Multiblock modelling on the study of the kinetic degradation of rosuvastatin calcium in the presence of retention time shifts and rank deficiency.

In pharmaceutical development, forced degradation studies are mandatory before the commercialization of any drug product. They aim at identifying the possible degradation routes and the potential products that may be formed during drug product shelf life. The most widely used techniques for monitoring this in the pharmaceutical industry are hyphenated techniques such as Liquid Chromatography coupled to ultraviolet diode array detector (LC-DAD). There are however some drawbacks, such as long analysis times required for the elution of all compounds and coelution, which is not easily detected since degradation products usually have spectra very similar to that of the drug. Chemometrics methods applied to LC-DAD data are capable of solving this issue, but the approaches described in the literature first require peak alignment to solve the rank deficiency problem, which is a delicate preprocessing method for high order data. The present work describes another approach where extra information - the kinetic degradation profiles - is included for the modelling, generating a third-order data set for each sample, resulting in a four-way array (sample x retention times x spectra x degradation profile). This approach has the advantage of using the information in the third mode to solve the peak co-elution problem without the need for peak alignment among samples. With the proposed approach, it was possible to study the degradation of calcium rosuvastatin, a modern cholesterol lowering drug, using a 2 min-run, despite all the challenges in the modelling of this data. The proposed strategy was compared to an approach based on augmenting the matrix in the spectral/kinetic modes (second order modelling strategy).

Mortality and morbidity in obstructive sleep apnoea-hypopnoea syndrome: results from a 30-year prospective cohort study.

BACKGROUND: Obstructive sleep apnoea-hypopnoea syndrome (OSAHS) carries substantial negative health consequences. This study examines factors affecting mortality and morbidity according to continuous positive airway pressure (CPAP) use and predictors affecting CPAP adherence in a longitudinal cohort of OSAHS patients. MATERIALS AND METHODS: This prospective, cohort study comprised 4502 patients who were diagnosed with OSAHS at a tertiary sleep disorders centre between 1982 and 2003. Of these, 1174 patients completed follow-up in 2012. Data collected included anthropometric, sleep and demographic characteristics, including comorbidities, ongoing medications and CPAP adherence. Patients were followed up for an average of 14.8±3.7 years. RESULTS: Imputation analysis showed that long-term CPAP users (>5 years) were 5.63 times more likely to be alive at study end than non-CPAP users (95% CI: 4.83-6.58, p<0.001) and 1.74-times more likely than short-term CPAP users (≤5 years) (95% CI: 1.49-2.02, p<0.001). Females had a significantly higher mortality rate during the follow-up period (26.8% versus 19.6%, p<0.001). Respiratory mortality was more common in patients with OSAHS, in particular those who did not use CPAP, compared to the general population (17.2% versus 12.2%, p=0.002 respectively), whereas deaths from cancer were less common compared to the general population (16.2% versus 25.6%, p<0.001). Compared to CPAP users, non-CPAP-users had a significantly increased incidence of type II diabetes mellitus (DMII) (27.9% versus 18.7%, p=0.003), ischaemic heart disease (IHD) (25.5% versus 12.7%, p<0.001) and myocardial infarction (MI) (14.7% versus 4.2%, p<0.001) at long-term follow-up. CONCLUSIONS: Long-term CPAP use in men and women with OSAHS reduces mortality and decreases the incidence of DMII and cardiovascular disease.

Setting the scene.

Doctors have a critical role in ensuring good teamworking which improves patient outcomes. UK hospitals with more doctors in their boards have lower morbidity and better patient satisfaction. In the USA, hospitals with doctors as the CEO have better performance, but in the UK less than 5% of hospitals have doctors as the CEO. There is an urgent need to improve training in medical leadership among UK doctors and to make careers in medical management more attractive to high fliers. The Faculty of Medical Leadership and Management has launched standards of medical leadership and management which will give credibility to this field and ensure that highly qualified candidates are appointed to all levels of management posts within the NHS.

