients with genetically determined defects of cell-mediated immunity, including abnormalities of the interleukin-12/interferon-gamma axis, certain human leukocyte antigen alleles, cystic fibrosis transmembrane conductance regulator mutations, and polymorphisms of solute carrier 11A1 (or natural resistance-associated macrophage protein 1) and the vitamin D receptor. Information is also accruing about acquired systemic causes of susceptibility to NTMLD, including inhibitory antibodies directed against interferon-gamma, post-menopausal waning of endogenous oestrogen levels, coeliac disease and exposure to use of dietary phyto-oestrogens. It is not known whether immunosuppressive factors, such as oral corticosteroid treatment, chronic renal failure, diabetes mellitus and other known risk factors for pulmonary tuberculosis, are also risk factors for the development of NTMLD. Caution is appropriate in managing such patients.

It was hypothesised that the time to detect Mycobacterium tuberculosis in liquid culture of sputum from patients with pulmonary tuberculosis may be a better indicator for the duration of respiratory isolation than sputum smear status. Pre-treatment and during-treatment sputum acid-fast bacilli (AFB) smear and culture results were reviewed in 284 patients with pulmonary tuberculosis. The time to detect M. tuberculosis in liquid culture (TTD-TB) was the number of days from inoculation of the Mycobacterial Growth Indicator Tube to culture detection and visualisation of AFB. The median (interquartile range) TTD-TB for smear group 0 (no bacilli seen) was 14 (12-20) days. This value was used as the standard at which release from isolation could be permitted. In smear group 4 (>9 AFB per high-power field (hpf) in sputum specimens before treatment) patients, the TTD-TB exceeded 14 days after a median of 25 days of treatment. The current authors recommend that patients in smear groups 1 and 2 (1-9 AFB per 100 hpf and 1-9 AFB per 10 hpf in sputum specimens before treatment, respectively) receive treatment in respiratory isolation for 7 days, provided the risk of drug resistance is low. Smear group 3 (1-9 AFB per hpf) and 4 patients should receive treatment in respiratory isolation for 14 and 25 days, respectively. These criteria would have reduced the duration of respiratory isolation by 1,516 days in the 143 study participants with sputum smear-positive pulmonary tuberculosis. Provided clinical and radiographical criteria are satisfactory, use of the time to detect Mycobacterium tuberculosis in liquid culture could enable the duration of respiratory isolation to be predicted from the pre-treatment sputum smear grade. The recommendations enable isolation to end well before sputum becomes smear negative, with considerable benefits to patients and healthcare providers.

Background and Objective: This study's aims were to identify the diagnoses, the public hospital costs and payments for non-New Zealand (non-NZ) patients referred because of possible tuberculosis (TB). There have been no previous financial studies in this area. Funding arrangements for these patients were also reviewed., Methods: A systematic, retrospective review was performed to identify the costs of investigating and managing non-NZ patients referred to the adult TB unit of a large, teaching hospital in Auckland, NZ. Patients were enrolled between 1 July 2002 and 30 June 2003., Results: Forty-five non-NZ patients were studied. The mean age was 33.8 (+/-13.4) years. Thirty-four (75.5%) were managed under compulsion through Section 9 of the NZ TB Act. Thirty-two (71%) patients received TB treatment: 11 (24%) had infectious pulmonary TB and four had active extra-pulmonary TB. There were no multi-drug-resistant isolates. Three TB cases accounted for 250 (39%) inpatient days. One patient with rifampicin-resistant TB was responsible for 117 (29%) day-patient ward visits. Four (13%) infectious TB cases were managed as inpatients for more than 6 weeks. The total cost of services (US dollars) for the 45 patients was 350,236 dollars. The cost range was 544-43,513 dollars per patient. Four patients incurred costs over 25,000 dollars., Conclusions: TB in non-residents is a costly problem in NZ. Current policy applying to this area and the ability to determine its cost-effectiveness are in need of review.

Governments and physician organizations in Canada have identified current and anticipated future shortages of physicians. The creation of opportunities for licensure for the sizeable population of unlicensed international medical graduates (IMG) residing in Canada can alleviate some of the shortage of medical manpower. We examine whether expenditures on IMG skills assessment, training and licensing are a socially desirable use of resources. We estimate the financial rate of return to Alberta taxpayers from resources allocated to the Alberta International Medical Graduate (AIMG) program, started in 2001. Our estimates show that resources allocated to providing skills assessment and residency training opportunities for IMGs that lead to licensing as a Canadian physician generate real annual rates of return of 9-13%.

