Enantioselective disposition of (R,R)-formoterol, (S,S)-formoterol and their respective glucuronides in urine following single inhaled dosing and application to doping control

Formoterol is a long‐acting beta2‐adrenoceptor agonist (LABA) used for treatment of asthma and exercise‐induced bronchoconstriction. Formoterol is usually administered as a racemic (rac‐) mixture of (R,R)‐ and (S,S)‐enantiomers. While formoterol is restricted by the World Anti‐Doping Agency (WADA), inhalation of formoterol is permitted to a predetermined dose (54 μg/24 hours) and a urine threshold of 40 ng/mL. However, chiral switch enantiopure (R,R)‐formoterol is available, effectively doubling the therapeutic advantage for the same threshold. The aim of this study was to investigate whether formoterol exhibits enantioselective urinary pharmacokinetics following inhalation. Six healthy volunteers were administered a 12 μg inhaled dose of rac‐formoterol. Urine was collected over 24‐hours and analysed by enantioselective UPLC‐MS/MS assay. Total (free drug plus conjugated metabolite) median (min‐max) rac‐formoterol urine levels following inhalation were 1.96(1.05‐13.4) ng/mL, 1.67(0.16‐9.67) ng/mL, 0.45(0.16‐1.51) ng/mL, 0.61(0.33‐0.78) ng/mL, and 0.17(0.08‐1.06) ng/mL at 2, 4, 8, 12 and 24 hours, respectively, well below the 2019 urine threshold. The proportion of conjugation differed between enantiomers with glucuronide conjugation much greater for (R,R)‐formoterol (around 30‐60% of total) compared to (S,S)‐formoterol (0‐30%). There was clear evidence of inter‐individual enantioselectivity observed in the ratios of (R,R):(S,S)‐formoterol, where (S,S)‐ was predominant in free formoterol, and (R,R)‐ predominant in the conjugated metabolite. In conclusion, rac‐formoterol delivered by inhalation exhibits enantioselective elimination in urine following single dose administration. Enantioselective assays should be employed in doping control to screen for banned beta2‐agonist chiral switch products such as (R,R)‐formoterol, and total hydrolysed rac‐formoterol is warranted to account for inter‐individual differences in enantioselective glucuronidation

A pilot randomised controlled trial of personalised care for depressed patients with symptomatic coronary heart disease in South London general practices: the UPBEAT-UK RCT protocol and recruitment.

ABSTRACT: Background: Community studies reveal people with coronary heart disease (CHD) are twice as likely to be depressed as the general population and that this co-morbidity negatively affects the course and outcome of both conditions. There is evidence for the efficacy of collaborative care and case management for depression treatment, and whilst NICE guidelines recommend these approaches only where depression has not responded to psychological, pharmacological, or combined treatments, these care approaches may be particularly relevant to the needs of people with CHD and depression in the earlier stages of stepped care in primary care settings. Methods: This pilot randomised controlled trial will evaluate whether a simple intervention involving a personalised care plan, elements of case management and regular telephone review is a feasible and acceptable intervention that leads to better mental and physical health outcomes for these patients. The comparator group will be usual general practitioner (GP) care. 81 participants have been recruited from CHD registers of 15 South London general practices. Eligible participants have probable major depression identified by a score of ≥8 on the Hospital Anxiety and Depression Scale depression subscale (HADS-D) together with symptomatic CHD identified using the Modified Rose Angina Questionnaire. Consenting participants are randomly allocated to usual care or the personalised care intervention which involves a comprehensive assessment of each participant’s physical and mental health needs which are documented in a care plan, followed by regular telephone reviews by the case manager over a 6-month period. At each review, the intervention participant’s mood, function and identified problems are reviewed and the case manager uses evidence based behaviour change techniques to facilitate achievement of goals specified by the patient with the aim of increasing the patient’s self efficacy to solve their problems. Depressive symptoms measured by HADS score will be collected at baseline and 1, 6- and 12 months post randomisation. Other outcomes include CHD symptoms, quality of life, wellbeing and health service utilisation. Discussion: This practical and patient-focused intervention is potentially an effective and accessible approach to the health and social care needs of people with depression and CHD in primary care. Trial registration: ISRCTN21615909