The effect of continuous positive airway pressure therapy on arterial stiffness and endothelial function in obstructive sleep apnea: a randomized controlled trial in patients without cardiovascular disease.

BACKGROUND: Obstructive sleep apnea (OSA) is associated with increased cardiovascular morbidity and mortality which may be mediated by increased arterial stiffness and endothelial dysfunction. Continuous positive airway pressure (CPAP) therapy improves excessive daytime somnolence (EDS), but its effect on vascular function in patients without preexisting cardiovascular disease (CVD) is unclear. METHODS: Fifty-three patients with OSA defined as an apnea-hypopnea index (AHI) of ⩾15 and without CVD were recruited into a double-blind, randomized, placebo-controlled, crossover trial of 12weeks of CPAP therapy, of whom 43 participants completed the study protocol. Arterial stiffness was assessed by measuring the augmentation index (AIx) and pulse wave velocity (PWV) by applanation tonometry and cardiovascular magnetic resonance imaging to determine aortic distensibility. Endothelial function was assessed by measuring vascular reactivity after administration of salbutamol and glyceryl trinitrate. RESULTS: CPAP therapy lowered systolic blood pressure (SBP) (126mmHg [standard deviation {SD}, 12] vs 129mmHg [SD, 14]; P=.03), with a trend towards reduced AIx (15.5 [SD, 11.9] vs 16.6 [SD, 11.7]%; P=.08) but did not modify endothelial function. When subjects with (n=24) and without (n=19) EDS were separately examined, no effect of CPAP therapy on vascular function was seen. CONCLUSIONS: In patients without overt CVD, CPAP therapy had a nonsignificant effect on AIx and did not modify endothelial function.

Arterial stiffness and endothelial function in obstructive sleep apnoea/hypopnoea syndrome.

BACKGROUND: Obstructive sleep apnoea-hypopnoea syndrome (OSAHS) is associated with increased cardiovascular morbidity and mortality. Our study examined arterial stiffness and endothelial function in subjects with OSAHS with no known cardiovascular disease compared to well-matched controls. METHODS: Twenty subjects with OSAHS (defined as apnoea-hypopnoea index [AHI] > or =15 and Epworth Sleepiness Scale score > or =11) without cardiovascular disease and 20 well-matched controls underwent a comprehensive evaluation of arterial stiffness and endothelial function. Arterial stiffness was measured by applanation tonometry and cardiovascular magnetic resonance imaging (MRI) and endothelial function assessed by measuring vascular reactivity after administration of glyceryl trinitrate and salbutamol. RESULTS: Subjects with OSAHS had increased arterial stiffness (augmentation index 19.3 [10.9] vs. 12.6 (10.2)%; p=0.017) and impaired endothelial function (change in augmentation index following salbutamol -4.3 (3.2) vs. -8.0 (4.9)%; p=0.02) compared to controls. Aortic distensibility, a measure of arterial stiffness, was negatively correlated with the AHI. CONCLUSIONS: Our findings suggest that even in the absence of known cardiovascular disease, subjects with OSAHS have increased arterial stiffness and impaired endothelial function and are at increased risk for cardiovascular disease.

A randomized, placebo-controlled trial of online cognitive behavioral therapy for chronic insomnia disorder delivered via an automated media-rich web application.