Background: Previous studies suggest that bronchoscopy and a single induced sputum sample are equally effective for diagnosing pulmonary tuberculosis., Methods: In a prospective study of subjects with possibly active pulmonary tuberculosis, the diagnostic yield of three induced sputum tests was compared with that of bronchoscopy. Subjects either produced no sputum or (acid fast) smear negative sputum. Bronchoscopy was only performed if at least two induced sputum samples were smear negative., Results: Of 129 subjects who completed all tests, 27 (21%) had smear negative and culture positive specimens, 14 (52%) on bronchoscopy and 26 (96%) on induced sputum (p<0.005). One patient was culture positive on bronchoscopy alone compared with 13 on induced sputum alone; 13 were culture positive on both tests. Induced sputum positivity was strikingly more prevalent when chest radiographic appearances showed any features of active tuberculosis (20/63, 32%) than when appearances suggested inactivity (1/44, 2%; p<0.005). Induced sputum costs were about one third those of bronchoscopy, and the ratio of costs of the two tests per case of tuberculosis diagnosed could be as much as 1:6., Conclusions: In subjects investigated for possibly active or inactive tuberculosis who produce no sputum or have smear negative sputum, the most cost effective strategy is to perform three induced sputum tests without bronchoscopy. Induced sputum testing carries a high risk of nosocomial tuberculosis unless performed in respiratory isolation conditions. The cost benefits shown could be lost if risk management measures are not observed.

We have previously demonstrated that p(1),p(4)-diadenosine 5'-tetraphosphate induces the release of NO and modulates the uptake of L-arginine by bovine aortic endothelial cells (BAEC) [Hilderman, R. H., and Christensen, E. F. (1998) FEBS Lett. 407, 320-324; Hilderman, R. H., Casey, T. E., and Pojoga, L. H. (2000) Arch. Biochem. Biophys. 375, 124-130]. In this communication we characterize the uptake of L-Arg by BAEC. L-Arg is transported into BAEC by at least two different transporter systems. One transporter system is protein synthesis dependent, and L-Arg transported by this system is incorporated into proteins. The second transporter system involved in L-Arg uptake is protein synthesis independent, and uptake occurs by facilitated diffusion. The L-Arg transported by facilitated diffusion is metabolized into L-argininosuccinate. Homologous and heterologous competition uptake studies were performed using a fixed concentration of radiolabeled L-Arg, L-lysine, and L-leucine with varying concentrations of competing nonradiolabeled amino acids. The results of these competition uptake studies are consistent with the protein-synthesis-dependent uptake of L-Arg taking place through a transporter system that is highly specific for L-Arg and with the facilitated diffusion uptake taking place through a transporter that is specific for L-Arg and L-Leu., (Copyright 2000 Academic Press.)

We evaluated an in vitro test of cell-mediated immunity, the tuberculin gamma interferon assay, QuantiFERON-TB (QIFN), in 455 individuals from three groups: group I, 237 immigrants from high-risk countries; group II, 127 health care workers undergoing Mantoux testing; group III, 91 patients being investigated for possible active tuberculosis (79 patients) or Mycobacterium avium-Mycobacterium intracellulare complex infection (12 patients). The QIFN results were compared either to those of the Mantoux test or to microbiological and clinical diagnosis, as appropriate. In each group the correlation between the diameter of induration for the skin test and the magnitude of QIFN response was significant and of moderate strength (Spearman's rank correlation coefficient; rho = 0.59 to 0.61; P < 0.001). For group I, the agreement between QIFN and Mantoux results was 89% for Mantoux-negative and 64% for Mantoux-positive individuals. For group II, when >/=10-mm-diameter induration was taken as positive, the agreement was 81% for Mantoux-negative and 67% for Mantoux-positive individuals. For group III, agreement was 81% for Mantoux-negative and 86% for Mantoux-positive patients. For patients being evaluated for active tuberculosis, the performance of the Mantoux test was not statistically different from that of the QIFN assay. In patients with active tuberculosis, the assay had a sensitivity of 77%, not significantly higher for extrapulmonary than pulmonary cases (83% versus 74%). QIFN sensitivity was not significantly different for smear-negative or smear-positive cases (80% versus 71%). The QIFN assay is a potential replacement for the Mantoux test. The acceptability of these performance values and those of similar evaluations will determine the place this test will have in detecting evidence of mycobacterial infection.

