Is an Antireflux Procedure Necessary for a Successful Appendicostomy? The Simplified Malone Antegrade Continence Enema Procedure.

Aim: The aim of this study was to present the long-term institutional experience and outcomes of our Malone antegrade continence enema (MACE) procedure using the proximal appendix without any antireflux procedure. Materials and Methods: A single-center prospective study of 29 children undergoing a simplified Malone antegrade continence enema (SMACE) procedure from 2006 to 2017 was conducted using the appendix, whole or split. The mean follow-up period was 11.5 years (ranging from 5 to 16 years). Results: In 25 children, the proximal appendix was used, and in 4 cases, the whole appendix was used as a conduit. On follow-up, the MACE channel has been working well in 29/29 patients. Among the complications, seven patients had stomal stenosis, which was managed by home dilatation. There was no reflux of stools seen in any of the patients. Conclusion: The SMACE procedure, without incorporating an antireflux mechanism, is technically simpler and saves operative time. Most importantly, the results are satisfactory and comparable with procedures using antireflux techniques.

Model-Based Analysis of Cell Cycle Responses to Dynamically Changing Environments.

Cell cycle progression is carefully coordinated with a cell's intra- and extracellular environment. While some pathways have been identified that communicate information from the environment to the cell cycle, a systematic understanding of how this information is dynamically processed is lacking. We address this by performing dynamic sensitivity analysis of three mathematical models of the cell cycle in Saccharomyces cerevisiae. We demonstrate that these models make broadly consistent qualitative predictions about cell cycle progression under dynamically changing conditions. For example, it is shown that the models predict anticorrelated changes in cell size and cell cycle duration under different environments independently of the growth rate. This prediction is validated by comparison to available literature data. Other consistent patterns emerge, such as widespread nonmonotonic changes in cell size down generations in response to parameter changes. We extend our analysis by investigating glucose signalling to the cell cycle, showing that known regulation of Cln3 translation and Cln1,2 transcription by glucose is sufficient to explain the experimentally observed changes in cell cycle dynamics at different glucose concentrations. Together, these results provide a framework for understanding the complex responses the cell cycle is capable of producing in response to dynamic environments.

Efficacy of accelerated hydrogen peroxide® disinfectant on foot-and-mouth disease virus, swine vesicular disease virus and Senecavirus A.

AIMS: In a laboratory, disinfectants used to inactivate pathogens on contaminated surfaces and to prevent spread of diseases often have adverse side effects on personnel and the environment. It is, therefore, essential to find safer, fast-acting and yet effective disinfectants. The objective of this study was to evaluate an accelerated hydrogen peroxide® (AHP® )-based disinfectant against high consequence foreign animal disease pathogens such as foot-and-mouth disease virus (FMDV) and swine vesicular disease virus (SVDV), as well as Senecavirus A (SVA), which causes similar lesions as FMDV and SVDV. METHODS AND RESULTS: We tested varying dilutions and contact times of AHP against FMDV, SVDV and SVA by the standard US EPA and modified methods. AHP was effective against all three viruses, albeit at a higher concentration and double the manufacturer recommended contact time when testing wet films of SVDV. CONCLUSIONS: AHP is an effective disinfectant against FMDV, SVDV and SVA. SIGNIFICANCE AND IMPACT OF THE STUDY: AHP-based disinfectant can, therefore, be used in high containment laboratories working with FMDV, SVDV and related pathogens.

Bridging the gap between modules in isolation and as part of networks: A systems framework for elucidating interaction and regulation of signalling modules.

While signalling and biochemical modules have been the focus of numerous studies, they are typically studied in isolation, with no examination of the effects of the ambient network. In this paper we formulate and develop a systems framework, rooted in dynamical systems, to understand such effects, by studying the interaction of signalling modules. The modules we consider are (i) basic covalent modification, (ii) monostable switches, (iii) bistable switches, (iv) adaptive modules, and (v) oscillatory modules. We systematically examine the interaction of these modules by analyzing (a) sequential interaction without shared components, (b) sequential interaction with shared components, and (c) oblique interactions. Our studies reveal that the behaviour of a module in isolation may be substantially different from that in a network, and explicitly demonstrate how the behaviour of a given module, the characteristics of the ambient network, and the possibility of shared components can result in new effects. Our global approach illuminates different aspects of the structure and functioning of modules, revealing the importance of dynamical characteristics as well as biochemical features; this provides a methodological platform for investigating the complexity of natural modules shaped by evolution, elucidating the effects of ambient networks on a module in multiple cellular contexts, and highlighting the capabilities and constraints for engineering robust synthetic modules. Overall, such a systems framework provides a platform for bridging the gap between non-linear information processing modules, in isolation and as parts of networks, and a basis for understanding new aspects of natural and engineered cellular networks.