STUDY OBJECTIVES: The internet provides a pervasive milieu for healthcare delivery. The purpose of this study was to determine the effectiveness of a novel web-based cognitive behavioral therapy (CBT) course delivered by an automated virtual therapist, when compared with a credible placebo; an approach required because web products may be intrinsically engaging, and vulnerable to placebo response. DESIGN: Randomized, placebo-controlled trial comprising 3 arms: CBT, imagery relief therapy (IRT: placebo), treatment as usual (TAU). SETTING: Online community of participants in the UK. PARTICIPANTS: One hundred sixty-four adults (120 F: [mean age 49y (18-78y)] meeting proposed DSM-5 criteria for Insomnia Disorder, randomly assigned to CBT (n = 55; 40 F), IRT placebo (n = 55; 42 F) or TAU (n = 54; 38 F). INTERVENTIONS: CBT and IRT each comprised 6 online sessions delivered by an animated personal therapist, with automated web and email support. Participants also had access to a video library/back catalogue of session content and Wikipedia style articles. Online CBT users had access to a moderated social network/community of users. TAU comprised no restrictions on usual care and access to an online sleep diary. MEASUREMENTS AND RESULTS: Major assessments at baseline, post-treatment, and at follow-up 8-weeks post-treatment; outcomes appraised by online sleep diaries and clinical status. On the primary endpoint of sleep efficiency (SE; total time asleep expressed as a percentage of the total time spent in bed), online CBT was associated with sustained improvement at post-treatment (+20%) relative to both TAU (+6%; d = 0.95) and IRT (+6%: d = 1.06), and at 8 weeks (+20%) relative to IRT (+7%: d = 1.00) and TAU (+9%: d = 0.69) These findings were mirrored across a range of sleep diary measures. Clinical benefits of CBT were evidenced by modest superiority over placebo on daytime outcomes (d = 0.23-0.37) and by substantial improved sleep-wake functioning on the Sleep Condition Indicator (range of d = 0.77-1.20). Three-quarters of CBT participants (76% [CBT] vs. 29% [IRT] and 18% [TAU]) completed treatment with SE > 80%, more than half (55% [CBT] vs. 17% [IRT] and 8% [TAU]) with SE > 85%, and over one-third (38% [CBT] vs. 6% [IRT] and 0% [TAU]) with SE > 90%; these improvements were largely maintained during follow-up. CONCLUSION: CBT delivered using a media-rich web application with automated support and a community forum is effective in improving the sleep and associated daytime functioning of adults with insomnia disorder. CLINICAL TRIAL REGISTRATION: ISRCTN - 44615689.

The association of angiotensin-converting enzyme gene insertion/deletion polymorphisms with OSA: a meta-analysis.

Obstructive sleep apnoea (OSA) is an independent risk factor for hypertension. Increased angiotensin-converting enzyme (ACE) activity may be a possible promoting mechanism with different ACE insertion/deletion (I/D) genotypes influencing this activity. Studies investigating the association of ACE I/D polymorphisms with OSA have shown conflicting results. We aimed to undertake a meta-analysis of existing studies exploring the association of ACE I/D polymorphisms with the risk of OSA and hypertension. 10 studies were included in a random effects meta-analysis, comprising 1,227 OSA subjects and 1,227 controls. The effect size was measured using the odds ratio. The risk of having OSA in carriers of the D allele was 0.92 (95% CI 0.69-1.23). There was statistically significant heterogeneity across the studies (I(2)=42%, p=0.08 and I(2)=74%, p<0.0001 for genotype and allele frequency, respectively). The association of D allele frequency with the risk of OSA remained nonsignificant after stratification based on ethnicity, source of population sample, and the presence of hypertension. Subgroup analysis failed to show any influence of genotype and allele frequency on OSA severity. This meta-analysis revealed no association between the ACE I/D polymorphisms and OSA susceptibility.

Randomized controlled trial of variable-pressure versus fixed-pressure continuous positive airway pressure (CPAP) treatment for patients with obstructive sleep apnea/hypopnea syndrome (OSAHS).

