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Objective: To describe the development, organization, and operation of several collaborative groups conducting investigator-initiated multicenter clinical research in adult critical care., Design: To review the process by which investigator-initiated critical care clinical research groups were created using examples from Europe, Australia, the United States, and Canada. Various models of group structure and function are discussed, highlighting complementary approaches to protocol development, multicenter study management, and project funding., Data Sources: Published peer review research and unpublished terms of reference documents on the structure and function of these groups., Data Synthesis: The overall goal of clinical critical care research groups engaged in multicenter studies is to improve patient outcomes through conducting large, rigorous investigations. Research programs we reviewed included the following: a) multicenter epidemiologic studies and surveys; b) technology evaluations of mechanical ventilation; c) investigations focused on three priority fields (acute lung injury, infection, and acute brain injury); d) a series of randomized trials of treatments for one syndrome (acute respiratory distress syndrome); and e) diverse methodologies addressing several clinical problems. The structure and function of these research groups differ according to their historical development, research culture, and enabling resources. Specific protocols emerge from clinical questions generated by investigators or from collectively prioritized research agendas. Project funding includes government support, peer-review grants, intensive care foundations, industry, local hospital funds, and hybrid models. Infrastructure for study management varies widely., Conclusions: Several national and international groups have engaged in investigator-initiated multicenter critical care research. The development, organization, and operational methods of these groups illustrate several collaborative models for clinical investigations in the intensive care unit. Common characteristics of these groups are a cohesive spirit, a sense of mission to achieve shared research goals, and acknowledgment that such an organization is much more than the sum of its parts.

Despite top-down professional body and government agency pressure to increase the research base of clinical practice, there remains a considerable body of evidence which suggests that many ineffective, and even dangerous, health care interventions continue to be practised in areas where there are significant contradictory findings. While numerous explanations have been put forward which implicate the role of structural, organizational and informational barriers to integrating research with practice, less attention has been focused on the individual and psychological contributions. The study reported here forms part of a larger scale project aimed at developing a diagnostic instrument for identifying research training needs, in the widest sense, within primary health care groups. To provide the instrument with content validity, following formal psychometric guidelines, opaque and transparent techniques of data collection were employed at the development stage. This yielded some interesting and unexpected results from the respondents, which suggested that despite overt statements to the contrary, the majority of the primary health care professionals studied perceived research as being unimportant and peripheral to their jobs, and the responsibility of other health care professionals. Moreover, the subjects' understanding of research and its methodologies was discordant both within and across professional groups. The implications of these results from this pilot phase suggest that fundamental and deep-seated attitudes which are resistant to research may be a contributory factor to the persistence of ritualistic, non-evidence-based care.

Guidelines for the protection of privacy in the conduct of medical research have been issued by the National Health and Medical Research Council, approved by the Commonwealth Privacy Commissioner, and gazetted on 1 July 1991 (Commonwealth of Australia Gazette No. P19) to remain in force until 30 June 1994. This paper examines the guidelines and seeks to inform researchers, institutional ethics committees and the institutions those committees represent of their content. Responsibilities are placed upon those engaged in the conduct of research and those involved in undertaking ethical review who now have to decide that the public interest in conducting the research substantially outweighs the public interest in privacy. There is also an emphasis on the requirement for surveillance of research projects by institutional ethics committees which has not previously been apparent. Questions are posed to assist in deciding whether a particular research protocol is subject to the guidelines.

In accordance with the Privacy Act 1988 (Cth), interium guidelines for the protection of privacy in the conduct of medical research have been issued by the National Health and Medical Research Council (NHMRC) with the approval of the Privacy Commissioner. The guidelines are intended to ensure that the privacy of the individual is not interfered with when a researcher seeks the release of personal information held by a Commonwealth agency, or when a Commonwealth agency conducts medical research, and to ensure that the conduct of medical research is not inhibited by the privacy legislation. However, the procedures established by the guidelines and the responsibilities placed upon researchers and institutional ethics committees could themselves have the effect of inhibiting research. In considering amendment, NHMRC and the Privacy Commissioner are urged to produce final guidelines which do not act as the straw to break the back of the current system of institutional ethics committees, which seeks to ensure proper ethical scrutiny and the facilitation of human research.

