PTPmu-targeted nanoparticles label invasive pediatric and adult glioblastoma.

Poor prognosis for glioblastoma (GBM) is a consequence of the aggressive and infiltrative nature of gliomas where individual cells migrate away from the main tumor to distant sites, making complete surgical resection and treatment difficult. In this manuscript, we characterize an invasive pediatric glioma model and determine if nanoparticles linked to a peptide recognizing the GBM tumor biomarker PTPmu can specifically target both the main tumor and invasive cancer cells in adult and pediatric glioma models. Using both iron and lipid-based nanoparticles, we demonstrate by magnetic resonance imaging, optical imaging, histology, and iron quantification that PTPmu-targeted nanoparticles effectively label adult gliomas. Using PTPmu-targeted nanoparticles in a newly characterized orthotopic pediatric SJ-GBM2 model, we demonstrate individual tumor cell labeling both within the solid tumor margins and at invasive and dispersive sites.

A PTPmu Biomarker is Associated with Increased Survival in Gliomas.

An integrated approach has been adopted by the World Health Organization (WHO) for diagnosing brain tumors. This approach relies on the molecular characterization of biopsied tissue in conjunction with standard histology. Diffuse gliomas (grade II to grade IV malignant brain tumors) have a wide range in overall survival, from months for the worst cases of glioblastoma (GBM) to years for lower grade astrocytic and oligodendroglial tumors. We previously identified a change in the cell adhesion molecule PTPmu in brain tumors that results in the generation of proteolytic fragments. We developed agents to detect this cell surface-associated biomarker of the tumor microenvironment. In the current study, we evaluated the PTPmu biomarker in tissue microarrays and individual tumor samples of adolescent and young adult (n = 25) and adult (n = 69) glioma populations using a fluorescent histochemical reagent, SBK4-TR, that recognizes the PTPmu biomarker. We correlated staining with clinical data and found that high levels of the PTPmu biomarker correlate with increased survival of glioma patients, including those with GBM. Patients with high PTPmu live for 48 months on average, whereas PTPmu low patients live only 22 months. PTPmu high staining indicates a doubling of patient survival. Use of the agent to detect the PTPmu biomarker would allow differentiation of glioma patients with distinct survival outcomes and would complement current molecular approaches used in glioma prognosis.

Regulation of development and cancer by the R2B subfamily of RPTPs and the implications of proteolysis.

The initial cloning of receptor protein tyrosine phosphatases (RPTPs) was met with excitement because of their hypothesized function in counterbalancing receptor tyrosine kinase signaling. In recent years, members of a subfamily of RPTPs with homophilic cell-cell adhesion capabilities, known as the R2B subfamily, have been shown to have functions beyond that of counteracting tyrosine kinase activity, by independently influencing cell signaling in their own right and by regulating cell adhesion. The R2B subfamily is composed of four members: PTPmu (PTPRM), PTPrho (PTPRT), PTPkappa (PTPRK), and PCP-2 (PTPRU). The effects of this small subfamily of RPTPs is far reaching, influencing several developmental processes and cancer. In fact, R2B RPTPs are predicted to be tumor suppressors and are among the most frequently mutated protein tyrosine phosphatases (PTPs) in cancer. Confounding these conclusions are more recent studies suggesting that proteolysis of the full-length R2B RPTPs result in oncogenic extracellular and intracellular protein fragments. This review discusses the current knowledge of the role of R2B RPTPs in development and cancer, with special detail given to the mechanisms and implications that proteolysis has on R2B RPTP function. We also touch upon the concept of exploiting R2B proteolysis to develop cancer imaging tools, and consider the effects of R2B proteolysis on axon guidance, perineural invasion and collective cell migration.

Quantitative Molecular Imaging with a Single Gd-Based Contrast Agent Reveals Specific Tumor Binding and Retention in Vivo.