Aims: To evaluate the role of fine needle aspiration (FNA) in the diagnosis of tuberculous and non-tuberculous mycobacterial cervical adenitis in Auckland, and to examine the demography of these conditions., Method: We reviewed the medical records of cases of mycobacterial adenitis in the Auckland region between 1991-1994. Cases were identified by cross-checking the reference mycobacteriology laboratory records, all hospital cytology reports from cases who had an FNA taken from the neck region and hospital discharge diagnosis databases., Results: Twenty-two cases of M tuberculosis adenitis, and 13 of M avium adenitis were identified. No FNAs were smear positive for mycobacteria. The FNA from 6/18 (33%) cases of M tuberculosis adenitis and from 4/6 (66%) M avium adenitis cases were culture positive. Bacteriological confirmation was obtained (by various methods) in 72% of tuberculous and in 100% of M avium adenitis cases. The clinical picture was different for the two organisms: tuberculous adenitis occurred mainly in caucasian adults, while M avium adenitis cases were predominantly caucasian children. None of the confirmed cases of tuberculous adenitis demonstrated drug resistance to standard anti-tuberculous agents., Conclusions: (1) Clinicians should more consistently include mycobacterial tests when investigating neck lumps. (2) FNA is not a reliable diagnostic test for mycobacterial cervical adenitis in New Zealand. Here, FNA should only be regarded as a screening test for mycobacterial adenitis. If anti-tuberculous treatment is required before it is known whether FNA has provided a positive culture, excision biopsy should first be performed to identify the mycobacterium and its susceptibility pattern.

Aims: To document the clinical and demographic features of cases of ethambutol ocular toxicity, to review the literature on this subject and to critically review current guidelines for ethambutol administration., Methods: Cases of ocular toxicity from ethambutol were sought retrospectively at Green Lane and Wellington Hospitals between 1992 and 1995. The records of cases identified were examined., Results: Four subjects with tuberculosis developed ocular toxicity 2 1/2, 7 1/2, 8 and 12 months after starting ethambutol. Normal visual acuity returned in three cases; one patient has severe, permanent visual impairment. Language difficulties were present in three subjects., Conclusions: Impaired communication was potentially very important in this series. Special care is needed in educating patients about ethambutol. We propose additional recommendations: 1. the usual daily dose of ethambutol should be 15 mg/kg/day, not 25 mg/kg/day; using 25 mg/kg/day (or lesser doses in the presence of renal impairment) should prompt regular formal ophthalmological evaluation (e.g. monthly) in cases with comprehension or communication difficulties; 3. both ethambutol and isoniazid should be stopped immediately if severe optic neuritis occurs. Isoniazid should be stopped if less severe optic neuritis does not improve within six weeks after stopping ethambutol.

Automated standard and sample preparation have been coupled with 96-well solid phase extraction (SPE) technology to produce a cost effective, high throughput system for the analysis of drugs in biological media. The system was originally designed using the Packard Multiprobe 104DT robotic sample processor (RSP) to improve throughput for the assay of doramectin in cattle plasma, and the assay has since been validated (0.5-100 ng ml[-1]) using the Tecan Genesis RSP 150/8. The robotic processor conducts all liquid handling procedures involved in sample extraction. These comprise preparation of calibration standards in plasma, dispensing and diluting of plasma samples and addition of internal standard. In addition, the robot primes the 96-well SPE block, applies calibration standards and samples, draws the mixtures through the 96-well SPE block, and finally washes the block ready for manual elution. The doramectin assay involves high-performance liquid chromatography (HPLC) with fluorescence detection, and requires the sample extracts to be derivatised prior to analysis. The derivatisation procedure is performed manually in situ in the polypropylene deep 96-well block into which the samples have been eluted from the SPE-block. The derivatised samples are taken directly from the deep well block and injected into the HPLC for analysis. This type of batch processing keeps sample transfer to a minimum. Automated sample preparation, in combination with the use of 96-well technology, has reduced both cost and effort required in the analysis of doramectin in cattle plasma samples, and has resulted in improved sample throughput.

Aims: To review all cases of multidrug resistant tuberculosis (MDRTb) in Auckland between 1988-95; and to look for ways in which the diagnosis and management may be improved., Methods: Cases of multidrug resistant tuberculosis were identified from Green Lane Hospital tuberculosis laboratory records. Clinical details were obtained from hospital case records, and radiographs were reviewed., Results: Nine of the 838 (1.1%) confirmed cases of tuberculosis had multidrug resistant tuberculosis. Eight were foreign-born and four had previously been treated for tuberculosis. Three patients underwent thoracic surgery. Two patients died and one was not treated, No relapses have occurred. Potential to improve on the treatment given was evident in retrospect in three patients., Conclusions: Assessment of risk factors for multidrug resistant tuberculosis and early transfer of specimens to a tuberculosis reference laboratory are required to enable multidrug resistance to be identified early. Extensive disease, drug side effects and coexistent medical problems make MDRTb very difficult to cure. Directly observed therapy is recommended for multidrug resistant tuberculosis cases and is underutilised in Auckland.