The historical and present role of lower (non-mammalian) vertebrates in biomedical research is discussed. Examples are given of disease problems and experimental studies. It is suggested that lower vertebrates may prove of increasing value in this field in the future.

Attributes of 21 Vertosols in 2 different regions of Tasmania were assessed using field and laboratory techniques to determine differences associated with 3 local forms of agricultural management (long-term pasture, rain-fed cropping, and irrigated cropping). Vertosols in the northern Midlands had better physical properties (lesser bulk density and penetration resistance, and greater porosities and water holding capacities), poorer nutrient status (lower pH, exchangeable bases, and extractable P), and better biological properties (greater organic carbon (OC), carbon fractions F1 and F3, and more worms) than south-eastern Vertosols. When adjusted for clay content, cropped sites had less soil OC than pasture sites at 0-75 mm depth. Readily oxidisable (fraction F1) carbon in the surface 75 mm was 3.6 mg/g and 6.9 mg/g under long-term pasture compared with 2.5 mg/g and 3.9 mg/g in irrigated cropped paddocks on south-eastern and Midlands sites, respectively. Soil organic carbon values were positively correlated with physical and chemical soil properties. Long-term pasture paddocks showed stronger structural development and had smaller aggregates than cropped paddocks, which had more larger clods. Vane shear strength and penetration resistance were less in rainfed cropped paddocks compared with long-term pasture but this effect was not apparent on irrigated cropped paddocks. Farmers considered that a majority of their soil attributes were healthy under all management histories but strategies for maintaining organic matter levels and minimising clod formation by tillage are essential for long-term sustainable use of these Vertosols. Additional keywords: carbon fractions, soil strength, aggregate size, land management, cropping., Introduction Vertosols are clay textured soils with shrink-swell properties that exhibit strong cracking when dry (Isbell 1996). In the northern Midlands of Tasmania, these soils are formed in alluvium on [...]

Background: Hypogammaglobulinemia (serum IgG levels < 7.0 g/L) has been associated with increased risk of COPD exacerbations but has not yet been shown to predict hospitalizations.Research Question: To determine the relationship between hypogammaglobulinemia and the risk of hospitalization in patients with COPD.Study Design and Methods: Serum IgG levels were measured on baseline samples from four COPD cohorts (n = 2,259): Azithromycin for Prevention of AECOPD (MACRO, n = 976); Simvastatin in the Prevention of AECOPD (STATCOPE, n = 653), Long-Term Oxygen Treatment Trial (LOTT, n = 354), and COPD Activity: Serotonin Transporter, Cytokines and Depression (CASCADE, n = 276). IgG levels were determined by immunonephelometry (MACRO; STATCOPE) or mass spectrometry (LOTT; CASCADE). The effect of hypogammaglobulinemia on COPD hospitalization risk was evaluated using cumulative incidence functions for this outcome and deaths (competing risk). Fine-Gray models were performed to obtain adjusted subdistribution hazard ratios (SHR) related to IgG levels for each study and then combined using a meta-analysis. Rates of COPD hospitalizations per person-year were compared according to IgG status.Results: The overall frequency of hypogammaglobulinemia was 28.4%. Higher incidence estimates of COPD hospitalizations were observed among participants with low IgG levels compared with those with normal levels (Gray's test, P < .001); pooled SHR (meta-analysis) was 1.29 (95% CI, 1.06-1.56, P = .01). Among patients with prior COPD admissions (n = 757), the pooled SHR increased to 1.58 (95% CI, 1.20-2.07, P < .01). The risk of COPD admissions, however, was similar between IgG groups in patients with no prior hospitalizations: pooled SHR = 1.15 (95% CI, 0.86-1.52, P =.34). The hypogammaglobulinemia group also showed significantly higher rates of COPD hospitalizations per person-year: 0.48 ± 2.01 vs 0.29 ± 0.83, P < .001.Interpretation: Hypogammaglobulinemia is associated with a higher risk of COPD hospital admissions. [ABSTRACT FROM AUTHOR]

Abstract Attributes of 25 Tasmanian ferrosols under 5 forms of management (low-input pasture, high-input pasture, intermittent cropping, continuous cropping, and pyrethrum production) were assessed using field and laboratory techniques, to [...]

Most of the world's shorelines are in a state of erosion. The only major exceptions are areas of high sediment supply, such as along the rims of active delta lobes [...]