Magnetic resonance imaging (MRI) has become an indispensable tool in the diagnosis and treatment of many diseases, especially cancer. However, the poor sensitivity of MRI relative to other imaging modalities, such as PET, has hindered the development and clinical use of molecular MRI contrast agents that could provide vital diagnostic information by specifically locating a molecular target altered in the disease process. This work describes the specific and sustained in vivo binding and retention of a protein tyrosine phosphatase mu (PTPµ)-targeted, molecular magnetic resonance (MR) contrast agent with a single gadolinium (Gd) chelate using a quantitative MRI T1 mapping technique in glioma xenografts. Quantitative T1 mapping is an imaging method used to measure the longitudinal relaxation time, the T1 relaxation time, of protons in a magnetic field after excitation by a radiofrequency pulse. T1 relaxation times can in turn be used to calculate the concentration of a gadolinium-containing contrast agent in a region of interest, thereby allowing the retention or clearance of an agent to be quantified. In this context, retention is a measure of molecular contrast agent binding. Using conventional peptide chemistry, a PTPµ-targeted peptide was linked to a chelator that had been conjugated to a lysine residue. Following complexation with Gd, this PTPµ-targeted molecular contrast agent containing a single Gd ion showed significant tumor enhancement and a sustained increase in Gd concentration in both heterotopic and orthotopic tumors using dynamic quantitative MRI. This single Gd-containing PTPµ agent was more effective than our previous version with three Gd ions. Differences between nonspecific and specific agents, due to specific tumor binding, can be determined within the first 30 min after agent administration by examining clearance rates. This more facile chemistry, when combined with quantitative MR techniques, allows for widespread adoption by academic and commercial entities in the field of molecular MRI ultimately leading to improved detection of disease.

A protease storm cleaves a cell-cell adhesion molecule in cancer: multiple proteases converge to regulate PTPmu in glioma cells.

Cleavage of the cell-cell adhesion molecule, PTPµ, occurs in human glioblastoma multiforme brain tumor tissue and glioma cell lines. PTPµ cleavage is linked to increased cell motility and growth factor independent survival of glioma cells in vitro. Previously, PTPµ was shown to be cleaved by furin in the endoplasmic reticulum to generate membrane associated E- (extracellular) and P- (phosphatase) subunits, and by ADAMs and the gamma secretase complex at the plasma membrane. We also identified the presence of additional extracellular and intracellular PTPµ fragments in brain tumors. We set out to biochemically analyze PTPµ cleavage in cancer cells. We determined that, in addition to the furin-processed form of PTPµ, a pool of 200 kDa full-length PTPµ exists at the plasma membrane that is cleaved directly by ADAM to generate a larger shed form of the PTPµ extracellular segment. Notably, in glioma cells, full-length PTPµ is also subject to calpain cleavage, which generates novel PTPµ fragments not found in other immortalized cells. We also observed glycosylation and phosphorylation differences in the cancer cells. Our data suggest that an additional serine protease also contributes to PTPµ shedding in glioma cells. We hypothesize that a "protease storm" occurs in cancer cells whereby multiple proteases converge to reduce the presence of cell-cell adhesion molecules at the plasma membrane and to generate protein fragments with unique biological functions. As a consequence, the "protease storm" could promote the migration and invasion of tumor cells.

Mild obstructive sleep apnoea in females: post hoc analysis of the MERGE randomised controlled trial.

Background: A post hoc analysis of the MERGE trial was conducted, to investigate whether sex differences are evident at the mildest end of the disease spectrum, for symptoms associated with obstructive sleep apnoea (OSA) and the response to continuous positive airway pressure (CPAP) treatment. Methods: MERGE participants with mild OSA (apnoea-hypopnoea index 5-15 events·h-1; American Academy of Sleep Medicine 2012 criteria) were randomised to either CPAP plus standard care (sleep hygiene counselling) or standard care alone for 3 months. Quality of life (QoL) was measured by questionnaires completed before and after the 3 months. This post hoc analysis of participants of the MERGE trial compared the symptom presentation, and response to CPAP, between the sexes. Results: 233 patients were included; 71 (30%) were female. Females were more symptomatic at baseline in all QoL questionnaires. Specifically, females had lower 36-item Short-Form Health Survey (SF-36) Vitality scores (mean±sd 39.1±10.1 versus 44.8±10.3) and higher Epworth Sleepiness Scale (ESS) scores (mean±sd 11.0±4.2 versus 9.5±4.4). Both sexes experienced snoring, but more females reported fatigue and more males reported witnessed apnoeas. All symptoms improved with CPAP for both sexes; however, females had larger improvements in SF-36 Vitality scores, which was the primary outcome of the MERGE trial (mean change 9.4 (95% CI 6.8-12.0) versus 6.0 (95% CI 4.3-7.7); p=0.034), and ESS (mean change -4.1 (95% CI -5.1- -3.0) versus -2.5 (95% CI -3.1- -1.8); p=0.015), after adjustment for baseline scores and CPAP usage. Conclusions: Sex differences are apparent in patients with mild OSA. Females experience worse QoL symptoms than males at presentation to the sleep clinic; however, these improve significantly with CPAP treatment.