1. The hepatic metabolism of the antimalarial drug amodiaquine was investigated in order to gain further insight into the postulated metabolic causation of the hepatotoxicity, which restricts the use of the drug. After intraportal (i.p.) administration (54 mumol/kg) to the anaesthetized rat, the drug was excreted in bile (23 +/- 3% dose over 5 h; mean +/- SD, n = 6) primarily as thioether conjugates. 2. After i.p. administration, 20% of the dose was excreted into urine over 24 h as parent compound and products of N-dealkylation and oxidative deamination. Desethylamodiaquine accumulated in liver, but was not a substrate for bioactivation as measured by biliary elimination of a glutathione adduct. 3. Prior administration of ketoconazole, an inhibitor of P450, reduced biliary excretion by 50% and effected a corresponding decrease in the amount of drug irreversibly bound to liver proteins. This indicated a role for P450 in the bioactivation of amodiaquine to a reactive metabolite that conjugates with glutathione and protein. 4. De-ethylation and irreversible binding were observed in vitro using male rat liver microsomes, and were again inhibited by ketoconazole. However, no such binding was observed with human (six individuals) hepatic microsomes despite extensive turnover of amodiaquine to desethylamodiaquine. 5. Amodiaquine quinoneimine underwent rapid reduction in the presence of either human or rat liver microsomes. Therefore in vitro studies may underestimate the bioactivation of amodiaquine in vivo. These data indicate that the extent of protein adduct formation in the liver will depend on the relative rates of oxidation of amodiaquine and reduction of its quinoneimine. This in turn may be a predisposing factor in the idiosyncratic hepatotoxicity associated with amodiaquine. 6. Substitution of a fluorine for the phenolic hydroxyl group in amodiaquine blocked bioactivation of the drug in vivo. Insertion of an N-hydroxyethyl function enabled partial clearance of amodiaquine and its deshydroxyfluoro analogue via O-glucuronidation and altered the balance between phase I oxidation and direct phase II conjugation of amodiaquine.

Amodiaquine (AQ) (2) is a 4-aminoquinoline antimalarial which causes adverse side effects such as agranulocytosis and liver damage. The observed drug toxicity is believed to be related to the formation of an electrophilic metabolite, amodiaquine quinone imine (AQQI), which can bind to cellular macro-molecules and initiate hypersensitivity reactions. 5'-Fluoroamodiaquine (5'-FAQ, 3), 5',6'-difluoroamodiaquine (5',6'-DIFAQ,4), 2',6'-difluoroamodiaquine (2',6'-DIFAQ,5), 2',5',6'-trifluoroamodiaquine (2',5',6'-TRIFAQ, 6) and 4'-dehydroxy-4'-fluoroamodiaquine (4'-deOH-4'-FAQ,7) have been synthesized to assess the effect of fluorine substitution on the oxidation potential, metabolism, and in vitro antimalarial activity of amodiaquine. The oxidation potentials were measured by cyclic voltammetry, and it was observed that substitution at the 2',6'- and the 4'-positions (2',6'-DIFAQ and 4'-deOH-4'-FAQ) produced analogues with significantly higher oxidation potentials than the parent drug. Fluorine substitution at the 2',6'-positions and the 4'-position also produced analogues that were more resistant to bioactivation. Thus 2',6'-DIFAQ and 4'-deOH-4'-FAQ produced thioether conjugates corresponding to 2.17% (SD: +/- 0.27%) and 0% of the dose compared with 11.87% (SD: +/- 1.31%) of the dose for amodiaquine. In general the fluorinated analogues had similar in vitro antimalarial activity to amodiaquine against the chloroquine resistant K1 strain of Plasmodium falciparum and the chloroquine sensitive T9-96 strain of P. falciparum with the notable exception of 2',5',6'-TRIFAQ (6). The data presented indicate that fluorine substitution at the 2',6'-positions and replacement of the 4'-hydroxyl of amodiaquine with fluorine produces analogues (5 and 7) that maintain antimalarial efficacy in vitro and are more resistant to oxidation and hence less likely to form toxic quinone imine metabolites in vivo.

