Obstructive sleep apnoea and type 2 diabetes mellitus: a bidirectional association.


Obstructive sleep apnoea and type 2 diabetes are common medical disorders that have important clinical, epidemiological, and public health implications. Research done in the past two decades indicates that obstructive sleep apnoea, through the effects of intermittent hypoxaemia and sleep fragmentation, could contribute independently to the development of insulin resistance, glucose intolerance, and type 2 diabetes. Conversely, type 2 diabetes might increase predisposition to, or accelerate progression of, obstructive and central sleep apnoea, possibly through the development of peripheral neuropathy and abnormalities of ventilatory and upper airway neural control. Although more research is needed to clarify the mechanisms underlying the bidirectional association between the two disorders, their frequent coexistence should prompt all health-care professionals to embrace clinical practices that include screening of a patient presenting with one disorder for the other. Early identification of obstructive sleep apnoea in patients with metabolic dysfunction, including type 2 diabetes, and assessment for metabolic abnormalities in those with obstructive sleep apnoea could reduce cardiovascular disease risk and improve the quality of life of patients with these chronic diseases.

Source: lancet

 

 

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Magnesium sulphate in acute severe asthma in children (MAGNETIC): a randomised, placebo-controlled trial.


Background

Little evidence is available for the effect of nebulised magnesium sulphate (MgSO4) in acute asthma in children. We assessed the effect of MgSO4 treatment in children with severe acute asthma.

Methods

In this randomised placebo-controlled, multi-centre, parallel trial, we enrolled children (aged 2—16 years) with severe acute asthma who did not respond to standard inhaled treatment from 30 hospitals in the UK. Children were randomly allocated (1:1) to receive nebulised salbutamol and ipratropium bromide with either 2·5 mL of isotonic MgSO4 (250 mmol/L; 151 mg per dose; MgSO4 group) or 2·5 mL of isotonic saline (placebo group) on three occasions at 20-min intervals. Randomisation was done with a computer-generated randomisation sequence, with random block sizes of two to four. Both patients and researchers were masked to treatment allocation. The primary outcome measure was the Yung Asthma Severity Score (ASS) at 60 min post-randomisation. We used a statistical significance level of p<0·05 for a between-group difference, but regarded a between-group difference in ASS of 0·5 as the minimal clinically significant treatment effect. Analysis was done by intention to treat. This trial is registered with controlled-trials.com, number ISRCTN81456894.

Findings

Between Jan 3, 2009, and March 20, 2011, we recruited and randomly assigned 508 children to treatment: 252 to MgSO4and 256 to placebo. Mean ASS at 60 min was lower in the MgSO4 group (4·72 [SD 1·37]) than it was in the placebo group (4·95 [SD 1·40]; adjusted difference −0·25, 95% CI −0·48 to −0·02; p=0·03). This difference, however, was not clinically significant. The clinical effect was larger in children with more severe asthma exacerbation (p=0·03) and those with symptoms present for less than 6 h (p=0·049). We detected no difference in the occurrence of adverse events between groups.

Interpretation

Overall, nebulised isotonic MgSO4, given as an adjuvant to standard treatment, did not show a clinically significant improvement in mean ASS in children with acute severe asthma. However, the greatest clinical response was seen in children with more severe attacks (SaO2<92%) at presentation and those with preceding symptoms lasting less than 6 h.

Source: lancet

 

Intravenous or nebulised magnesium sulphate versus standard therapy for severe acute asthma (3Mg trial): a double-blind, randomised controlled trial.


Background

Previous studies suggested intravenous or nebulised magnesium sulphate (MgSO4) might improve respiratory function in patients with acute asthma. We aimed to determine whether intravenous or nebulised MgSO4 improve symptoms of breathlessness and reduce the need for hospital admission in adults with severe acute asthma.

