The distribution of fitness effects of beneficial mutations in Pseudomonas aeruginosa.

Understanding how beneficial mutations affect fitness is crucial to our understanding of adaptation by natural selection. Here, using adaptation to the antibiotic rifampicin in the opportunistic pathogen Pseudomonas aeruginosa as a model system, we investigate the underlying distribution of fitness effects of beneficial mutations on which natural selection acts. Consistent with theory, the effects of beneficial mutations are exponentially distributed where the fitness of the wild type is moderate to high.

Cost-effectiveness modeling of abatacept versus other biologic agents in DMARDS and anti-TNF inadequate responders for the management of moderate to severe rheumatoid arthritis.

To assess the cost-effectiveness of abatacept compared to different biologic treatment strategies for moderate to severe rheumatoid arthritis based on current medical practices in Canada. A model was constructed to assess the cost-effectiveness of various biologic treatments over a 2-year time horizon, using two effectiveness endpoints: "low disease activity state" (LDAS) and "remission". Abatacept, as first biologic agent after an inadequate response to DMARDs, provides greater treatment success rate for achieving LDAS (29.

The direct and indirect cost burden of Crohn's disease and ulcerative colitis.

Objective: To estimate the direct medical and indirect (absenteeism and short-term disability) cost burden of Crohn's Disease (CD) and Ulcerative Colitis (UC).

Methods: Data were obtained from 1999 to 2005 MarketScan databases. Twelve-month expenditures for patients with CD and UC were compared to expenditures among an equal number of propensity score matched comparison group patients.

Experimental adaptive radiation in Pseudomonas.

We studied the importance of selection and constraint in determining the limits of adaptive radiation and the consequences of adaptive radiation in an experimental system. We propagated four replicate lines of the bacterium Pseudomonas fluorescens derived from a single ancestral clone in 95 environments, where growth was limited by the availability of a single carbon source for 1,000 generations. We then assayed the growth of the ancestral clone and the evolved lines in all 95 environments.

Cost-effectiveness of abatacept in patients with moderately to severely active rheumatoid arthritis and inadequate response to tumor necrosis factor-alpha antagonists.

Objective: To assess cost-effectiveness of abatacept in patients with rheumatoid arthritis (RA) with inadequate response to tumor necrosis factor-alpha antagonists (anti-TNF).

Methods: We developed a simulation model to depict progression of disability [in terms of Health Assessment Questionnaire Disability Index (HAQ-DI)] in women aged 55-64 years with moderately to severely active RA and inadequate response to anti-TNF. At model entry, patients were assumed to receive either oral disease modifying antirheumatic drugs (DMARD) only or oral DMARD plus abatacept.

The use of ecarin chromogenic assay and prothrombinase induced clotting time in the monitoring of lepirudin for the treatment of heparin-induced thrombocytopenia.

Lepirudin (r-hirudin) is one of the two alternative anticoagulants licensed to treat patients with heparin-induced thrombocytopenia (HIT). Manufacturer's guidelines state that lepirudin should be monitored using the activated partial thromboplastin time (APTT) ratio. However, several studies have demonstrated a plateau effect of higher concentrations of lepirudin on APTT ratios and variable results when comparing different APTT reagents.

Treatment impact on estimated medical expenditure and job loss likelihood in rheumatoid arthritis: re-examining quality of life outcomes from a randomized placebo-controlled clinical trial with abatacept.

Objectives: Quality of life (QoL) improvement is important to demonstrate in RA clinical trials, but can be abstract. More meaningful measures of QoL include medical expenditure and job loss, aspects that have marked importance for RA patients, physicians and society. We re-examined previous positive QoL findings for abatacept over placebo by converting existing QoL measures into estimated medical expenditure and estimated likelihood of job loss.

The tragedy of the commons in microbial populations: insights from theoretical, comparative and experimental studies.