Spatial Control of Biochemical Modification Cascades and Pathways.

Information transmission in cells occurs through complex networks of proteins and genes and is relayed through cascades of biochemical modifications, which are typically studied through ordinary differential equations. However, it is becoming increasingly clear that spatial factors can strongly influence chemical information transmission in cells. In this article, we systematically disentangle the effects of space in signaling cascades. This is done by examining the effects of localization/compartmentalization and diffusion of enzymes and substrates in multiple variants of chemical modification cascades. This includes situations where the modified form of species at one stage 1) acts as an enzyme for the next stage; 2) acts as a substrate for the next stage; and 3) is involved in phosphotransfer. Our analysis reveals the multiple effects of space in signal transduction cascades. Although in some cases space plays a modulatory effect (itself of interest), in other cases, spatial regulation and control can profoundly affect the nature of information processing as a result of the subtle interplay between the patterns of localization of species, diffusion, and the nature of the modification cascades. Our results provide a platform for disentangling the role of space and spatial control in multiple cellular contexts and a basis for engineering spatial control in signaling cascades through localization/compartmentalization.

Regulation of release factor expression using a translational negative feedback loop: a systems analysis.

The essential eukaryote release factor eRF1, encoded by the yeast SUP45 gene, recognizes stop codons during ribosomal translation. SUP45 nonsense alleles are, however, viable due to the establishment of feedback-regulated readthrough of the premature termination codon; reductions in full-length eRF1 promote tRNA-mediated stop codon readthrough, which, in turn, drives partial production of full-length eRF1. A deterministic mathematical model of this eRF1 feedback loop was developed using a staged increase in model complexity. Model predictions matched the experimental observation that strains carrying the mutant SUQ5 tRNA (a weak UAA suppressor) in combination with any of the tested sup45(UAA) nonsense alleles exhibit threefold more stop codon readthrough than that of an SUQ5 yeast strain. The model also successfully predicted that eRF1 feedback control in an SUQ5 sup45(UAA) mutant would resist, but not completely prevent, imposed changes in eRF1 expression. In these experiments, the introduction of a plasmid-borne SUQ5 copy into a sup45(UAA) SUQ5 mutant directed additional readthrough and full-length eRF1 expression, despite feedback. Secondly, induction of additional sup45(UAA) mRNA expression in a sup45(UAA) SUQ5 strain also directed increased full-length eRF1 expression. The autogenous sup45 control mechanism therefore acts not to precisely control eRF1 expression, but rather as a damping mechanism that only partially resists changes in release factor expression level. The validated model predicts that the degree of feedback damping (i.e., control precision) is proportional to eRF1 affinity for the premature stop codon. The validated model represents an important tool to analyze this and other translational negative feedback loops.

The behaviour of basic autocatalytic signalling modules in isolation and embedded in networks.

In this paper, we examine the behaviour of basic autocatalytic feedback modules involving a species catalyzing its own production, either directly or indirectly. We first perform a systematic study of the autocatalytic feedback module in isolation, examining the effect of different factors, showing how this module is capable of exhibiting monostable threshold and bistable switch-like behaviour. We then study the behaviour of this module embedded in different kinds of basic networks including (essentially) irreversible cycles, open and closed reversible chains, and networks with additional feedback. We study the behaviour of the networks deterministically and also stochastically, using simulations, analytical work, and bifurcation analysis. We find that (i) there are significant differences between the behaviour of this module in isolation and in a network: thresholds may be altered or destroyed and bistability may be destroyed or even induced, even when the ambient network is simple. The global characteristics and topology of this network and the position of the module in the ambient network can play important and unexpected roles. (ii) There can be important differences between the deterministic and stochastic dynamics of the module embedded in networks, which may be accentuated by the ambient network. This provides new insights into the functioning of such enzymatic modules individually and as part of networks, with relevance to other enzymatic signalling modules as well.

A systems framework for investigating the roles of multiple transporters and their impact on drug resistance.