Aims: to assess the results of the first two years experience with intermittent supervised treatment of tuberculosis (IST) in Auckland, looking especially at practical problems., Method: the hospital records of the 16 patients who received IST during 1987-8 were reviewed retrospectively, and public health nurses who administered the medications were questioned about problems that were encountered., Results: two-thirds of those who were given IST were Polynesian. In retrospect, the need for IST could have been anticipated in eight of the 12 patients (67%) who failed to comply with daily treatment. Five of the 16 IST patients presented major problems to the nurses supervising the twice weekly treatment. Poor motivation, itinerancy and alcohol abuse were the most common factors causing difficulty. IST was successfully completed in 13/16 patients (81%) and was abandoned in only one patient. Only two patients completed IST with a drug regimen for resistant organisms. Health nurse supervision resulted in improvements in understanding and attitude to tuberculosis, eventually enabling two patients to self medicate without supervision., Conclusions: IST is a practical treatment method in New Zealand, permitting curative therapy in a group of tuberculosis patients who would otherwise create risks of drug resistance, disease reactivation and spreading the disease.

A glutathione conjugate of amodiaquine has been isolated and characterized from rat bile after administration of [14C]amodiaquine (50 mumol/kg, 5.0 muCi/rat) to anaesthetized male Wistar rats. Thioether conjugates of amodiaquine in rat bile accounted for a total of 12% of the dose, 5 hr after administration of the drug. In addition, 1% of the dose remained in the liver covalently bound to tissue proteins after 5 hr. These findings provide direct evidence that a chemically reactive metabolite, amodiaquine quinoneimine, has been formed from the drug in vivo. A second major metabolite, desethylamodiaquine, accounting for 14% of the given dose, was present in the liver after 5 hr. Enzyme inhibition studies with ketoconazole-pretreated rats showed that both amodiaquine quinoneimine and desethylamodiaquine formation can be catalysed by cytochrome P450. The demonstration that amodiaquine readily and extensively forms a metabolite in vivo, with strong reactivity towards protein and non-protein thiol groups, may help to explain the idiosyncratic toxicity observed in man.

A 32 year old man with chronic severe asthma, requiring maintenance oral corticosteroids, was started on a weekly dose of methotrexate. Eleven weeks later he developed Pneumocystis carinii pneumonia. In the two years following treatment there has been no recurrence while oral corticosteroid treatment has been continued. Pneumocystis pneumonia should be considered in asthmatic patients taking methotrexate who present with fever, pulmonary infiltrates, and hypoxia.

To investigate the combined effect of water immersion (WI) and lean body mass on cardiac output (Q), 12 healthy young men, 6 lean (fat less than 9%) and 6 fat (fat greater than 18%), were studied at rest and during steady state exercise approximating 30-40% Vo2 max under three experimental conditions. There were on land at 24 degrees C (LND), and immersed in water at 33-34 degrees C to hip level (HIP), and to the xiphoid (XIP). Metabolic measures were determined during 30-s periods from the average breath measurements. Mixed venous PCO2 (PVCO2) was estimated using rebreathing equilibration technique. Cardiac output was calculated by the indirect Fick's principle. In the lean individuals the average Q rose from a resting value of 5.43 +/- 0.43 (LND) to an exercise value of 7.25 +/- 0.40 L/min (XIP), and from resting value of 5.62 +/- 0.40 to an exercise 6.47 +/- 0.5 L/min in the fat individuals. During exercise, the associated increase in Q with increasing WI was significantly (p less than 0.05) higher compared with the land experiments. Inspection of the mean profile corresponding to this increase indicated that an increase in the level of immersion results in a significant (p less than 0.05) increase in the average Q for the lean group. For the fat group, the average Q was significantly (p less than 0.05) larger only at XIP level. At rest, heart rate dropped from 67 +/- 3.36 (LND) to 60 +/- 4.13 (XIP), and from 79 +/- 3.73 to 73 +/- 4.10 BPM for the lean and fat group, respectively. MANOVA analysis showed a significant (p less than 0.05) interaction between WI and group membership, indicating that the effect of WI is significantly different between the two groups. These data indicate that the change in central blood volume with WI depends, in part, on the lean mass of the body.