STUDY OBJECTIVE: To determine whether fixed-pressure or variable-pressure CPAP was preferred by patients and gave better outcomes in patients with the obstructive sleep apnea/hypopnea syndrome (OSAHS). DESIGN: Randomized blinded cross-over trial with 6 weeks of fixed and 6 weeks of variable-pressure CPAP. SETTING: Sleep center. PATIENTS: 200 consecutive consenting CPAP naïve patients with daytime sleepiness and > 15 apneas + hypopneas/h after an attended auto-CPAP titration night. INTERVENTIONS: CPAP therapy using the same device (Autoset Spirit) set for 6 weeks in fixed pressure mode and for 6 weeks in variable pressure mode, the order of therapies being randomized. MEASUREMENTS AND RESULTS: All measurements were recorded at the end of each limb by a researcher blind to treatment. These included symptoms, Epworth Score, CPAP usage, objective sleepiness by modified Osler test, vigilance and health related quality of life. A total of 181 of 200 patients completed the study. At the end of the study, patients expressed no significant difference in the primary outcome, patient preference, 72 patients preferring fixed and 69 preferring variable-pressure CPAP. Epworth score was lower on variable (9.5, SEM 0.4) than fixed-pressure CPAP (10.0, SEM 0.3; P = 0.031). Mean CPAP use was higher on variable (4.2, SEM 0.2 h/night) than fixed-pressure CPAP (4.0, SEM 0.2 h/night; P = 0.047). There were no other significant differences between treatments. CONCLUSIONS This study shows no difference in patient preference and only a marginal benefit of variable over fixed-pressure CPAP in OSAHS in terms of subjective sleepiness and CPAP use. The clinical value of this difference remains to be determined. CLINICAL TRIAL INFORMATION: Variable-pressure versus fixed-pressure continuous positive airway pressure (CPAP) treatment for patients with obstructive sleep apnoea/hypopnoea syndrome (OSAHS); Registration # ISRCTN43085025.http://www.controlled-trials.com//SRCTN43085025.

Sleepiness and sleep-related accidents in commercial bus drivers.

INTRODUCTION: Professional drivers are at high risk of sleepiness due to a combination of factors including shift work and obstructive sleep apnea/hypopnea syndrome (OSAHS), and sleepiness in professional drivers is highly dangerous. This study aimed to determine the prevalence of excessive daytime sleepiness and accident rates in bus drivers. MATERIALS AND METHODS: Drivers employed at bus depots within 30 miles of Edinburgh were given a sleep questionnaire. One thousand eight hundred fifty-four drivers were approached, and 677 (37%; 25 female) completed questionnaires with a 97% response rate among the 456 given directly to drivers by the researcher. RESULTS: Of the responding drivers, 133 (20% of total, 19% of researcher-delivered questionnaires) reported an Epworth sleepiness score >10. Eight percent of drivers reported falling asleep at the wheel at least once/month, and 7% having an accident, and 18% a near-miss accident due to sleepiness while working. DISCUSSION: This study shows a concerningly high rate of sleepiness and sleep-related accidents among bus drivers. Screening for OSAHS among commercial drivers needs to be seriously evaluated with some urgency.

Randomized controlled clinical effectiveness trial of cognitive behavior therapy compared with treatment as usual for persistent insomnia in patients with cancer.

PURPOSE: Persistent insomnia is a common complaint in cancer survivors, but is seldom satisfactorily addressed. The adaptation to cancer care of a validated, cost-effective intervention may offer a practicable solution. The aim of this study was to investigate the clinical effectiveness of protocol-driven cognitive behavior therapy (CBT) for insomnia, delivered by oncology nurses. PATIENTS AND METHODS: Randomized, controlled, pragmatic, two-center trial of CBT versus treatment as usual (TAU) in 150 patients (103 females; mean age, 61 years.) who had completed active therapy for breast, prostate, colorectal, or gynecological cancer. The study conformed to CONSORT guidelines. Primary outcomes were sleep diary measures at baseline, post-treatment, and 6-month follow-up. Actigraphic sleep, health-related quality of life (QOL), psychopathology, and fatigue were secondary measures. CBT comprised five, small group sessions across consecutive weeks, after a manualized protocol. TAU represented normal clinical practice; the appropriate control for a clinical effectiveness study. RESULTS: CBT was associated with mean reductions in wakefulness of 55 minutes per night compared with no change in TAU. These outcomes were sustained 6 months after treatment. Standardized relative effect sizes were large for complaints of difficulty initiating sleep, waking from sleep during the night, and for sleep efficiency (percentage of time in bed spent asleep). CBT was associated with moderate to large effect sizes for five of seven QOL outcomes, including significant reduction in daytime fatigue. There was no significant interaction effect between any of these outcomes and baseline demographic, clinical, or sleep characteristics. CONCLUSION: CBT for insomnia may be both clinically effective and feasible to deliver in real world practice.