Background. Self-harm is a common reason for Emergency Department (ED) attendance. We aimed to develop a clinical tool to help identify patients at higher risk of repeat self-harm, or suicide, within 6 months of an ED self-harm presentation. Method. The tool, the ReACT Self-Harm Rule, was derived using multicentre data from a prospective cohort study. Binary recursive partitioning was applied to data from two centres, and data from a separate centre were used to test the tool. There were 29 571 self-harm presentations to five hospital EDs between January 2003 and June 2007, involving 18 680 adults aged ≥ 16 years. We estimated sensitivity, specificity and positive and negative predictive values to measure the performance of the tool. Results. A self-harm presentation was classified as higher risk if at least one of the following factors was present: recent self-harm (in the past year), living alone or homelessness, cutting as a method of harm and treatment for a current psychiatric disorder. The rule performed with 95% sensitivity [95% confidence interval (CI) 94-95] and 21% specificity (95% CI 21-22), and had a positive predictive value of 30% (95% CI 30-31) and a negative predictive value of 91 % (95% CI 90-92) in the derivation centres; it identified 83/92 of all subsequent suicides. Conclusions. The ReACT Self-Harm Rule might be used as a screening tool to inform the process of assessing self- harm presentations to ED. The four risk factors could also be used as an adjunct to in-depth psychosocial assessment to help guide risk formulation. The use of multicentre data helped to maximize the generalizability of the tool, but we need to further verify its external validity in other localities. [ABSTRACT FROM AUTHOR]

BackgroundMortality, including suicide and accidents, is elevated in self-harm populations. Although risk factors for suicide following self-harm are often investigated, rarely have those for accidents been studied. Our aim was to compare risk factors for suicide and accidents.MethodA prospective cohort (n=30 202) from the Multicentre Study of Self-harm in England, 2000–2007, was followed up to 2010 using national death registers. Risk factors for suicide (intentional self-harm and undetermined intent) and accidents (narcotic poisoning, non-narcotic poisoning, and non-poisoning) following the last hospital presentation for self-harm were estimated using Cox models.ResultsDuring follow-up, 1833 individuals died, 378 (20.6%) by suicide and 242 (13.2%) by accidents. Independent predictors of both suicide and accidents were: male gender, age ⩾35 years (except accidental narcotic poisoning) and psychiatric treatment (except accidental narcotic poisoning). Factors differentiating suicide from accident risk were previous self-harm, last method of self-harm (twofold increased risks for cutting and violent self-injury versus self-poisoning) and mental health problems. A risk factor specific to accidental narcotic poisoning was recreational/illicit drug problems, and a risk factor specific to accidental non-narcotic poisoning and non-poisoning accidents was alcohol involvement with self-harm.ConclusionsThe similarity of risk factors for suicide and accidents indicates common experiences of socio-economic disadvantage, life problems and psychopathology resulting in a variety of self-destructive behaviour. Of factors associated with the accidental death groups, those for non-narcotic poisoning and other accidents were most similar to suicide; differences seemed to be related to criteria coroners use in reaching verdicts. Our findings support the idea of a continuum of premature death. [ABSTRACT FROM PUBLISHER]

The purpose of this study was to determine the effect of a post-exercise active cool-down on von Willebrand factor and fibrinolysis. Ten subjects performed two maximal oxygen uptake (VO2max) tests followed by a 10-min passive (PC) or an active (AC) cool-down. Blood samples were obtained pre-exercise, post-exercise, post-PC/AC, and 1 h post-exercise and analyzed for von Willebrand factor antigen (vWf:Ag), tissue plasminogen activator (tPA) antigen and activity and plasminogen activator inhibitor-1 (PAI-1) activity. Data were analyzed using repeated measures analysis of variance. No significant differences were found between VO2max tests for treadmill time, VO2max, respiratory exchange ratio, maximal heart rate, or maximal blood lactate concentration. vWf:Ag was significantly elevated (P <0.05)following PC [198.4 (18.3)% normal] versus AC [174.5 (15.6)% normal] and remained elevated 1-h post-exercise [179.4 (16.4)% normal for PC vs 158.6 (13.8)% normal for AC]. There were no differences between tests for tPA or PAI-1 activity, although tPA antigen was significantly elevated following PC versus AC (P <0.05). Following the cool-down, hematocrit was higher (P <0.05) for the PC test [48.90 (0.36)] compared with AC [47.43 (0.51)]. An AC reduces post-exercise vWf:Ag and tPA antigen without affecting tPA or PAI-1 activity. [ABSTRACT FROM AUTHOR]