Bronchial hyperresponsiveness (BHR) to inhaled histamine has often been cited as the gold standard in asthma diagnosis, but recently this has been questioned. This report assesses the relationship of BHR to asthma symptoms and asthma diagnosis in a large community-based sample of children. A total of 2,053 children 7 to 10 yr of age were randomly sampled from Auckland primary schools and assessed by a questionnaire and histamine inhalation challenge. In all, 14.3% had had asthma diagnosed, 29.6% reported having had one of the four respiratory symptoms in in the previous 12 months, and 15.9% had BHR (PD20 less than or equal to 7.8 mumol histamine). After a cumulative dose of 3.9 mumol histamine, the percent change in FEV1 from postsaline FEV1 was unimodally distributed, with those in whom asthma had been diagnosed dominating the severe end of the spectrum. However, 53% of those with BHR had no asthma diagnosis, and 41% had no current asthma symptoms. On the other hand, 48% of all subjects with diagnosed asthma and 42% of children with diagnosed asthma and current symptoms did not have BHR. Although severity of BHR tended to increase with wheezing frequency, all grades of severity (including no BHR) were found for any given frequency of wheeze. An existing diagnosis of asthma identified symptomatic children more accurately than did BHR, regardless of the criteria used for BHR or for "symptomatic" and irrespective of ethnic group. In conclusion, BHR is related to, but not identical to, clinical asthma. Bronchial challenge testing is an important tool of respiratory research, but cannot reliably or precisely separate asthmatics from nonasthmatics in the general community.

The purpose of this study was to examine the effects of the interval training on metabolic parameters at maximal work and at the anaerobic threshold in 11 year olds. The subjects were five healthy male children. They trained outdoor for 50 min a day, five times a week for six weeks, using interval work at 25 and 50% above their anaerobic threshold. Before and after training program, they performed a progressive exercise test on a cycle ergometer. During the last 15 sec of each power output measurements were made of oxygen uptake (VO2), carbon dioxide output (VCO2), heart rate (HR), ventilation (VE), ventilatory equivalent for oxygen (VEO2) and ventilatory equivalent for carbon dioxide VECO2). Following training, the group increased their anaerobic threshold (expressed as %VO2max) significantly (P less than 0.05) during the progressive exercise test, by 22%. Also at the anaerobic threshold level, increases were observed following training in CO2 output (VCO2-AT) and respiratory exchange ratio (R). Oxygen uptake (VO2, l.min-1) was increased by 19%, but the difference was not significant (P greater than 0.05). Maximal ventilatory equivalent for (VECO2max) decreased significantly (P less than 0.05). Maximal heart rate was reduced significantly (P less than 0.05). We conclude that training led to an increase of both anaerobic and aerobic metabolism, at any submaximal work above the anaerobic threshold, for this specific age group.

Maoris and Pacific Islanders in New Zealand have a higher asthma mortality and hospital admission rates than Europeans. To determine whether difference in asthma prevalence is the major factor underlying these differences in mortality, 2053 Auckland children aged 7-10 years (European 1084, Maori 509, Pacific Islander 460) were randomly sampled from school classes in the Auckland Urban Area, and studied by questionnaire (completed by parents) and histamine inhalation challenge to assess the provocative dose of histamine causing a 20% fall in FEV1 (PD20). Maoris had the highest prevalence rates of respiratory symptoms, and Europeans had rates similar to Pacific Islanders. For "any current wheeze" for example, the prevalence in Maoris was 22.2% compared with 16.1% and 16.3% in the Europeans and Pacific Islanders. The prevalence of diagnosed asthma was similar in the three groups. When bronchial hyperresponsiveness (defined as a PD20 less than or equal to 7.8 mumol histamine) was considered, Europeans had the highest rates (20%), followed by Maoris (13%), and then Pacific Islanders (8.7%). These differences were not accounted for by differences in socioeconomic status, rates of smoking in the home, age, gender, or height. It is concluded that differences in asthma prevalence do not satisfactorily explain the mortality and admission rate differences, although the higher symptom prevalence in the Maoris could be relevant to the higher mortality rate. Maori and Pacific Island children with symptoms of asthma were less likely to be taking prophylactic medication than European children. It is proposed that differences in management are important factors relevant to the increased mortality and morbidity from asthma in Polynesians.

A survey of six New Zealand hospitals, each of which employs at least one respiratory physician, demonstrated lack of uniformity and several deficiencies in measures to prevent nosocomial tuberculosis. Preemployment screening measures in particular were frequently suboptimal. Suggested improvements include upgrading tuberculosis control policies at a national level, with input from hospital boards, clinicians, and the Department of Health. Future policy changes should be based upon local and national experience and this requires the auditing of hospital control measures. The number of health workers amongst new cases of tuberculosis should also be recorded and taken into account.