Single cell molecular recognition of migrating and invading tumor cells using a targeted fluorescent probe to receptor PTPmu.

Detection of an extracellular cleaved fragment of a cell-cell adhesion molecule represents a new paradigm in molecular recognition and imaging of tumors. We previously demonstrated that probes that recognize the cleaved extracellular domain of receptor protein tyrosine phosphatase mu (PTPmu) label human glioblastoma brain tumor sections and the main tumor mass of intracranial xenograft gliomas. In this article, we examine whether one of these probes, SBK2, can label dispersed glioma cells that are no longer connected to the main tumor mass. Live mice with highly dispersive glioma tumors were injected intravenously with the fluorescent PTPmu probe to test the ability of the probe to label the dispersive glioma cells in vivo. Analysis was performed using a unique three-dimensional (3D) cryo-imaging technique to reveal highly migratory and invasive glioma cell dispersal within the brain and the extent of colabeling by the PTPmu probe. The PTPmu probe labeled the main tumor site and dispersed cells up to 3.5 mm away. The cryo-images of tumors labeled with the PTPmu probe provide a novel, high-resolution view of molecular tumor recognition, with excellent 3D detail regarding the pathways of tumor cell migration. Our data demonstrate that the PTPmu probe recognizes distant tumor cells even in parts of the brain where the blood-brain barrier is likely intact. The PTPmu probe has potential translational significance for recognizing tumor cells to facilitate molecular imaging, a more complete tumor resection and to serve as a molecular targeting agent to deliver chemotherapeutics to the main tumor mass and distant dispersive tumor cells.

Leukoaraiosis on MRI in patients with minimally symptomatic obstructive sleep apnoea.

BACKGROUND: Obstructive sleep apnoea (OSA) is associated with hypertension, nocturnal blood pressure (BP) surges, and increased risk of stroke. It may therefore also be associated with a higher risk of developing leukoaraiosis. Only few data about the prevalence of leukoaraiosis in patients with OSA, and any association between degrees of severity of either condition, exist. METHODS: We studied patients who were part of a clinical trial (MOSAIC) in minimally symptomatic OSA. All patients had brain MRI (T2, FLAIR) at baseline. A single observer assessed the images for the presence and severity of leukoaraiosis (ARWMC-score). We related the extent of leukoaraiosis to the severity of OSA (measured by oxygen desaturation index [ODI]) and the presence of other vascular risk factors. RESULTS: 183 patients (156 men, 85.2%; mean age ± SD = 57.7 ± 7.4 years; median oxygen desaturation index = 9.6, interquartile range = 4.6-16.0) took part in the study. Although 135 (74%) patients had some leukoaraiosis, this was generally mild. We confirmed the well-known risk factor associations between leukoaraiosis, increasing age (p < 0.0001) and hypertension (p = 0.003), but we did not find any association between OSA and leukoaraiosis (p = 0.33), despite both conditions being associated with increasing current BP and a history of hypertension. CONCLUSION: Our data confirm the well-known association between leukoaraiosis, age and increasing BP. However, we found no association between OSA and leukoaraiosis despite some shared risk factor associations. Our findings suggest that OSA is not a strong independent risk factor for leukoaraiosis. Confounding by hypertension may explain any apparent association in previously reported studies of patients with severer OSA.

Wnt regulation of hematopoietic stem cell development and disease.

Hematopoietic stem cells (HSCs) are multipotent stem cells that give rise to all cells of the blood and most immune cells. Due to their capacity for unlimited self-renewal, long-term HSCs replenish the blood and immune cells of an organism throughout its life. HSC development, maintenance, and differentiation are all tightly regulated by cell signaling pathways, including the Wnt pathway. Wnt signaling is initiated extracellularly by secreted ligands which bind to cell surface receptors and give rise to several different downstream signaling cascades. These are classically categorized either ß-catenin dependent (BCD) or ß-catenin independent (BCI) signaling, depending on their reliance on the ß-catenin transcriptional activator. HSC development, homeostasis, and differentiation is influenced by both BCD and BCI, with a high degree of sensitivity to the timing and dosage of Wnt signaling. Importantly, dysregulated Wnt signals can result in hematological malignancies such as leukemia, lymphoma, and myeloma. Here, we review how Wnt signaling impacts HSCs during development and in disease.