Methods

In our double-blind, placebo-controlled trial, we enrolled adults (aged ≥16 years) with severe acute asthma at emergency departments of 34 hospitals in the UK. We excluded patients with life-threatening features or contraindication to study drugs. We used a central randomisation system to allocate participants to intravenous MgSO4 (2 g in 20 min) or nebulised MgSO4 (three 500 mg doses in 1 h) alongside standard therapy including salbutamol, or placebo control plus standard therapy alone. We assessed two primary outcome measures in all eligible participants who started treatment, according to assigned treatment group: the proportion of patients admitted to hospital within 7 days and breathlessness measured on a 100 mm visual analogue scale (VAS) in the 2 h after initiation of treatment. We adjusted for multiple testing using Simes’s method. The trial stopped before recruitment was completed because funding expired. This study is registered, number ISRCTN04417063.

Findings

Between July 30, 2008, and June 30, 2012, we recruited 1109 (92%) of 1200 patients proposed by the power calculation. 261 (79%) of 332 patients allocated nebulised MgSO4 were admitted to hospital before 7 days, as were 285 (72%) of 394 patients allocated intravenous MgSO4 and 281 (78%) of 358 controls. Breathlessness was assessed in 296 (89%) patients allocated nebulised MgSO4, 357 (91%) patients allocated intravenous MgSO4, and 323 (90%) controls. Rates of hospital admission did not differ between patients treated with either form of MgSO4 compared with controls or between those treated with nebulised MgSO4 and intravenous MgSO4. Change in VAS breathlessness did not differ between active treatments and control, but change in VAS was greater for patients in the intravenous MgSO4 group than it was in the nebulised MgSO4 group (5·1 mm, 0·8 to 9·4; p=0·019). Intravenous or nebulised MgSO4 did not significantly decrease rates of hospital admission and breathlessness compared with placebo: intravenous MgSO4 was associated with an odds ratio of 0·73 (95% CI 0·51 to 1·04; p=0·083) for hospital admission and a change in VAS breathlessness of 2·6 mm (—1·6 to 6·8; p=0·231) compared with placebo; nebulised MgSO4 was associated with an odds ratio of 0·96 (0·65 to 1·40; p=0·819) for hospital admission and a change in VAS breathlessness of −2·6 mm (—7·0 to 1·8; p=0·253) compared with placebo.

Source: lancet

 

 

Get moving to breathe easy.


In April, 2013, The American Lung Association (ALA) released their latest State of the Air report, which highlighted mixed results in reducing air pollution in the USA. While in the UK, air quality was also a key concern, with the UK Supreme Court reporting that the country is in breach of the European Union’s air quality directive for nitrogen dioxide levels from traffic pollution. This ruling is welcome as it could force the UK Government into action to avoid punitive fines by finally addressing the growing issue of increased traffic on its roads and the consequences for air quality.

So what are the key challenges when considering air pollution, and where should we start? A reduction in life expectancy from cardiovascular and respiratory diseases as a result of air pollution is well established. However, studies at the recent American Thoracic Society’s 2013 conference showed that risks can be greater than previously thought, and can have multiple effects on respiratory diseases; for example, even low levels of traffic pollution has been shown to increase asthma morbidity in pregnant women, and expectant mothers living near major roads have children at increased risk of respiratory infections before the age of 3 years. But even a small reduction in particulate matter (PM) 2·5 can improve life expectancy; a study in Epidemiology earlier this year showed an increase in mean life expectancy of 0·35 years for a 10 μg/m3 decrease in PM 2·5. Unfortunately, as in this paper, most data on pollution and its effects on health are derived from association studies, and considered weak evidence, because quantifying the risk and benefit of any single factor can be difficult, and data are affected by chance, confounding, and interlinking risks. Furthermore, it might not be in governments’ interests to monitor accurately the levels of any pollution, and government and independent measures can differ. Independent studies are therefore vital to improve the evidence base and prompt action.

The ALA report is a good basis on which to build quality evidence and action plans that could be applied globally. Data for the report were compiled by the US Environmental Protection Agency (EPA) which measured levels of two major pollutants, ozone and PM 2·5, from 2009 to 2011. Encouragingly, 18 cities had reduced annual average PM 2·5 in this latest 2013 ALA report, and a record number of four cities were on all three of the cleanest cities lists. However, 42% of the US population (more than 131 million people) still live in counties with unhealthy levels of either smog or PM 2·5. Nevertheless, much progress has been made recently in major industrial countries to tackle the enormity of the problem. Legislation in the USA and Europe, such as the Clean Air Act of 1970 and EU Directive on ambient air quality and cleaner air (2008/50/EC), have provided a framework for regulatory agencies and governments to tackle major types of air pollution, with the requirements of EU directives from 2004 and 2008 being transferred into English law in the 2010 Air Quality Standards Regulation.