Efflux transporters are a fundamental component of both prokaryotic and eukaryotic cells, play a crucial role in maintaining cellular homeostasis, and represent a key bridge between single cell and population levels. From a biomedical perspective, they play a crucial role in drug resistance (and especially multi-drug resistance, MDR) in a range of systems spanning bacteria and human cancer cells. Typically, multiple efflux transporters are present in these cells, and the efflux transporters transport a range of substrates (with partially overlapping substrates between transporters). Furthermore, in the context of drug resistance, the levels of transporters may be elevated either due to extra or intracellular factors (feedforward regulation) or due to the drug itself (feedback regulation). As a consequence, there is a real need for a transparent systems-level understanding of the collective functioning of a set of transporters and their response to one or more drugs. We develop a systems framework for this purpose and examine the functioning of sets of transporters, their interplay with one or more drugs and their regulation (both feedforward and feedback). Using computational and analytical work, we obtain transparent insights into the systems level functioning of a set of transporters arising from the interplay between the multiplicity of drugs and transporters, different drug-transporter interaction parameters, sequestration and feedback and feedforward regulation. These insights transparently arising from the most basic consideration of a multiplicity of transporters have broad relevance in natural biology, biomedical engineering and synthetic biology. Insight, Innovation, Integration: Innovation: creating a structured systems framework for evaluating the impact of multiple transporters on drug efflux and drug resistance. Systematic analysis allows us to evaluate the effect of multiple transporters on one/more drugs, and dissect associated resistance mechanisms. Integration allows for elucidation of key cause-and-effect relationships and a transparent systems-level understanding of the collective functioning of transporters and their impact on resistance, revealing the interplay of key underlying factors. Systems-level insights include the essentially different behaviour of transporters as part of a group; unintuitive effects of influx; effects of elevated transporter-levels by feedforward and drug-induced mechanisms. Relevance: a systems understanding of efflux, their role in MDR, providing a framework/platform for use in designing treatment, and in synthetic biology design.

Covalent modification cycles through the spatial prism.

Covalent modification cycles are basic units and building blocks of posttranslational modification and cellular signal transduction. We systematically explore different spatial aspects of signal transduction in covalent modification cycles by starting with a basic temporal cycle as a reference and focusing on steady-state signal transduction. We consider, in turn, the effect of diffusion on spatial signal transduction, spatial analogs of ultrasensitive behavior, and the interplay between enzyme localization and substrate diffusion. Our analysis reveals the need to explicitly account for kinetics and diffusional transport (and localization) of enzymes, substrates, and complexes. It demonstrates a complex and subtle interplay between spatial heterogeneity, diffusion, and localization. Overall, examining the spatial dimension of covalent modification reveals that 1), there are important differences between spatial and temporal signal transduction even in this cycle; and 2), spatial aspects may play a substantial role in affecting and distorting information transfer in modules/networks that are usually studied in purely temporal terms. This has important implications for the systematic understanding of signaling in covalent modification cycles, pathways, and networks in multiple cellular contexts.

A unified approach to dissecting biphasic responses in cell signaling.

Biphasic responses are encountered at all levels in biological systems. At the cellular level, biphasic dose-responses are widely encountered in cell signaling and post-translational modification systems and represent safeguards against overactivation or overexpression of species. In this paper, we provide a unified theoretical synthesis of biphasic responses in cell signaling systems, by assessing signaling systems ranging from basic biochemical building blocks to canonical network structures to well-characterized exemplars on one hand, and examining different types of doses on the other. By using analytical and computational approaches applied to a range of systems across levels (described by broadly employed models), we reveal (i) design principles enabling the presence of biphasic responses, including in almost all instances, an explicit characterization of the parameter space (ii) structural factors which preclude the possibility of biphasic responses (iii) different combinations of the presence or absence of enzyme-biphasic and substrate-biphasic responses, representing safeguards against overactivation and overexpression, respectively (iv) the possibility of broadly robust biphasic responses (v) the complete alteration of signaling behavior in a network due to biphasic interactions between species (biphasic regulation) (vi) the propensity of different co-existing biphasic responses in the Erk signaling network. These results both individually and in totality have a number of important consequences for systems and synthetic biology.

Network regulation meets substrate modification chemistry.