Astrobiological Complexity with Probabilistic Cellular Automata

Search for extraterrestrial life and intelligence constitutes one of the major endeavors in science, but has yet been quantitatively modeled only rarely and in a cursory and superficial fashion. We argue that probabilistic cellular automata (PCA) represent the best quantitative framework for modeling astrobiological history of the Milky Way and its Galactic Habitable Zone. The relevant astrobiological parameters are to be modeled as the elements of the input probability matrix for the PCA kernel. With the underlying simplicity of the cellular automata constructs, this approach enables a quick analysis of large and ambiguous input parameters' space. We perform a simple clustering analysis of typical astrobiological histories and discuss the relevant boundary conditions of practical importance for planning and guiding actual empirical astrobiological and SETI projects. In addition to showing how the present framework is adaptable to more complex situations and updated observational databases from current and near-future space missions, we demonstrate how numerical results could offer a cautious rationale for continuation of practical SETI searches.Comment: 37 pages, 11 figures, 2 tables; added journal reference belo

Accelerated Profile HMM Searches

Profile hidden Markov models (profile HMMs) and probabilistic inference methods have made important contributions to the theory of sequence database homology search. However, practical use of profile HMM methods has been hindered by the computational expense of existing software implementations. Here I describe an acceleration heuristic for profile HMMs, the “multiple segment Viterbi” (MSV) algorithm. The MSV algorithm computes an optimal sum of multiple ungapped local alignment segments using a striped vector-parallel approach previously described for fast Smith/Waterman alignment. MSV scores follow the same statistical distribution as gapped optimal local alignment scores, allowing rapid evaluation of significance of an MSV score and thus facilitating its use as a heuristic filter. I also describe a 20-fold acceleration of the standard profile HMM Forward/Backward algorithms using a method I call “sparse rescaling”. These methods are assembled in a pipeline in which high-scoring MSV hits are passed on for reanalysis with the full HMM Forward/Backward algorithm. This accelerated pipeline is implemented in the freely available HMMER3 software package. Performance benchmarks show that the use of the heuristic MSV filter sacrifices negligible sensitivity compared to unaccelerated profile HMM searches. HMMER3 is substantially more sensitive and 100- to 1000-fold faster than HMMER2. HMMER3 is now about as fast as BLAST for protein searches

Variation and ethnic inequalities in treatment of common mental disorders before, during and after pregnancy : combined analysis of routine and research data in the Born in Bradford cohort

BACKGROUND: Common mental disorders (CMD) such as anxiety and depression during the maternal period can cause significant morbidity to the mother in addition to disrupting biological, attachment and parenting processes that affect child development. Pharmacological treatment is a first-line option for moderate to severe episodes. Many women prescribed pharmacological treatments cease them during pregnancy but it is unclear to what extent non-pharmacological options are offered as replacement. There are also concerns that treatments offered may not be proportionate to need in minority ethnic groups, but few data exist on treatment disparities in the maternal period. We examined these questions in a multi-ethnic cohort of women with CMD living in Bradford, England before, during and up to one year after pregnancy. METHODS: We searched the primary care records of women enrolled in the Born in Bradford cohort for diagnoses, symptoms, signs ('identification'), referrals for treatment, non-pharmacological and pharmacological treatment and monitoring ('treatment') related to CMD. Records were linked with maternity data to classify women identified with a CMD as treated prior to, and one year after, delivery. We examined rates and types of treatment during pregnancy, and analysed potential ethnic group differences using adjusted Poisson and multinomial logistic regression models. RESULTS: We analysed data on 2,234 women with indicators of CMD. Most women were discontinued from pharmacological treatment early in pregnancy, but this was accompanied by recorded access to non-drug treatments in only 15 % at the time of delivery. Fewer minority ethnic women accessed treatments compared to White British women despite minority ethnic women being 55-70 % more likely than White British women to have been identified with anxiety in their medical record. CONCLUSIONS: Very few women who discontinued pharmacological treatment early in their pregnancy were offered other non-pharmacological treatments as replacement, and most appeared to complete their pregnancy untreated. Further investigation is warranted to replicate the finding that minority ethnic women are more likely to be identified as being anxious or having anxiety and understand what causes the variation in access to treatments