But despite some progress, there is no room for complacency, and monetary support should be diverted from projects likely to increase pollution to those that encourage greener transport, transport-free areas, improved road infrastructure, and safety for cyclists. The EPA has recently announced funding of around US$9 million for projects that reduce diesel emissions, while President Obama launched a publicly accessible platform in May, 2013, that will search and synthesise metadata to help to analyse links between climate change and health. Projects such as green walls at major traffic intersections are additional admirable efforts, and many countries, often at city level, are embracing efforts to increase and protect cyclists on the road, and to try and encourage motorists out of their cars. Plane travel could be reduced through use of modern telecommunications, lessening the need for physical face-to-face meetings and additional runways. Carbon offsetting has also been at the forefront of individual and industry efforts to protect air quality and the environment. However, the ruling by the UK Supreme Court suggests that the innovation and forward thinking that is required at the government level to address pollution is still some way off fruition, at least in the UK, perhaps because air quality in the UK is a devolved responsibility.

The industrial revolution has changed forever the societies of developed countries and the irony of this progress is that individuals have become increasingly sedentary. This lack of movement has not only polluted the air we breathe, from increased traffic and reduced green spaces, but has also spread insidious tentacles of morbidity, disease, and death that act synergistically in a vicious circle. Practical incentives and action plans must be set to break down this circle at both the government and individual level. Current efforts should be acknowledged, but must be escalated if we are all to breathe easy in the future.

Source: lancet

 

Are inhaled longacting β2 agonists detrimental to asthma?


Possible adverse effects of adrenergic bronchodilators in asthma have been the subject of discussion for more than half a century, with recent intense debate about the safety of longacting β agonists (LABAs). In this Debate, we consider the issues of bronchodilator and bronchoprotective tolerance resulting from the frequent use of bronchodilators, which is noted particularly with shortacting drugs, but has also been shown to occur quicker and to a greater extent with LABAs. Increased allergen responsiveness and masking allowing inflammation to increase, while symptoms and lung function remain apparently controlled, have also been observed. Studies in which LABAs were used as monotherapy were associated with increased mortality. However, several studies have shown the benefits of adding LABAs to inhaled corticosteroids (ICS). Meta-analyses of asthma clinical trials involving LABAs showed that, when given with mandatory ICS, LABAs were not associated with an increased risk of death, intubations, or hospital admission for exacerbations when compared with use of the same dose of ICS only. Withdrawal of LABA therapy once symptom control is achieved is often associated with subsequent loss of symptom control. When used for appropriate indications, LABAs should be combined with ICS in one inhaler so that monotherapy is not possible.

Source: lancet

 

Pulmonary hypertension in β thalassaemia.


Pulmonary hypertension is one of the leading causes of morbidity and mortality in patients with haemolytic disorders and is a frequent finding in echocardiographic screening of patients with β thalassaemia. Substantial progress has been made in understanding of the multifactorial pathophysiology of pulmonary hypertension in β thalassaemia. Haemolysis, reduced nitric oxide bioavailability, iron overload, and hypercoagulopathy are among the main pathogenetic mechanisms. Various disease-directed therapeutic methods, such as transfusion, chelation, and splenectomy, have important roles in the development of pulmonary hypertension in β thalassaemia. Studies investigating the prevalence of pulmonary hypertension in β thalassaemia are mostly based on echocardiographic findings, and are thus limited by the scarcity of information derived from right heart catheterisation. Invasive pulmonary haemodynamic data are needed to clarify the true prevalence of pulmonary hypertension in β thalassaemia, to better understand the underlying pathophysiology and risk factors, and to define the optimum therapy for this devastating complication.

Source: lancet

Reproductive organ involvement in non-Hodgkin lymphoma during pregnancy: a systematic review.