The effect of substrate characteristics on primary human bone cell response to mechanical loading was investigated in this study. The substrates comprised organic and inorganic materials with a range of hydrophilic and hydrophobic features. Substrate surface topography varied from smooth to particulate to porous. It was found that hydrophilic substrates such as borosilicate glass facilitated bone cell adhesion, in contrast to hydrophobic substrates such as poly(L-lactic acid), in which clumps of cells grew unevenly across the substrate surface. All primary bone cells cultured in the various collagen-coated substrates were responsive to mechanical stimulation. The study showed that, at a low strain level of 1000 µstrain, mechanical stimulation enhanced bone cell differentiation rather than proliferation. Coating the substrates with collagen type I enhanced cell adhesion and promoted an elongated cell morphology, indicating that the presence of specific binding sites on a substrate may be more important than its hydrophilic properties, regardless of the substrate topography. [ABSTRACT FROM AUTHOR]

Background: Wilson's disease (WD) is caused by mutations in a P-type ATPase and is associated with copper deposition in liver and brain. The WD protein is present in the trans-Golgi network and may also be imported into mitochondria. The WD protein functions as a P-type copper transporting ATPase in the Golgi but any action in mitochondria is at present unknown.Methods: We studied mitochondrial function and aconitase activity in WD liver tissue and compared the results with those in a series of healthy controls and patients without WD.Findings: There was evidence of severe mitochondrial dysfunction in the livers of patients with WD. Enzyme activities were decreased as follows: complex I by 62%, complex II+III by 52%, complex IV by 33%, and aconitase by 71%. These defects did not seem to be secondary to penicillamine use, cholestasis, or poor hepatocellular synthetic function.Interpretation: The results show that there is a defect of energy metabolism in WD. The pattern of enzyme defects suggests that free-radical formation and oxidative damage, probably mediated via mitochondrial copper accumulation, are important in WD pathogenesis. These results provide a rationale for a study of the use of antioxidants in WD. [ABSTRACT FROM AUTHOR]

We hypothesized that there is no synthesis of butyric acid within organs or tissues not drained by the portal vein (PV). Two experiments were performed. In six piglets, the colonic vasculature was clamped (n = 4) or the entire colon resected while [1-13C]-butyric acid (99% enriched) was infused into a jejunal vein for 120 min; 13C enrichment of butyric acid was measured in the PV and carotid artery (ART) during the last 30 min of the infusion. In a second experiment, butyric acid tracer and unlabeled disaccharide were infused into the cecum for 120 min, and blood again was sampled from the PV and ART. For the four piglets studied during ligation of the colonic vasculature, the mean (+/- SD) ratio of the butyric acid enrichment in the ART to that in the PV (ART/PV) was 0.80+/-0.05 (ART vs. PV, P = 0.002) and for all six piglets in expt. 1, the ART/PV ratio was 0.74+/-0.1 (ART vs. PV, P = 0.001). The enrichment of butyric acid in the PV averaged 96.0% for the six studies, implying that splanchnic tissues other than the colon did not produce a substantial amount of butyric acid. For the second experiment, the ART/PV ratio was 0.80+/-0.15 (ART vs. PV, P = 0.03). These studies provide the first evidence for endogenous synthesis of butyric acid by piglets. [ABSTRACT FROM AUTHOR]