Got WNTS? Insight into bone health from a WNT perspective.

WNT signaling, essential for many aspects of development, is among the most commonly altered pathways associated with human disease. While initially studied in cancer, dysregulation of WNT signaling has been determined to be essential for skeletal development and the maintenance of bone health throughout life. In this review, we discuss the role of Wnt signaling in bone development and disease with a particular focus on two areas. First, we discuss the roles of WNT signaling pathways in skeletal development, with an emphasis on congenital and idiopathic skeletal syndromes and diseases that are associated with genetic variations in WNT signaling components. Next, we cover a topic that has long been an interest of our laboratory, how high and low levels of WNT signaling affects the establishment and maintenance of healthy bone mass. We conclude with a discussion of the status of WNT-based therapeutics in the treatment of skeletal disease.

An Integrated View of Stressors as Causative Agents in OA Pathogenesis.

Cells in the body are exposed to dynamic external and internal environments, many of which cause cell damage. The cell's response to this damage, broadly called the stress response, is meant to promote survival and repair or remove damage. However, not all damage can be repaired, and sometimes, even worse, the stress response can overtax the system itself, further aggravating homeostasis and leading to its loss. Aging phenotypes are considered a manifestation of accumulated cellular damage and defective repair. This is particularly apparent in the primary cell type of the articular joint, the articular chondrocytes. Articular chondrocytes are constantly facing the challenge of stressors, including mechanical overloading, oxidation, DNA damage, proteostatic stress, and metabolic imbalance. The consequence of the accumulation of stress on articular chondrocytes is aberrant mitogenesis and differentiation, defective extracellular matrix production and turnover, cellular senescence, and cell death. The most severe form of stress-induced chondrocyte dysfunction in the joints is osteoarthritis (OA). Here, we summarize studies on the cellular effects of stressors on articular chondrocytes and demonstrate that the molecular effectors of the stress pathways connect to amplify articular joint dysfunction and OA development.

TRIM28 secures skeletal stem cell fate during skeletogenesis by silencing neural gene expression and repressing GREM1/AKT/mTOR signaling axis.

Long bones are generated by mesoderm-derived skeletal progenitor/stem cells (SSCs) through endochondral ossification, a process of sequential chondrogenic and osteogenic differentiation tightly controlled by the synergy between intrinsic and microenvironment cues. Here, we report that loss of TRIM28, a transcriptional corepressor, in mesoderm-derived cells expands the SSC pool, weakens SSC osteochondrogenic potential, and endows SSCs with properties of ectoderm-derived neural crest cells (NCCs), leading to severe defects of skeletogenesis. TRIM28 preferentially enhances H3K9 trimethylation and DNA methylation on chromatin regions more accessible in NCCs; loss of this silencing upregulates neural gene expression and enhances neurogenic potential. Moreover, TRIM28 loss causes hyperexpression of GREM1, which is an extracellular signaling factor promoting SSC self-renewal and SSC neurogenic potential by activating AKT/mTORC1 signaling. Our results suggest that TRIM28-mediated chromatin silencing establishes a barrier for maintaining the SSC lineage trajectory and preventing a transition to ectodermal fate by regulating both intrinsic and microenvironment cues.

SUMOylation in Skeletal Development, Homeostasis, and Disease.

The modification of proteins by small ubiquitin-related modifier (SUMO) molecules, SUMOylation, is a key post-translational modification involved in a variety of biological processes, such as chromosome organization, DNA replication and repair, transcription, nuclear transport, and cell signaling transduction. In recent years, emerging evidence has shown that SUMOylation regulates the development and homeostasis of the skeletal system, with its dysregulation causing skeletal diseases, suggesting that SUMOylation pathways may serve as a promising therapeutic target. In this review, we summarize the current understanding of the molecular mechanisms by which SUMOylation pathways regulate skeletal cells in physiological and disease contexts.

Identification of phospholipase C gamma1 as a protein tyrosine phosphatase mu substrate that regulates cell migration.