Data for pregnancy-associated non-Hodgkin lymphoma are limited to case reports, making it difficult to define this disorder. We did a systematic search for articles published between 1967 and 2011 with the aim to determine the characteristics, management, and outcome of pregnancy-associated non-Hodgkin lymphoma. We identified 121 patients from 74 papers. Most patients with stage information available presented with stage IV disease (75%, 82 of 108 patients). Patients were classified into three clinical groups; those with indolent lymphomas accounted for 5% (five of 108), aggressive lymphomas (diffuse large B-cell lymphoma and T-cell lymphomas) made up 48% of patients (52 of 108), and highly aggressive lymphomas (Burkitt’s lymphoma, immunoblastic lymphoma, and unspecified highly aggressive lymphomas) accounted for 47% of patients (51 of 108). Reproductive organ involvement (breast, ovary, uterus, placenta) was reported in 49% of 110 patients with information available on extranodal involvement, and prevailed in endemic Burkitt’s lymphoma (100%, 19 of 19), followed by non-endemic Burkitt lymphoma (70%, 14 of 20), immunoblastic lymphoma (67%, two of three), peripheral T-cell lymphoma (46%, six of 13), and indolent (40%, two of five) and diffuse large cell lymphoma (23%, nine of 40). Most patients received antepartum (45%, 55 of 121) or postpartum therapy (45%, 54 of 121), resulting in 6-month survival of 53% for mothers and a livebirth rate of 83%. Pregnancy-associated non-Hodgkin lymphoma has unique clinical characteristics with frequent reproductive organ involvement. Collaborative prospective studies are needed to further characterise pathophysiological and clinical aspects of this complication.

Source: lancet

 

 

Efficacy and safety of 12-weekly versus 4-weekly zoledronic acid for prolonged treatment of patients with bone metastases from breast cancer (ZOOM): a phase 3, open-label, randomised, non-inferiority trial.


Background

Zoledronic acid reduces skeletal-related events in patients with breast cancer, but concerns have been raised about prolonged monthly administration. We assessed the efficacy and safety of a reduced dosing frequency of zoledronic acid in women treated previously with monthly zoledronic acid.

Methods

We did this non-inferiority, phase 3 trial in 62 centres in Italy. We enrolled patients with breast cancer who had one or more bone metastases and had completed 12—15 months of monthly treatment with zoledronic acid. Patients were randomly assigned with a permutated block (size four to eight) random list stratified by centre in a 1:1 ratio to zoledronic acid 4 mg once every 12 weeks or once every 4 weeks, and followed up for at least 1 year. Neither patients nor investigators were masked to treatment allocation. The primary outcome was skeletal morbidity rate (skeletal-related events per patient per year) in the intention-to-treat population. We used a non-inferiority margin of 0·19. The trial is registered with EudraCT, number 2005-004942-15.

Findings

We screened 430 patients and enrolled 425, of whom 209 were assigned to the 12-week group and 216 to the 4-week group. The skeletal morbidity rate was 0·26 (95% CI 0·15—0·37) in the 12-week group versus 0·22 (0·14—0·29) in the 4-week group. The between-group difference was 0·04 and the upper limit of one-tailed 97·5% CI was 0·17, which is lower than the non-inferiority margin. The most common grade 3—4 adverse events were bone pain (56 [27%] patients in the 12-week group vs 65 [30%] in the 4-week group), nausea (24 [11%] vs 33 [15%]), and asthenia (18 [9%] vs 33 [15%]). Renal adverse events occurred in one patient (<1%) in the 12-week group versus two (1%) in the 4-week group. One patient (<1%) in the 4-week group had grade 1 acute renal failure. Osteonecrosis of the jaw occurred in four patients in the 12-week group versus three in the 4-week group. No treatment-related deaths were reported. Median N-terminal telopeptide concentration changed from baseline more in the 12-week group than in the 4-week group after 12 months (12·2% vs 0·0%; p=0·011).

Interpretation

Our results raise the possibility of decreasing administration of zoledronic acid to a 12-weekly regimen to reduce exposure during the second year, while maintaining its therapeutic effects. However, the effects on N-terminal telopeptide should be investigated further before changing current practice.

Source: lancet

Galactomannan and PCR versus culture and histology for directing use of antifungal treatment for invasive aspergillosis in high-risk haematology patients: a randomised controlled trial.