We compared doxorubicin and metabolite pharmacokinetic data obtained from thin-layer chromatography (TLC) and high-performance liquid chromatography (HPLC) assay of plasma samples from six patients who had been treated with doxorubicin. Duplicate 1-ml samples were extracted with chloroform: isopropanol (1:1) and assayed using a sensitive HPLC system incorporating a dual pump gradient with tetrahydrofuran as the mobile phase and fluorescence detection. Duplicate 1-ml samples from the same specimens were assayed using a modification of a previously described TLC assay. Areas under the curve for doxorubicin by HPLC (3.36 +/- 2.30 microM X h) and TLC (4.16 +/- 2.50 microM X h) were not significantly different (P = 0.5). Terminal half-life of doxorubicin by HPLC (28.0 +/- 6.98 h) and TLC (23.2 +/- 7.8) (P = 0.29) and the calculated total-body clearances by HPLC (0.55 +/- 0.29 l/min) and TLC (0.45 +/- 0.23) (P = 0.55) were not significantly different. Areas under the curve for doxorubicinol by HPLC (2.75 +/- 1.4 microM X h) and TLC (2.53 +/- 7.1 microM X h) (P = 0.73) showed no significant differences. HPLC detected a mixed 7-deoxydoxorubicinol aglycone-doxorubicin aglycone peak, 7-deoxydoxorubicin aglycone, and two nonpolar, unidentified metabolites. TLC detected the following aglycone metabolites: doxorubicin aglycone, doxorubicinol aglycone, 7-deoxydoxorubicinol aglycone, an unidentified polar metabolite, and several unidentified nonpolar metabolites. From these data we conclude that HPLC and TLC detect concentrations of doxorubicin and doxorubicinol from human plasma equally well to concentrations of 7.0 nM (4 pmol injected doxorubicin). Aglycones do circulate in human plasma at concentrations above the detection limits of both assays. Doxorubicinol aglycone, which is detected by TLC but not by HPLC, may be formed from artifactual breakdown of doxorubicinol during TLC development. Unidentified nonpolar compounds seen on HPLC and TLC may represent further doxorubicin metabolism than previously described. [ABSTRACT FROM AUTHOR]

Studies of reaction time in Parkinson's disease (PD) have suggested a selective deficit in simple reaction time (SRT), compared with choice reaction time (CRT). This finding has been interpreted as a deficit in motor preprogramming but could involve other factors, such as attentional focussing and stimulus predictability. Moreover, not all studies show the same selective deficit, possibly because of differences in patient selection and treatment effects. The neurochemical basis of RT deficits in PD remains unclear. Accordingly, the contribution of cognitive factors to impaired RT was assessed in a large group of PD patients, including early untreated cases, and performance was examined in relation to clinical variables and the effect of treatment in longitudinal study. Motor output was constant in both SRT and CRT tasks. In the SRT task, all stimuli required a response; in the CRT task, subjects were required to respond to only one of the two possible stimuli. Attentional focussing on SRT was examined by variation of the interval between cue and stimulus; effects of stimulus uncertainty were evaluated from a comparison of SRT and CRT; temporal predictability of the stimulus was examined from a comparison of conditions in which the interval between warning signal and imperative stimulus was constant or variable. The PD patients showed similar deficits in SRT and CRT, but normal effects of cue-stimulus interval and temporal predictability. Reaction time correlated with measures of global cognitive capacity and frontal-lobe function, as well as motor disability. Treatment had no effect on SRT or CRT, despite clinical benefit. These findings indicate that RT deficits in PD are not due to impaired attentional focussing or stimulus predictability but are compatible with a deficit in higher-order processes concerned with the orientation of both cognitive and motor responses to a stimulus. These processes are not substantially dopamine-dependent but may be served by non-dopaminergic neurotransmission. [ABSTRACT FROM AUTHOR]

Paradigms of isometric force control allow study of the generation and release of movement in the absence of complications due to disordered visuomotor coordination. The onset and release of isometric force in Parkinson's disease (PD) was studied, using computerised determinants of latency of response and rate of force generation and release. Components of isometric force control were related to measures of cognitive, affective and clinical motor disability. The effects of treatment were determined by longitudinal study of de novo patients. Patients with PD showed impairment in latency and rate of force change for movement release as well as onset. Rate of force change correlated with depression, clinical motor disability and memory quotient but latency showed no correlation with any of these measures. Treatment improved rate of force release, in concert with clinical motor disability, but not latency. These results suggest dissociations between latency and rate of force change that may be linked to different neurochemical deficits. Further, they demonstrate akinetic deficits in force release that argue against the "neural energy hypothesis" of akinesia. [ABSTRACT FROM AUTHOR]