Biochemical networks are at the heart of cellular information processing. These networks contain distinct facets: (i) processing of information from the environment via cascades/pathways along with network regulation and (ii) modification of substrates in different ways, to confer protein functionality, stability and processing. While many studies focus on these factors individually, how they interact and the consequences for cellular systems behaviour are poorly understood. We develop a systems framework for this purpose by examining the interplay of network regulation (canonical feedback and feed-forward circuits) and multisite modification, as an exemplar of substrate modification. Using computational, analytical and semi-analytical approaches, we reveal distinct and unexpected ways in which the substrate modification and network levels combine and the emergent behaviour arising therefrom. This has important consequences for dissecting the behaviour of specific signalling networks, tracing the origins of systems behaviour, inference of networks from data, robustness/evolvability and multi-level engineering of biomolecular networks. Overall, we repeatedly demonstrate how focusing on only one level (say network regulation) can lead to profoundly misleading conclusions about all these aspects, and reveal a number of important consequences for experimental/theoretical/data-driven interrogations of cellular signalling systems.

Prevalence of hiatal hernia by blinded multidetector CT in patients with idiopathic pulmonary fibrosis.

Hiatal hernia (HH) is associated with gastro-oesophageal reflux (GOR) and/or GOR disease and may contribute to idiopathic pulmonary fibrosis (IPF). We hypothesised that HH evaluated by computed tomography is more common in IPF than in asthma or chronic obstructive pulmonary disease (COPD), and correlates with abnormal GOR measured by pH probe testing. Rates of HH were compared in three cohorts, IPF (n=100), COPD (n=60) and asthma (n=24), and evaluated for inter-observer agreement. In IPF, symptoms and anti-reflux medications were correlated with diffusing capacity of the lung for carbon monoxide (D(L,CO)) and composite physiologic index (CPI). HH was correlated with pH probe testing in IPF patients (n=14). HH was higher in IPF (39%) than either COPD (13.3%, p=0.00009) or asthma (16.67%, p=0.0139). The HH inter-observer κ agreement was substantial in IPF (κ=0.78) and asthma (κ=0.86), and moderate in COPD (κ=0.42). In IPF, HH did not correlate with lung function, except in those on anti-reflux therapy, who had a better D(L,CO) (p<0.03) and CPI (p<0.04). HH correlated with GOR as measured by DeMeester scores (p<0.04). HH is more common in IPF than COPD or asthma. In an IPF cohort, HH correlated with higher DeMeester scores, confirming abnormal acid GOR. Presence of HH alone was not associated with decreased lung function.

Effects of multiple enzyme-substrate interactions in basic units of cellular signal processing.

Covalent modification cycles are a ubiquitous feature of cellular signalling networks. In these systems, the interaction of an active enzyme with the unmodified form of its substrate is essential for signalling to occur. However, this interaction is not necessarily the only enzyme-substrate interaction possible. In this paper, we analyse the behaviour of a basic model of signalling in which additional, non-essential enzyme-substrate interactions are possible. These interactions include those between the inactive form of an enzyme and its substrate, and between the active form of an enzyme and its product. We find that these additional interactions can result in increased sensitivity and biphasic responses, respectively. The dynamics of the responses are also significantly altered by the presence of additional interactions. Finally, we evaluate the consequences of these interactions in two variations of our basic model, involving double modification of substrate and scaffold-mediated signalling, respectively. We conclude that the molecular details of protein-protein interactions are important in determining the signalling properties of enzymatic signalling pathways.

An investigation of design principles underlying repulsive and attractive gradient sensing and their switching.

Many important cellular processes rely on cellular responses to spatially graded signals. This response may be either attractive, indicating a positive bias, or repulsive indicating a negative bias. In this paper we consider cells which exhibit both repulsive and attractive gradient sensing responses and aim to uncover the underlying design principles and features of how the networks are wired which could allow a cell to exhibit both responses. We use a modular approach to examine different configurations which will allow for a cell to exhibit both responses and analyse how this depends on the basic characteristics of gradient sensing and downstream signal propagation. Overall our analysis provides insights into how gradient responses can be switched and the key factors which affect this switching.

A systems-based mathematical modelling framework for investigating the effect of drugs on solid tumours.

