When to use single-inhaler triple therapy in COPD: a practical approach for primary care health care professionals.

While single-inhaler triple therapy (SITT) devices were not available when the Global Initiative for Chronic Obstructive Lung Disease strategy and National Institute for Health and Care Excellence guidelines were developed, two devices are now available in the UK. This paper offers practical, patient-focused advice to optimize placement of SITT in the management of COPD. A survey of UK health care professionals (HCPs) identified issues around, and attitudes toward, SITT, which informed a multidisciplinary expert panel's discussions. The survey confirmed the need to clarify the place of SITT in COPD management. The panel suggested three criteria, any one of which identifies a high-risk patient where escalation to triple therapy from monotherapy or double combination treatment is appropriate: 1) at least two exacerbations treated with oral corticosteroids, antibiotics, or both in the previous year; 2) at least one severe exacerbation that required hospital admission in the previous year; 3) one exacerbation a year on a repeated basis for 2 consecutive years. Appropriate non-pharmacological management is essential for all patients and should be considered before stepping up treatment. Regular review is essential. During each review, HCPs should consider stepping treatment up or down. If patients exacerbate despite adhering to triple therapy, an individualized approach should be considered if the inhaled corticosteroid (ICS) confers benefit or causes side effects. In this situation, the blood eosinophil count could aid decision making. ICSs should be continued when the history suggests that asthma overlaps with COPD. Training, counseling, and education should be individualized. HCPs should consider referral: 1) when there is limited response to treatment and persistent exacerbations; 2) where there is diagnostic uncertainty or suspected comorbidity; 3) whenever they feel "out of their depth." Overall, the panel concurred that when used correctly, SITT has the potential to improve adherence, symptom control, and quality of life, and reduce exacerbations. Studies using real-world evidence need to confirm these benefits.

Monitoring growth in asthmatic children treated with high dose inhaled glucocorticoids does not predict adrenal suppression.

AIMS: To determine whether routine outpatient monitoring of growth predicts adrenal suppression in prepubertal children treated with high dose inhaled glucocorticoid. METHODS: Observational study of 35 prepubertal children (aged 4-10 years) treated with at least 1000 microg/day of inhaled budesonide or equivalent potency glucocorticoid for at least six months. Main outcome measures were: changes in HtSDS over 6 and 12 month periods preceding adrenal function testing, and increment and peak cortisol after stimulation by low dose tetracosactrin test. Adrenal suppression was defined as a peak cortisol < or =500 nmol/l. RESULTS: The areas under the receiver operator characteristic curves for a decrease in HtSDS as a predictor of adrenal insufficiency 6 and 12 months prior to adrenal testing were 0.50 (SE 0.10) and 0.59 (SE 0.10). Prediction values of an HtSDS change of -0.5 for adrenal insufficiency at 12 months prior to testing were: sensitivity 13%, specificity 95%, and positive likelihood ratio of 2.4. Peak cortisol reached correlated poorly with change in HtSDS (rho = 0.23, p = 0.19 at 6 months; rho = 0.33, p = 0.06 at 12 months). CONCLUSIONS: Monitoring growth does not enable prediction of which children treated with high dose inhaled glucocorticoids are at risk of potentially serious adrenal suppression. Both growth and adrenal function should be monitored in patients on high dose inhaled glucocorticoids. Further research is required to determine the optimal frequency of monitoring adrenal function.

Prescribing practice for intermittent oxygen therapy: a GP survey.

INTRODUCTION: UK figures show that the prescription of home oxygen cylinders for intermittent use is substantial. AIM: To examine GP assessment criteria and prescribing practice for intermittent oxygen therapy in patients with a diagnosis of chronic obstructive pulmonary disease (COPD) in Northern Ireland. METHODS: A postal questionnaire was sent to all GPs (n = 534) in two health boards who had prescribed cylinder oxygen in a six month period prior to the study. The questionnaire was piloted to establish reliability and validity. RESULTS: Completed questionnaires were returned by 52% (280/534) of GPs. GPs 'most frequently' used advice from hospital specialists [82% (230/280)] to determine the need for intermittent oxygen. Criteria such as breathlessness score on exercise (e.g., BORG), oximetry on exercise, local guidelines or national guidelines were used less frequently or never. CONCLUSIONS: Most patients are likely to have been prescribed intermittent oxygen without any objective assessment. Implementation of evidence-based guidelines and a formal oxygen assessment service, would rationalize the use of intermittent oxygen therapy and enable better targeting of this expensive resource.

Quantification of interventions and outcomes in an outpatient telemanagement and care management congestive heart failure program.

The congestive heart failure continuum was developed in collaboration with the medical management committee of our hospital in response to a need to decrease readmissions for this chronic and progressive disease. This is accomplished via a multidisciplinary team that provides education and long-term telemanagement, as well as care management to assist these patients in maintaining an optimum level of functioning and the ability to remain in their homes for as long as possible. Since October 1996 there have been 375 patients referred with a decrease in the 31-day readmission rate from 21% to an average of 5%. Costs are presently $55.00 per month per patient. Evaluation of the congestive heart failure phone management tool revealed a strong 77% positive correlation between the patient's score and the number of interventions needed to stabilize the patient. Care management visits, when necessary, help reduce the need for hospitalization. (c)2000 by CHF, Inc.