Reliability and tolerance comparison in water supply networks

The final publication is available at Springer via http://dx.doi.org/10.1007/s11269-010-9753-2Urban water supply is a high priority service and so looped networks are extensively used in order to considerably reduce the number of consumers affected by a failure. Looped networks may be redundant in connectivity and capacity. The concept of reliability has been introduced in an attempt to quantitatively measure the possibility of maintaining an adequate service for a given period. Numerous researchers have considered reliability as a measure of redundancy. This concept is usually implicit, but some researchers have even stated it explicitly. This paper shows why reliability cannot be considered a measure of redundancy given that branched networks can achieve high values of reliability and this would deny the fact that a looped network is more reliable than a branched network with a similar layout and size. To this end the paper discusses two quantitative indices for measuring expected network behavior: reliability and tolerance. These indices are calculated and a comparison is made between looped, branched, and mixed networks. © 2011 Springer Science+Business Media B.V.The authors wish to acknowledge the support received from project IDAWAS, DPI2009-11591, of the Directorate-General of Research at the Spanish Ministry of Education, the grant PAID-02-09 for a stay at the Universidad Politecnica de Valencia by the first author, and a grant MAEC-AECI 0000202066 awarded to the second author by the Ministerio de Asuntos Exteriores y Cooperacion of Spain. The use of English in this paper was revised by John Rawlins; and the revision was funded by the Universidad Politecnica de Valencia, Spain.Martínez-Rodríguez, JB.; Montalvo Arango, I.; Izquierdo Sebastián, J.; Pérez García, R. (2011). Reliability and tolerance comparison in water supply networks. 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The sensitivity of the tropical circulation and Maritime Continent precipitation to climate model resolution

The dependence of the annual mean tropical precipitation on horizontal resolution is investigated in the atmospheric version of the Hadley Centre General Environment Model (HadGEM1). Reducing the grid spacing from about 350 km to 110 km improves the precipitation distribution in most of the tropics. In particular, characteristic dry biases over South and Southeast Asia including the Maritime Continent as well as wet biases over the western tropical oceans are reduced. The annual-mean precipitation bias is reduced by about one third over the Maritime Continent and the neighbouring ocean basins associated with it via the Walker circulation. Sensitivity experiments show that much of the improvement with resolution in the Maritime Continent region is due to the specification of better resolved surface boundary conditions (land fraction, soil and vegetation parameters) at the higher resolution. It is shown that in particular the formulation of the coastal tiling scheme may cause resolution sensitivity of the mean simulated climate. The improvement in the tropical mean precipitation in this region is not primarily associated with the better representation of orography at the higher resolution, nor with changes in the eddy transport of moisture. Sizeable sensitivity to changes in the surface fields may be one of the reasons for the large variation of the mean tropical precipitation distribution seen across climate models

A study of indoor carbon dioxide levels and sick leave among office workers

BACKGROUND: A previous observational study detected a strong positive relationship between sick leave absences and carbon dioxide (CO(2)) concentrations in office buildings in the Boston area. The authors speculated that the observed association was due to a causal effect associated with low dilution ventilation, perhaps increased airborne transmission of respiratory infections. This study was undertaken to explore this association. METHODS: We conducted an intervention study of indoor CO(2) levels and sick leave among hourly office workers employed by a large corporation. Outdoor air supply rates were adjusted periodically to increase the range of CO(2) concentrations. We recorded indoor CO(2) concentrations every 10 minutes and calculated a CO(2) concentration differential as a measure of outdoor air supply per person by subtracting the 1–3 a.m. average CO(2) concentration from the same-day 9 a.m. – 5 a.m. average concentration. The metric of CO(2) differential was used as a surrogate for the concentration of exhaled breath and for potential exposure to human source airborne respiratory pathogens. RESULTS: The weekly mean, workday, CO(2) concentration differential ranged from 37 to 250 ppm with a peak CO(2) concentration above background of 312 ppm as compared with the American Society of Heating, Refrigeration and Air-conditioning Engineers (ASHRAE) recommended maximum differential of 700 ppm. We determined the frequency of sick leave among 294 hourly workers scheduled to work approximately 49,804.2 days in the study areas using company records. We found no association between sick leave and CO(2) differential CONCLUSIONS: The CO(2) differential was in the range of very low values, as compared with the ASHRAE recommended maximum differential of 700 ppm. Although no effect was found, this study was unable to test whether higher CO(2) differentials may be associated with increased sick leave