BACKGROUND: Elucidating the effects of drugs on solid tumours is a highly challenging multi-level problem, since this involves many complexities associated with transport and cellular response, which in turn is characterized by highly non-linear chemical signal transduction. Appropriate systems frameworks are needed to seriously address the sources of these complexities, especially from the cellular side. RESULTS: We develop a skeletal modelling framework incorporating interstitial drug transport, intracellular signal processing and cell population descriptions. The descriptions aim to appropriately capture the nature of information flow. The model is deliberately formulated to start with simple intracellular descriptions so that additional features can be incorporated in a modular fashion. Two kinds of intracellular signalling modules which describe the drug effect were considered, one a monostable switch and the other a bistable switch. Analysis of our model revealed how different drug stimuli can lead to cell killing in the tumour. Interestingly both modules considered exhibited similar trends. The effects of important parameters were also studied. CONCLUSIONS: We have created a predictive systems platform integrating drug transport and cellular response which can be systematically augmented to include additional layers of cellular complexity. Our results indicate that intracellular signalling models which are qualitatively different can give rise to similar behaviour to simple (and typical) stimuli, and that validating intracellular descriptions must be performed with care by considering a variety of drug stimuli.

Implications of paper vs stainless steel biological indicator substrates for formaldehyde gas decontamination.

AIMS: This study was undertaken to determine the effectiveness of biological indicators currently being employed during formaldehyde decontamination. Data suggest that detectable amounts of formaldehyde are absorbed into the paper strips contained in currently used biological indicators. Absorbed formaldehyde has the potential to inhibit the growth of indicator spores, thus leading to false negative results. Indicators composed of either stainless steel carriers or paper strips were investigated to determine whether stainless steel carriers can be used as an alternative to paper strip indicators. METHODS AND RESULTS: Biological indicators were exposed to formaldehyde gas and were tested for the presence of formaldehyde and any possible inhibition of spore growth. Absorbed formaldehyde was detected in the paper strip carriers while no formaldehyde was detected from any of the stainless steel carriers. Exposed paper strips were found to inhibit growth of up to 1 × 10(6) spores while the stainless steel carriers did not inhibit the growth of spores. CONCLUSIONS: During decontamination, biological indicators composed of paper spore strips absorb formaldehyde and inhibit growth of any surviving spores. Stainless steel carriers do not absorb formaldehyde and are an ideal alternative substrate for biological indicators. SIGNIFICANCE AND IMPACT OF THE STUDY: The popular paper strip biological indicator can lead to false negative results during decontamination and is unsuitable for validating formaldehyde decontamination.

Symmetry breaking meets multisite modification.

Multisite modification is a basic way of conferring functionality to proteins and a key component of post-translational modification networks. Additional interest in multisite modification stems from its capability of acting as complex information processors. In this paper, we connect two seemingly disparate themes: symmetry and multisite modification. We examine different classes of random modification networks of substrates involving separate or common enzymes. We demonstrate that under different instances of symmetry of the modification network (invoked explicitly or implicitly and discussed in the literature), the biochemistry of multisite modification can lead to the symmetry being broken. This is shown computationally and consolidated analytically, revealing parameter regions where this can (and in fact does) happen, and characteristics of the symmetry-broken state. We discuss the relevance of these results in situations where exact symmetry is not present. Overall, through our study we show how symmetry breaking (i) can confer new capabilities to protein networks, including concentration robustness of different combinations of species (in conjunction with multiple steady states); (ii) could have been the basis for ordering of multisite modification, which is widely observed in cells; (iii) can significantly impact information processing in multisite modification and in cell signalling networks/pathways where multisite modification is present; and (iv) can be a fruitful new angle for engineering in synthetic biology and chemistry. All in all, the emerging conceptual synthesis provides a new vantage point for the elucidation and the engineering of molecular systems at the junction of chemical and biological systems.

Proteins help our cells perform the chemical reactions necessary for life. Once proteins are made, they can also be modified in different ways. This can simply change their activity, or otherwise make them better suited for their specific jobs within the cell. Biological 'catalysts' called enzymes carry out protein modifications by reversibly adding (or removing) chemical groups, such as phosphate groups. 'Multisite modifications' occur when a protein has two or more modifications in different areas, which can be added randomly or in a specific sequence. The combination of all the modifications attached to a protein acts like a chemical barcode and confers a specific function to the protein. Modification networks add levels of complexity above individual proteins. These encompass not only the proteins in a cell or tissue, but also the different enzymes that can modify them, and how they all interact with each other. Although our knowledge of these networks is substantial, basic aspects, such as how the ordering of multisite modification systems emerges, is still not well understood. Using a simple set of multisite modifications, Ramesh and Krishnan set out to study the potential mechanisms allowing the creation of order in this context. Symmetry is a pervasive theme across the sciences. In biology, symmetry and how it may be broken, is important to understand, for example, how organism develop. Ramesh and Krishnan used the perspective of symmetry in protein networks to uncover the origins of ordering. First, mathematical models of simple modification networks were created based on their basic descriptions. This system centred on proteins that could have phosphate modifications at two possible sites. The network was 'symmetric', meaning that the rate of different sets of chemical reactions was identical, as were the amounts of all the enzymes involved. Dissecting the simulated network using a variety of mathematical approaches showed that its initial symmetry could break, giving rise to sets of ordered multisite modifications. Breaking symmetry did not require any additional features or factors; the basic chemical 'ingredients' of protein modification were all that was needed. The prism of symmetry also revealed other aspects of these multisite modification networks, such as robustness and oscillations. This study sheds new light on the mechanism behind ordering of protein modifications. In the future, Ramesh and Krishnan hope that this approach can be applied to the study of not just proteins but also a wider range of biochemical networks.