Diagnosis of sleep-disordered breathing in patients with chronic heart failure: evaluation of a portable limited sleep study system.

Sleep-disordered breathing (SDB) is common in chronic heart failure (CHF), affects disease progression and presents a potential therapeutic target. This study was designed to test the hypothesis that there would be good agreement in diagnostic outcome between home limited sleep studies and in-laboratory polysomnography (PSG) in the identification of SDB in patients with CHF. We performed synchronous in-laboratory Embletta and PSG, and home Embletta studies, prospectively in 20 consecutive patients with stable symptomatic CHF (ejection fraction 33 +/- 12%) on optimal medical therapy. Sleep efficiency was poor at 57 +/- 21%. Unlike synchronous in-laboratory Embletta (kappa coefficient 0.63, P < 0.01), home Embletta showed poor agreement with PSG (kappa coefficient 0.27, P = 0.06). Positive and negative predictive values for home Embletta in detecting SDB were 83% and 57% respectively. In this relatively small study, agreement in diagnostic outcome between home Embletta and PSG, and negative predictive value for the home Embletta, were poor. We explore possible explanations for this, both technical and situational, which should be taken into consideration when considering potential screening or diagnostic tools for SDB in patients with CHF.

Randomized clinical effectiveness trial of nurse-administered small-group cognitive behavior therapy for persistent insomnia in general practice.

STUDY OBJECTIVES: Persistent insomnia, although very common in general practice, often proves problematic to manage. This study investigates the clinical effectiveness and the feasibility of applying cognitive behavior therapy (CBT) methods for insomnia in primary care. DESIGN: Pragmatic randomized controlled trial of CBT versus treatment as usual. SETTING: General medical practice. PARTICIPANTS: Two hundred one adults (mean age, 54 years) randomly assigned to receive CBT (n = 107; 72 women) or treatment as usual (n = 94; 65 women). INTERVENTION: CBT comprised 5 sessions delivered in small groups by primary care nurses. Treatment as usual comprised usual care from general practitioners. MEASUREMENTS AND RESULTS: Assessments were completed at baseline, after treatment, and at 6-month follow-up visits. Sleep outcomes were appraised by sleep diary, actigraphy, and clinical endpoint. CBT was associated with improvements in self-reported sleep latency, wakefulness after sleep onset, and sleep efficiency. Improvements were partly sustained at follow-up. Effect sizes were moderate for the index variable of sleep efficiency. Participants receiving treatment as usual did not improve. Actigraphically estimated sleep improved modestly after CBT, relative to no change in treatment as usual. CBT was also associated with significant positive changes in mental health and energy/vitality. Comorbid physical and mental health difficulties did not impair sleep improvement following CBT. CONCLUSION: This study suggests that trained and supervised nurses can effectively deliver CBT for insomnia in routine general medical practice. Treatment response to small-group service delivery was encouraging, although effect sizes were smaller than those obtained in efficacy studies. Further research is required to consider the possibility that CBT could become the treatment of first choice for persistent insomnia in primary healthcare.

Auto-titrating continuous positive airway pressure therapy in patients with chronic heart failure and obstructive sleep apnoea: a randomized placebo-controlled trial.