The receptor protein tyrosine phosphatase PTPµ has a cell-adhesion molecule-like extracellular segment and a catalytically active intracellular segment. This structure gives PTPµ the ability to transduce signals in response to cell-cell adhesion. Full-length PTPµ is down-regulated in glioma cells by proteolysis which is linked to increased migration of these cells in the brain. To gain insight into the substrates PTPµ may be dephosphorylating to suppress glioma cell migration, we used a substrate trapping method to identify PTPµ substrates in tumor cell lines. We identified both PKCδ and PLCγ1 as PTPµ substrates. As PLCγ1 activation is linked to increased invasion of cancer cells, we set out to determine whether PTPµ may be upstream of PLCγ1 in regulating glioma cell migration. We conducted brain slice assays using U87-MG human glioma cells in which PTPµ expression was reduced by shRNA to induce migration. Treatment of the same cells with PTPµ shRNA and a PLCγ1 inhibitor prevented migration of the cells within the brain slice. These data suggest that PLCγ1 is downstream of PTPµ and that dephosphorylation of PLCγ1 is likely to be a major pathway through which PTPµ suppresses glioma cell migration.

Physically-cross-linked poly(vinyl alcohol) cell culture plate coatings facilitate preservation of cell-cell interactions, spheroid formation, and stemness.

We employed aqueous solutions of highly-hydrolyzed (>99+%) poly(vinyl alcohol), PVA, to coat plastic dishes as a method to efficiently induce three-dimensional (3D) culturing of cells. The coatings were prepared by simple evaporation of 3 wt/vol% solutions of PVA in water and require no additional processing steps after air drying under sterile conditions. The coating allows spheroids to form in solution. Spheroid formation is usually preferable to two-dimensional (2D) culturing as it creates a more realistic ex vivo model of some human tissues and tumors. Using PVA-coated cell culture plates, we demonstrated that we can grow reproducibly sized spheroids using several human glioma cell lines, including LN229, U87 MG, and Gli36, and the embryonic kidney cell line, 293T. Spheroids formed on PVA-coated plates grow as well as on other commercially-available, low-attachment plates, and have excellent optical imaging properties. As spheroids, LN229 cells express markers of cancer stem cells. Finally, we confirmed that spheroids generated on PVA-coated plates are sensitive to molecular perturbations, as increased expression of the cell adhesion molecule PTPµ significantly increased the size of spheroids. The PVA hydrogel layer is an effective tool for creating a more realistic ex vivo culture system than traditional 2D culture and can be used to generate cell spheroids for potential application in drug screening and personalized medicine for diseases such as cancer.

Detection of Tumor-Specific PTPmu in Gynecological Cancer and Patient Derived Xenografts.

BACKGROUND: We developed a fluorophore-conjugated peptide agent, SBK4, that detects a tumor-specific proteolyzed form of the cell adhesion molecule, PTPmu, found in the tumor microenvironment. We previously demonstrated its tissue specific distribution in high-grade brain tumors. To extend those studies to other aggressive solid tumor types, we assessed the tissue distribution of PTPmu/SBK4 in a set of matched gynecologic cancer patient derived xenografts (PDXs) and primary patient tumors, as well as a limited cohort of tumors from gynecological cancer patients. PDXs isolated from the tissues of cancer patients have been shown to yield experimentally manipulatable models that replicate the clinical characteristics of individual patients' tumors. In this study, gynecological cancer PDXs and patient biopsies were examined to determine if tumor-specific proteolyzed PTPmu was present. METHODS: We used the peptide agent SBK4 conjugated to the fluorophore Texas Red (TR) to label tumor tissue microarrays (TMAs) containing patient and/or PDX samples from several high-grade gynecologic cancer types, and quantified the level of staining with Image J. In one TMA, we were able to directly compare the patient and the matched PDX tissue on the same slide. RESULTS: While normal tissue had very little SBK4-TR staining, both primary tumor tissue and PDXs have higher labeling with SBK4-TR. Matched PDXs and patient samples from high-grade endometrial and ovarian cancers demonstrated higher levels of PTPmu by staining with SBK4 than normal tissue. CONCLUSION: In this sample set, all PDXs and high-grade ovarian cancer samples had increased labeling by SBK4-TR compared with the normal controls. Our results indicate that proteolyzed PTPmu and its novel peptide detection agent, SBK4, allow for the visualization of tumor-specific changes in cell adhesion molecules by tissue-based staining, providing a rationale for further development as an imaging agent in aggressive solid tumors, including gynecological cancers.