Dialysis dementia is a progressive and usually fatal neurologic syndrome occurring in patients on chronic hemodialysis. These patients may also have elevated levels of aluminum (Al+3) in the cerebral cortex. Possible relations between brain Al+3, increased Al+3 intake, and dementia were evaluated. Studies were done in seven groups of patients and five groups of experimental animals. In both normal dogs and rats and those with renal failure, oral Al+3 loading (Al[OH]3), resulted in significant increases of brain Al+3 (P less than 0.01). In patients with renal failure, who were neither demented nor treated with dialysis, brain Al+3 was more than seven times normal (P less than 0.01), whereas in patients with dialysis dementia, mean brain Al+3 was more than 15 times normal. However, the two groups were not significantly different. Brain Al+3 was also significantly elevated in patients who had either metastatic cancer or hepatic coma. Apparently brain Al+3 can be elevated as a consequence of Al+3 loading, renal failure, and abnormalities of the blood-brain barrier. It is most likely that dialysis dementia has multifactoral causation and is probably not caused by elevated brain content of Al+3 alone. [ABSTRACT FROM AUTHOR]

The article focuses on presentation and structure of present psychiatric classifications in reference to ICD-9 and -10. The main features of the 10th revision of the International Classification of Diseases or ICD-10 are examined on their structure and presentation. The general principles and main changes from ICD-9 is highlighted such as the use of clinical descriptions and diagnostic guidelines. Tables on how ICD-10 is structured are also presented and discussed. It is suggested psychiatric services and general medical care will realize the importance of usefulness of collecting data for future classification purposes.

A complete, unselected series of 68 patients who were seen during their first episode of an undoubtedly schizophrenic illness, and followed up one year later (for 56 patients) is described clinically. Depressive symptoms were common at onset, and 22% of patients could have been considered cases of depression from these symptoms alone. At follow-up, depressive symptoms had reduced in prevalence and only 7% of subjects were depressed cases. Only two cases of depression at follow-up had not been cases at onset. These changes could not be attributed to the use of antidepressants or ECT. Depressive syndromes could be distinguished from akinesia and the negative syndromes. The findings indicate that depression cannot be attributed solely to the administration of neuroleptics. [ABSTRACT FROM AUTHOR]

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People with cancer and other advanced diseases often develop fatigue, which has a significant impact on their quality of life and those around them (Purcell et al 2009, Cramp and Daniel (2009). It is disruptive, impacts social roles, causes distress to patients for the burden of care it imposes and to carers for the meaning of difficult symptoms (Lindqvist et al 2004, Givens et al 2005). It may have no identifiable cause, making management a primarily supportive approach, yet evidence for available interventions, often provided by a variety of HCPs, is limited for this multi-factorial symptom (Yennurajaligam and Bruera 2010). Relaxation techniques have been used to support symptoms like anxiety and pain, often provided by OTs. This has been offered at RMH for some time, but the current 'Tool Kit' approach, with additional fatigue management advice, had not been evaluated. The impact on carer's lives and their relationships is vast, but little evidence is available about intervention impacts, considering psycho-social perspectives from patient and carers (NCCN 2007, Barsevick et al 2008). A 'grounded theory' approach study was undertaken to ask: What is the experience of a fatigue management programme at the end of life for patients and carers? Additional objectives were identified to explore the experience of fatigue. Ethical approval was granted (13/LO/0810). By the end of the study 9 patients (from a possible 13) and 2 carers were recruited to the study and interviewed after completion of the intervention, reflecting challenges researching palliative populations. Analysis has highlighted the programme value held by participants, particularly the therapeutic relationships developed with the OT's and relaxation. Other aspects were less valued by participants, suggesting adjustments to the programme. This process and developments will be discussed in detail, adding to the evidence base for complex OT interventions. [ABSTRACT FROM AUTHOR]

Examines patients with acute pacreatitis in whom serum amylase level was normal by researchers from Rotherham. Morbidity and mortality of severe acute pancreatitis; Significance of early detection and treatment to reduce complications; Sensitivity and accuracy of urinary trypsinogen-2 testing in identifying patients with acute pacreatitis.

The article answers a question on whether a simple clinical rule can predict repetitions of self harm or suicide in the next six months in patients who are presented to the emergency department with self-harm. Results of research indicates that the Manchester Self Harm Rule had good sensitivity but poor specificity for predicting repetitions of self-harm or suicide in patients presented with self harm.