AIMS: Obstructive sleep apnoea (OSA) is highly prevalent in patients with chronic heart failure (CHF) and may contribute to CHF progression. We aimed to determine whether treatment of OSA with continuous positive airway pressure (CPAP) would improve subjective and objective measures of heart failure severity in patients with CHF and OSA. METHODS AND RESULTS: Twenty-six patients with stable symptomatic CHF and OSA were randomized to nocturnal auto-titrating CPAP or sham CPAP for 6 weeks each in crossover design. Study co-primary endpoints were changes in peak VO(2) and 6 min walk distance. Secondary endpoints were changes in left ventricular ejection fraction, VE/VCO(2) slope, plasma neurohormonal markers, and quality-of-life measures. Twenty-three patients completed the study protocol. Mean CPAP and sham CPAP usage were 3.5 +/- 2.5 and 3.3 +/- 2.2 h/night, respectively (P = 0.31). CPAP treatment was associated with improvements in daytime sleepiness (Epworth Sleepiness Score 7 +/- 4 vs. 8 +/- 5, P = 0.04) but not in other quality-of-life measures. There were no changes in other study endpoints. CONCLUSION: In patients with CHF and OSA, auto-titrating CPAP improves daytime sleepiness but not other subjective or objective measures of CHF severity. These data suggest that the potential therapeutic benefits of CPAP in CHF are achieved by alleviation of OSA rather than by improvement in cardiac function.

Application of support vector machines to 1H NMR data of fish oils: methodology for the confirmation of wild and farmed salmon and their origins.

Support vector machines (SVMs) were used as a novel learning machine in the authentication of the origin of salmon. SVMs have the advantage of relying on a well-developed theory and have already proved to be successful in a number of practical applications. This paper provides a new and effective method for the discrimination between wild and farm salmon and eliminates the possibility of fraud through misrepresentation of the country of origin of salmon. The method requires a very simple sample preparation of the fish oils extracted from the white muscle of salmon samples. (1)H NMR spectroscopic analysis provides data that is very informative for analysing the fatty acid constituents of the fish oils. The SVM has been able to distinguish correctly between the wild and farmed salmon; however ca. 5% of the country of origins were misclassified.

Comparison of CPAP titration at home or the sleep laboratory in the sleep apnea hypopnea syndrome.

STUDY OBJECTIVES: Continuous positive airway pressure (CPAP) for the treatment of obstructive sleep apnea hypopnea syndrome (OSAHS) is conventionally started after in-laboratory overnight titration. This use of sleep laboratory space is both costly and limits access for diagnostic studies. This study aimed to evaluate whether automated CPAP titration in the home produced patient outcomes equal to those following laboratory-based automated CPAP titration. The main outcomes were Epworth Sleepiness Scale score, objective daytime sleepiness (Oxford SLEep Resistance test or OSLER test), and CPAP use; we also performed quality-of-life questionnaires: Functional Outcomes of Sleep Questionnaire and SF-36. DESIGN: Prospective, randomized, single-blind, parallel-group, controlled trial SETTING: Regional sleep center and patients' homes. PATIENTS: Two hundred CPAP-naïve patients with OSAHS requiring CPAP treatment. INTERVENTIONS: One hundred patients were randomly assigned to a standard 1-night in-hospital CPAP titration and 100 to 3 nights' home CPAP titration and then issued with fixed pressure CPAP. Data were analyzed on an intention-to-treat basis. MEASUREMENTS AND RESULTS: The patient groups did not differ at baseline. The CPAP pressures defined at titration (mean+/- SEM: 10.6+/-0.2, 10.4+/-0.2 cm H20, p = .19), number of mask leaks, and initial acceptance rates were similar in the sleep-laboratory and home-titrated groups. At 3-month follow-up, there was no significant difference in CPAP use (mean+/-SEM: 4.39+/-0.25, 4.38+/-0.25 h/night; p > .9), Epworth Sleepiness Scale score (9.5+/-0.5, 8.5+/-0.5, p = .14), OSLER, Functional Outcomes of Sleep Questionnaire, or SF-36 between the sleep-laboratory and home-titrated groups. CONCLUSIONS: Home-based automated CPAP titration is as effective as automatic in-laboratory titrations in initiating treatment for OSAHS.