Linear growth of very young asthmatic children treated with high-dose nebulized budesonide.

The aim of this open study was to observe linear growth in young children with asthma treated with nebulized budesonide. Infants and young children (< 3 years old) with severe uncontrolled asthma were studied. They were treated with nebulized budesonide (1-4 mg day-1) and treated for at least 6 months. Height standard deviation scores (HtSDS) were measured before ("pre-measurements") immediately prior to commencing nebulized budesonide therapy (baseline) and after at least 6 months of therapy ("post-measurements"). The mean HtSDS score at pretreatment was -0.21 and at baseline had fallen further to -0.46. The mean HtSDS increased to -0.17 when the post-measurements were made (p = 0.035) after at least 6 months of nebulized budesonide therapy. Treatment with nebulized budesonide for longer than 6 months in very young children with severe asthma was not associated with reduced linear growth.

Induction of cold-responsive proteins in Vibrio vulnificus.

We have studied the response of Vibrio vulnificus to temperature shifts (23 to 13 degrees C) within the organism's permissive growth range. Cold shift induced a diminution in protein synthesis. Following a short lag, cells began growth at a new rate. Forty proteins were induced by this downshift.

H-NS over-expression induces an artificial stationary phase by silencing global transcription.

Bacteria organize their chromosomes in a complex interwound supercoiled structure called the nucleoid through the action of topoisomerases and a set of small (10-20 kDa) proteins. The two most abundant nucleoid-associated proteins are HU and H-NS. H-NS increases in abundance during stationary phase. Over-expression of HU is well tolerated and compatible with transcription and cell growth. Increasing the concentration of H-NS leads to a rapid silencing of global transcription and produces a growth-arrested state reminiscent of stationary phase. H-NS over-expression also induces a substantial loss of supercoiling in plasmid DNA during the time that transcription is arrested. Comparing the effects of over-expression of these two proteins gives some insight into the differential roles of these proteins in the activity of the chromosome. These observations are interpreted in a model of nucleoid organization.

Mutations altering chromosomal protein H-NS induce mini-Mu transposition.

Bacteriophage Mu is one of the most efficient transposons known, capable of moving a hundred viral copies to new positions in the bacterial chromosome in an hour. Mu also forms stable lysogens. In bacteria lysogenic for the defective protein fusion-forming phage MudII1681, which can transpose and replicate but does not encode genes for DNA packaging and cell lysis, the frequency of transposition changes as colonies age. To find host genes that alter the spontaneous Mu transposition frequency, we used a genetic screen with mini-MudlacZ fusion formation as an assay. H-NS (also called H1a and B1) is an abundant nonspecific DNA-binding protein localized to the bacterial chromosome. H-NS has an unusual structure of interspersed patches of acidic and basic residues reminiscent of eukaryotic HMG proteins. Mutations in hns caused an increase in Mu-specific transcription and a dramatic increase in MudII1681 transposition rates when cells were put under certain growth conditions. Purified H-NS stabilized Mu repressor-DNA complexes in vitro, suggesting that H-NS contributes to the organization of transcriptionally inactive DNA in vivo.

The classification of malignant melanoma, its histological reporting and registration: a revision of the 1972 Sydney classification.

A group of pathologists with an interest in malignant melanoma met in Sydney in 1982 to update the classification of melanoma formulated in Sydney in 1972. The group recommended that malignant melanoma be classified as follows: malignant melanoma with an adjacent component of superficial spreading type, malignant melanoma with an adjacent component of lentigo maligna type, malignant melanoma with an adjacent component of acral lentiginous type, malignant melanoma with an adjacent component of mucosal lentiginous type, malignant melanoma with no adjacent component, malignant melanoma of unclassifiable histogenetic type. The data recorded in the surgical pathology report should include: diagnosis of primary malignant melanoma, histogenetic classification, presence/absence of ulceration, micrometer-measured thickness, microanatomical level, mitotic rate/mm2, presence/absence of vascular invasion, presence/absence of regression, completeness of resection. The recommendations for the examination of specimens and the recording of data for research purposes and for tumour registries are described.

Histogenesis of malignant melanoma with an adjacent component of the superficial spreading type.