Background: Observational studies suggest that beta-blockers may reduce the risk of exacerbations and death in patients with moderate or severe chronic obstructive pulmonary disease (COPD), but these findings have not been confirmed in randomized trials.Methods: In this prospective, randomized trial, we assigned patients between the ages of 40 and 85 years who had COPD to receive either a beta-blocker (extended-release metoprolol) or placebo. All the patients had a clinical history of COPD, along with moderate airflow limitation and an increased risk of exacerbations, as evidenced by a history of exacerbations during the previous year or the prescribed use of supplemental oxygen. We excluded patients who were already taking a beta-blocker or who had an established indication for the use of such drugs. The primary end point was the time until the first exacerbation of COPD during the treatment period, which ranged from 336 to 350 days, depending on the adjusted dose of metoprolol.Results: A total of 532 patients underwent randomization. The mean (±SD) age of the patients was 65.0±7.8 years; the mean forced expiratory volume in 1 second (FEV1) was 41.1±16.3% of the predicted value. The trial was stopped early because of futility with respect to the primary end point and safety concerns. There was no significant between-group difference in the median time until the first exacerbation, which was 202 days in the metoprolol group and 222 days in the placebo group (hazard ratio for metoprolol vs. placebo, 1.05; 95% confidence interval [CI], 0.84 to 1.32; P = 0.66). Metoprolol was associated with a higher risk of exacerbation leading to hospitalization (hazard ratio, 1.91; 95% CI, 1.29 to 2.83). The frequency of side effects that were possibly related to metoprolol was similar in the two groups, as was the overall rate of nonrespiratory serious adverse events. During the treatment period, there were 11 deaths in the metoprolol group and 5 in the placebo group.Conclusions: Among patients with moderate or severe COPD who did not have an established indication for beta-blocker use, the time until the first COPD exacerbation was similar in the metoprolol group and the placebo group. Hospitalization for exacerbation was more common among the patients treated with metoprolol. (Funded by the Department of Defense; BLOCK COPD ClinicalTrials.gov number, NCT02587351.). [ABSTRACT FROM AUTHOR]

Background: Long-term treatment with supplemental oxygen has unknown efficacy in patients with stable chronic obstructive pulmonary disease (COPD) and resting or exercise-induced moderate desaturation.Methods: We originally designed the trial to test whether long-term treatment with supplemental oxygen would result in a longer time to death than no use of supplemental oxygen among patients who had stable COPD with moderate resting desaturation (oxyhemoglobin saturation as measured by pulse oximetry [Spo2], 89 to 93%). After 7 months and the randomization of 34 patients, the trial was redesigned to also include patients who had stable COPD with moderate exercise-induced desaturation (during the 6-minute walk test, Spo2 ≥80% for ≥5 minutes and <90% for ≥10 seconds) and to incorporate the time to the first hospitalization for any cause into the new composite primary outcome. Patients were randomly assigned, in a 1:1 ratio, to receive long-term supplemental oxygen (supplemental-oxygen group) or no long-term supplemental oxygen (no-supplemental-oxygen group). In the supplemental-oxygen group, patients with resting desaturation were prescribed 24-hour oxygen, and those with desaturation only during exercise were prescribed oxygen during exercise and sleep. The trial-group assignment was not masked.Results: A total of 738 patients at 42 centers were followed for 1 to 6 years. In a time-to-event analysis, we found no significant difference between the supplemental-oxygen group and the no-supplemental-oxygen group in the time to death or first hospitalization (hazard ratio, 0.94; 95% confidence interval [CI], 0.79 to 1.12; P=0.52), nor in the rates of all hospitalizations (rate ratio, 1.01; 95% CI, 0.91 to 1.13), COPD exacerbations (rate ratio, 1.08; 95% CI, 0.98 to 1.19), and COPD-related hospitalizations (rate ratio, 0.99; 95% CI, 0.83 to 1.17). We found no consistent between-group differences in measures of quality of life, lung function, and the distance walked in 6 minutes.Conclusions: In patients with stable COPD and resting or exercise-induced moderate desaturation, the prescription of long-term supplemental oxygen did not result in a longer time to death or first hospitalization than no long-term supplemental oxygen, nor did it provide sustained benefit with regard to any of the other measured outcomes. (Funded by the National Heart, Lung, and Blood Institute and the Centers for Medicare and Medicaid Services; LOTT ClinicalTrials.gov number, NCT00692198 .). [ABSTRACT FROM AUTHOR]