Background

Empirical treatment with antifungal drugs is often used in haematology patients at high risk of invasive aspergillosis. We compared a standard diagnostic strategy (culture and histology) with a rapid biomarker-based diagnostic strategy (aspergillus galactomannan and PCR) for directing the use of antifungal treatment in this group of patients.

Methods

In this open-label, parallel-group, randomised controlled trial, eligible patients were adults undergoing allogeneic stem-cell transplantation or chemotherapy for acute leukaemia, with no history of invasive fungal disease. Enrolled patients were randomly assigned (1:1) by a computer-generated schedule to follow either a standard diagnostic strategy (based on culture and histology) or a biomarker-based diagnostic strategy (aspergillus galactomannan and PCR) to direct treatment with antifungal drugs. Patients, were followed up for 26 weeks or until death. Masking of the use of different diagnostic tests was not possible for patients, treating physicians, or investigators. The primary endpoint was empirical treatment with antifungal drugs in the 26 weeks after enrolment (for the biomarker-based diagnostic strategy, a single postive galactomannan or PCR result was deemed insufficient to confirm invasive aspergillosis, so treatment in this context was classified as empirical). This outcome was assessed by an independent data review committee from which the study allocations were masked. Analyses were by intention to treat and included all enrolled patients. This study is registered withClinicalTrial.gov, number NCT00163722.

Findings

240 eligible patients were recruited from six Australian centres between Sept 30, 2005, and Nov 19, 2009. 122 were assigned the standard diagnostic strategy and 118 the biomarker-based diagnostic strategy. 39 patients (32%) in the standard diagnosis group and 18 (15%) in the biomarker diagnosis group received empirical antifungal treatment (difference 17%, 95% CI 4—26; p=0·002). The numbers of patients who had hepatotoxic and nephrotoxic effects did not differ significantly between the standard diagnosis and biomarker diagnosis groups (hepatotoxic effects: 21 [17%] vs 12 [10%], p=0·11; nephrotoxic effects: 52 [43%] vs 60 [51%], p=0·20).

Interpretation

Use of aspergillus galactomannan and PCR to direct treatment reduced use of empirical antifungal treatment. This approach is an effective strategy for the management of invasive aspergillosis in high-risk haematology patients.

Source: lancet

Soil-transmitted helminth infection in South America: a systematic review and geostatistical meta-analysis.


Background

The four common soil-transmitted helminth species—Ascaris lumbricoidesTrichuris trichiura, and the two hookworm species Ancylostoma duodenale and Necator americanus—are endemic in South America, but their distribution, infection prevalence, and regional burden are poorly understood. We aimed to estimate the risk and number of people infected with A lumbricoidesT trichiura, and hookworm across South America.

Methods

We did a systematic review of reports on the prevalence of soil-transmitted helminth infection in South America published up to May 14, 2012. We extracted and georeferenced relevant survey data and did a meta-analysis of the data to assess the geographical distribution of the infection risk with Bayesian geostatistical models. We used advanced Bayesian variable selection to identify environmental determinants that govern the distribution of soil-transmitted helminth infections.

Findings

We screened 4085 scientific papers and identified 174 articles containing relevant survey prevalence data. We georeferenced 6948 survey locations and entered the data into the open-access Global Neglected Tropical Diseases database. Survey data were sparse for the south of the continent and for the western coast, and we identified no relevant information for Uruguay and little data for smaller countries such as Suriname, Guyana, French Guiana, and Ecuador. Population-adjusted prevalence of infection with A lumbricoides was 15·6%, with T trichiura was 12·5%, and with hookworm was 11·9% from 2005 onwards. Risks of contracting soil-transmitted helminth infection have substantially reduced since 2005 (odds ratio 0·47 [95% Bayesian credible interval 0·46—0·47] for A lumbricoides, 0·54 [0·54—0·55] for T trichiura, and 0·58 [0·58—0·59] for hookworm infection).

Interpretation

Our findings offer important baseline support for spatial targeting of soil-transmitted helminthiasis control, and suggest that more information about the prevalence of soil-transmitted helminth infection is needed, especially in countries in which we estimate prevalence of infection to be high but for which current data are scarce.

Source: lancet