There has been a world-wide exponential increase in the incidence of thin malignant melanoma. At the Sydney Melanoma Unit, the proportion of patients diagnosed as having superficial spreading melanoma has more than doubled from 33% prior to 1960 to 78% during 1980-83. A study was made of the non-invasive component of malignant melanoma with an adjacent non-invasive component of the superficial spreading type in an attempt to elucidate the pathogenetic mechanisms involved in these changing trends. In this study on 723 cases of melanoma with a superficial spreading component, there was evidence that 39% originated in a precursor lesion. In the remaining 61%, the adjacent superficial spreading component consisted of melanoma in situ, suggesting that these were melanomas from the beginning. The latter lesions were thinner and had a lower degree of mitotic activity than melanomas commencing in a precursor lesion. Despite the large increase in incidence of superficial spreading melanomas and the shift to thinner lesions over time, there appeared to be no difference in the proportion of lesions commencing de novo to those commencing in a precursor lesion. This suggests that the precursor lesion may be of genetic origin.

Head and neck melanoma in 534 clinical Stage I patients. A prognostic factors analysis and results of surgical treatment.

Single and multifactorial analyses were used to evaluate prognosis and results of surgical treatment in 534 clinical Stage I patients with head and neck cutaneous melanoma treated at the University of Alabama in Birmingham (U.S.A.) and the University of Sydney (Australia). This computerized data base was prospectively accumulated in over 90% of cases. Melanomas were about equally distributed between men and women. They were located on the skin of the face in 47%, neck in 27%, scalp in 13%, and the ear in 13% of patients. Both the results of the prognostic factors analyses and the surgical treatment demonstrated that lentigo maligna melanoma (LMM) was distinct from the other two growth patterns, superficial spreading melanoma and nodular melanoma (SSM and NM). In a multifactorial analysis of the 453 patients with SSM and NM, the dominant prognostic variables were tumor thickness (p less than 0.00001), anatomic subsite (p = 0.0213), and ulceration (p = 0.0289). Patients with melanomas on the scalp or neck subsites fared worse than those with tumors located on the face or ear. The results differed for LMM, where thickness was not a significant predictor of survival, and the most dominant prognostic variable was ulceration (p = 0.0042). Local recurrence rates were low, being 2.4% for tumors less than 2.5 mm in thickness, but were 12.3% for tumors greater than or equal to 4.0 mm in thickness. Patients with SSM and NM lesions located on the head and neck had a lower survival rate than those with extremity melanomas in every tumor thickness category, although only those in the 0.76 to 1.49 mm thickness subgroup were significantly different (p = 0.0007). After 5 years of follow-up, patients who underwent an elective lymph node dissection for SSM and NM with a thickness range of 1.5 to 3.99 mm had a better survival (72%) than patients with melanomas of equivalent thickness whose initial treatment was wide excision alone (45%). LMM had a less aggressive biologic behavior compared to SSM or NM and was treated more conservatively. Thus, LMM lesions had an 85% 10-year survival rate with wide excision only, and there was no significant improvement in survival with ELND. Growth patterns, tumor thickness, ulceration, and anatomic subsites should be considered when evaluating risk factors and when making treatment decisions in head and neck melanoma patients.

Changing trends in cutaneous melanoma over a quarter century in Alabama, USA, and New South Wales, Australia.

Clinical and pathologic characteristics of melanoma were compared among 1647 clinical Stage I patients treated at the University of Alabama in Birmingham (USA) and The University of Sydney (Australia) between 1955 and 1980 to determine what changes occurred over a quarter century. Over this period, the number of patients treated annually has increased substantially. There was a steady increase in the proportion of patients presenting with localized disease (clinical Stage I). Melanomas became thinner, less invasive, less ulcerative and thus more curable. They also exhibited more of a radial growth phase. The median thickness of melanomas decreased in Australia from 2.5 mm prior to 1960 to 1.1 mm during the period 1976 to 1980, while in Alabama it has decreased from 3.3 to 1.4 mm. There was a significant increase in melanomas located on the trunk in males and a corresponding decrease in male head and neck melanomas. No significant change in the site distribution was observed for any major anatomical area on female patients. There were minimal differences in the incidence of both clinical and pathologic parameters among melanoma patients in Alabama, USA and in New South Wales, Australia even when accounting for their year of diagnosis. Long-term survival rates in patients with localized disease were found to increase slightly during the 25 year time frame of this analysis. The changes that have occurred are likely due to earlier diagnosis and changes in the biological nature of the disease.

Prognostic significance of a polypoid configuration in malignant melanoma.

In a review of 2296 patients with malignant melanoma, the overall incidence of a polypoid configuration was 21.5%. A markedly higher proportion of patients with polypoid melanoma than with dome-shaped melanoma first presented for melanoma treatment already with metastases (i.e. clinical stage II or III). In patients with localized disease, more men than women tended to present with polypoid lesions. The majority of these lesions were of the nodular histogenetic type, greater than 3.0 mm thick and ulcerated. When patients with polypoid and dome lesions were matched according to three known important prognostic determinants: sex of patient, the thickness of their primary lesion and whether their lesion showed microscopic evidence of ulceration, no consistent differences in prognosis were detected between patients with polypoid and dome lesions. Thus it appeared that the poor prognosis for patients with polypoid lesions was not attributable to the configuration of their lesion per se but primarily due to the fact that they were typically thick, ulcerated lesions.