Randomised, cOntrolled Multicentre trial of 26 weeks subcutaneous liraglutide (a glucagon-like peptide-1 receptor Agonist), with or without contiNuous positive airway pressure (CPAP), in patients with type 2 diabetes mellitus (T2DM) and obstructive sleep apnoEa (OSA) (ROMANCE): study protocol assessing the effects of weight loss on the apnea-hypnoea index (AHI).

INTRODUCTION: Obstructive sleep apnoea (OSA) and type 2 diabetes mellitus (T2DM) often occur concurrently, and untreated OSA may potentially amplify the high risk of cardiovascular disease in T2DM. Compliance with continuous positive airway pressure (CPAP), the conventional treatment for OSA, can be poor and considering weight loss is the most effective treatment for OSA. This trial examines whether the glucagon-like peptide-1 receptor agonist liraglutide, a glucose-lowering therapy associated with significant weight loss used in T2DM, can improve the severity and symptoms of OSA. METHODS AND ANALYSIS: This is an outpatient, single-centred, open-labelled, prospective, phase IV randomised controlled trial in a two-by-two factorial design. One hundred and thirty-two patients with newly diagnosed OSA (apnoea-hypopnoea index (AHI) ≥15 events/hour), and existing obesity and T2DM (glycated haemoglobin (HbA1c) ≥47 mmol/mol), will be recruited from diabetes and sleep medicine outpatient clinics in primary and secondary care settings across Liverpool. Patients will be allocated equally, using computer-generated random, permuted blocks of unequal sizes, to each of the four treatment arms for 26 weeks: (i) liraglutide (1.8 mg once per day) alone, (ii) liraglutide 1.8 mg once per day with CPAP, (iii) CPAP alone (conventional care) or (iv) no treatment (control). The primary outcome measure is change in OSA severity, determined by AHI. Secondary outcome measures include effects on glycaemic control (glycated haemoglobin (HbA1c)), body weight and quality of life measures. Exploratory measures include measures of physical activity, MRI-derived measures of regional body composition including fat mass (abdominal subcutaneous, visceral, neck and liver fat) and skeletal muscle mass (cross-sectional analysis of thigh), indices of cardiac function (using transthoracic echocardiography) and endothelial function. ETHICAL APPROVAL: The study has been approved by the North West Liverpool Central Research Ethics Committee (14/NW/1019) and it is being conducted in accordance with the Declaration of Helsinki and Good Clinical Practice. TRIAL REGISTRATION NUMBERS: ISRCTN16250774. EUDRACT No. 2014-000988-41. UTN U1111-1139-0677.

Continuous positive airway pressure versus standard care for the treatment of people with mild obstructive sleep apnoea (MERGE): a multicentre, randomised controlled trial.

BACKGROUND: The evidence base for the treatment of mild obstructive sleep apnoea is limited and definitions of disease severity vary. The MERGE trial investigated the clinical effectiveness of continuous positive airway pressure in patients with mild obstructive sleep apnoea. METHODS: MERGE, a multicentre, parallel, randomised controlled trial enrolled patients (≥18 years to ≤80 years) with mild obstructive sleep apnoea (apnoea-hypopnoea index [AHI] ≥5 to ≤15 events per h using either AASM 2007 or AASM 2012 scoring criteria) from 11 UK sleep centres. Participants were assigned (1:1) to either 3 months of continuous positive airway pressure plus standard care (sleep counselling), or standard care alone, by computer-generated randomisation; neither participants nor researchers were blinded. The primary outcome was a change in the score on the Short Form-36 questionnaire vitality scale in the intention-to-treat population of patients with mild obstructive sleep apnoea diagnosed using the American Academy of Sleep Medicine 2012 scoring criteria. The study is registered with ClinicalTrials.gov, NCT02699463. FINDINGS: Between Nov 28, 2016 and Feb 12, 2019, 301 patients were recruited and randomised. 233 had mild obstructive sleep apnoea using AASM 2012 criteria and were included in the intention-to-treat analysis: 115 were allocated to receive continuous positive airway pressure and 118 to receive standard care. 209 (90%) of these participants completed the trial. The vitality score significantly increased with a treatment effect of a mean of 10·0 points (95% CI 7·2-12·8; p<0·0001) after 3 months of continuous positive airway pressure, compared with standard care alone (9·2 points [6·8 to 11·6] vs -0·8 points [-3·2 to 1·5]). Using the ANCOVA last-observation-carried-forward analysis, a more conservative estimate, the vitality score also significantly increased with a treatment effect of a mean of 7·5 points (95% CI 5·3 to 9·6; p<0·0001) after 3 months of continuous positive airway pressure, compared with standard care alone (7·5 points [6·0 to 9·0] vs 0·0 points [-1·5 to 1·5]). Three serious adverse events occurred (one allocated to the continuous positive airway pressure group) and all were unrelated to the intervention. INTERPRETATION: 3 months of treatment with continuous positive airway pressure improved the quality of life in patients with mild obstructive sleep apnoea. These results highlight the need for health-care professionals and providers to consider treatment for patients with mild obstructive sleep apnoea. FUNDING: ResMed Ltd.