Spatial localisation meets biomolecular networks.

Spatial organisation through localisation/compartmentalisation of species is a ubiquitous but poorly understood feature of cellular biomolecular networks. Current technologies in systems and synthetic biology (spatial proteomics, imaging, synthetic compartmentalisation) necessitate a systematic approach to elucidating the interplay of networks and spatial organisation. We develop a systems framework towards this end and focus on the effect of spatial localisation of network components revealing its multiple facets: (i) As a key distinct regulator of network behaviour, and an enabler of new network capabilities (ii) As a potent new regulator of pattern formation and self-organisation (iii) As an often hidden factor impacting inference of temporal networks from data (iv) As an engineering tool for rewiring networks and network/circuit design. These insights, transparently arising from the most basic considerations of networks and spatial organisation, have broad relevance in natural and engineered biology and in related areas such as cell-free systems, systems chemistry and bionanotechnology.

Decontamination of common healthcare facility surfaces contaminated with SARS-CoV-2 using peracetic acid dry fogging.

BACKGROUND: The SARS-CoV-2 pandemic has highlighted the urgent need for safe and effective surface decontamination methods, particularly in healthcare settings. AIM: To evaluate the effectiveness of peracetic acid (PAA) dry fogging in decontaminating healthcare facility surfaces experimentally contaminated with SARS-CoV-2. METHODS: Nine materials (stainless steel, latex painted wood, unsealed hardwood, melamine countertop, vinyl flooring, clear plastic, faux leather, computer keyboard button, and smartphone touch screen) were surface contaminated with >106 median tissue culture infectious dose (TCID50) of SARS-CoV-2, and allowed to dry before exposing to PAA dry fogging. FINDINGS: When fumigated with PAA dry fog for 1 h, no infectious SARS-CoV-2 virus was recovered from any of the experimentally inoculated surface types. By contrast, high titres of infectious virus were recovered from corresponding untreated drying controls of the same materials. CONCLUSION: Standard surface decontamination processes, including sprays and wipes, are laborious and frequently cannot completely decontaminate sensitive electronic equipment. The ease of use, low cost, and overall effectiveness of a PAA dry fogging suggest that it should be considered for decontaminating healthcare settings, particularly intensive care units where severely ill SARS-CoV-2 patients are cared for.

CPAP and survival in moderate-to-severe obstructive sleep apnoea syndrome and hypoxaemic COPD.

Obstructive sleep apnoea syndrome (OSAS) often coexists in patients with chronic obstructive pulmonary disease (COPD). The present prospective cohort study tested the effect of OSAS treatment with continuous positive airway pressure (CPAP) on the survival of hypoxaemic COPD patients. It was hypothesised that CPAP treatment would be associated with higher survival in patients with moderate-to-severe OSAS and hypoxaemic COPD receiving long-term oxygen therapy (LTOT). Prospective study participants attended two outpatient advanced lung disease LTOT clinics in São Paulo, Brazil, between January 1996 and July 2006. Of 603 hypoxaemic COPD patients receiving LTOT, 95 were diagnosed with moderate-to-severe OSAS. Of this OSAS group, 61 (64%) patients accepted and were adherent to CPAP treatment, and 34 did not accept or were not adherent and were considered not treated. The 5-yr survival estimate was 71% (95% confidence interval 53-83%) and 26% (12-43%) in the CPAP-treated and nontreated groups, respectively (p<0.01). After adjusting for several confounders, patients treated with CPAP showed a significantly lower risk of death (hazard ratio of death versus nontreated 0.19 (0.08-0.48)). The present study found that CPAP treatment was associated with higher survival in patients with moderate-to-severe OSAS and hypoxaemic COPD receiving LTOT.