Effects of continuous positive airway pressure on quality of life in patients with moderate to severe obstructive sleep apnea: data from a randomized controlled trial.

STUDY OBJECTIVES: Previous studies have shown that CPAP has a substantial impact on daytime symptoms and quality of life (QOL). It remains unclear which outcome measures best identify real CPAP effects and carry independent information. METHODS: One hundred-two men with moderate-severe obstructive sleep apnea were randomized to either "real" or "sham" CPAP for one month. Outcome measures were subjective sleepiness (Epworth Sleepiness Scale [ESS]) and QOL measures includiig SF-36/SF-12 and Calgary Sleep Apnea Quality of Life Index (SAQLI). The bed partner's QOL and rating of patient's response to CPAP were assessed with the Dublin questionnaire. All data were standardized using effect sizes and expressed as real minus sham to remove the nonspecific effects of placebo. RESULTS: Real CPAP was superior to sham CPAP in almost all outcome measures. ESS, patient's component from Dublin, and social interactions from SAQLI showed the largest differences in effect sizes between real and sham (1.33, 0.98, and 0.92 respectively). ESS carried the highest predictive power of real CPAP response (P < 0.0001, r2 = 0.21). Question number 5 from Dublin (partner assessed patient's sleep quality) and question 6 from ESS (dozing while talking) were the best single item predictors of real CPAP response. CONCLUSIONS: Real CPAP reduces subjective sleepiness and improves QOL of both patients and bed partners. ESS is the best score; question number 5 from Dublin and question number 6 from ESS are the best single item predictors of real CPAP response. This information should allow the selection of appropriate questions in clinical practice and research protocols.

In patients with minimally symptomatic OSA can baseline characteristics and early patterns of CPAP usage predict those who are likely to be longer-term users of CPAP.

BACKGROUND: Long-term continuous positive airway pressure (CPAP) usage varies between individuals. It would be of value to be able to identify those who are likely to benefit from CPAP (and use it long term), versus those who would not, and might therefore benefit from additional help early on. First, we explored whether baseline characteristics predicted CPAP usage in minimally symptomatic obstructive sleep apnoea (OSA) patients, a group who would be expected to have low usage. Second, we explored if early CPAP usage was predictive of longer-term usage, as has been shown in more symptomatic OSA patients. METHODS: The MOSAIC trial was a multi-centre randomised controlled trial where minimally symptomatic OSA patients were randomised to CPAP, or standard care, for 6 months. Here we have studied only those patients randomised to CPAP treatment. Baseline characteristics including symptoms, questionnaires [including the Epworth sleepiness score (ESS)] and sleep study parameters were recorded. CPAP usage was recorded at 2-4 weeks after initiation and after 6 months. The correlation and association between baseline characteristics and 6 months CPAP usage was assessed, as was the correlation between 2 and 4 weeks CPAP usage and 6 months CPAP usage. RESULTS: One hundred and ninety-five patients randomised to CPAP therapy had median [interquartile range (IQR)] CPAP usage of 2:49 (0:44, 5:13) h:min/night (h/n) at the 2-4 weeks visit, and 2:17 (0:08, 4:54) h/n at the 6 months follow-up visit. Only male gender was associated with increased long-term CPAP use (male usage 2:56 h/n, female 1:57 h/n; P=0.02). There was a moderate correlation between the usage of CPAP at 2-4 weeks and 6 months, with about 50% of the variability in long-term use being predicted by the short-term use. CONCLUSIONS: In patients with minimally symptomatic OSA, our study has shown that male gender (and not OSA severity or symptom burden) is associated with increased long-term use of CPAP at 6 months. Although, in general, early patterns of CPAP usage predicted longer term use, there are patients in whom this is not the case, and patients with low initial usage may need to extend their CPAP trial before a decision about longer-term use is made.