First principles of thermodynamics imply that metabolic pathways are faced with a trade-off between the rate and yield of ATP production. Simple evolutionary models argue that this trade-off generates a fundamental social conflict in microbial populations: average fitness in a population is highest if all individuals exploit common resources efficiently, but individual reproductive rate is maximized by consuming common resources at the highest possible rate, a scenario known as the tragedy of the commons. In this paper, I review studies that have addressed two key questions: What is the evidence that the rate-yield trade-off is an evolutionary constraint on metabolic pathways? And, if so, what determines evolutionary outcome of the conflicts generated by this trade-off? Comparative studies and microbial experiments provide evidence that the rate-yield trade-off is an evolutionary constraint that is driven by thermodynamic constraints that are common to all metabolic pathways and pathway-specific constraints that reflect the evolutionary history of populations.

Persistent right aortic arch and cribiform plate aplasia in a northern elephant seal (Mirounga angustirostris).

A female weanling northern elephant seal (Mirounga angustirostris) presented to The Marine Mammal Center in Sausalito, California, USA, in poor body condition. An esophageal obstruction was diagnosed by contrast radiography and esophagoscopy, but despite extensive diagnostics and supportive care, the seal died 6 days later. On postmortem examination, the right aortic arch was persistent, forming a vascular ring anomaly with a patent ductus arteriosus that compressed the distal esophagus.

Cost-effectiveness of abatacept in patients with moderately to severely active rheumatoid arthritis and inadequate response to methotrexate.

Objective: To assess cost-effectiveness of abatacept in patients with moderately to severely active RA and inadequate response to MTX.

Methods: We developed a simulation model to depict progression of disability [in terms of the HAQ Disability Index (HAQ-DI)] in women aged 55-64 yrs with moderately to severely active RA and inadequate response to MTX. At model entry, patients were assumed to receive either only MTX or MTX plus abatacept.

Diversity and productivity peak at intermediate dispersal rate in evolving metacommunities.

Positive relationships between species diversity and productivity have been reported for a number of ecosystems. Theoretical and experimental studies have attempted to determine the mechanisms that generate this pattern over short timescales, but little attention has been given to the problem of understanding how diversity and productivity are linked over evolutionary timescales. Here, we investigate the role of dispersal in determining both diversity and productivity over evolutionary timescales, using experimental metacommunities of the bacterium Pseudomonas fluorescens assembled by divergent natural selection.

Propofol anesthesia in loggerhead (Caretta caretta) sea turtles.

Rapid, safe, and effective methods of anesthetic induction and recovery are needed for sea turtles, especially in cases eligible for immediate release. This study demonstrates that intravenous propofol provides a rapid induction of anesthesia in loggerhead (Caretta caretta) sea turtles and results in rapid recovery, allowing safe return to water shortly after the procedure. Forty-nine loggerhead sea turtles were recovered as local fishery by-catch in pound nets and transported to a surgical suite for laparoscopic sex determination.

An index of only patient-reported outcome measures, routine assessment of patient index data 3 (RAPID3), in two abatacept clinical trials: similar results to disease activity score (DAS28) and other RAPID indices that include physician-reported measures.

Objectives: To analyse the capacity of routine assessment of patient index data 3 (RAPID3), an index of only the three patient-reported outcome (PRO) measures in the RA Core Data Set-physical function, pain and global status-to distinguish abatacept from control treatments in two clinical trials, and to compare RAPID3 results with the disease activity score 28 (DAS28) and RAPID-based indices that add a tender or swollen joint count and/or physician/assessor global estimate of status.

Methods: Clinical trial data from AIM (Abatacept in Inadequate response to Methotrexate) and ATTAIN [Abatacept Trial in Treatment of Anti-tumor necrosis factor (anti-TNF) INadequate responders] were reanalysed. Mean values were computed at baseline, endpoint and for change between baseline and endpoint for RAPID3, DAS28 and additional RAPID indices to study whether they had greater capacity to distinguish abatacept from control therapy.

Productivity cost model of the treatment of rheumatoid arthritis with abatacept.

Background: The cost of the biological drug abatacept may be partly offset by reductions in the cost of productivity losses due to employee absences and reduced effectiveness at work because of rheumatoid arthritis (RA).

Methods: This was a 1-year productivity cost model based on epidemiologic and economic data. The setting was private industry in the US and the primary outcome measure was the difference in the costs of lost productivity and drug treatment with and without abatacept ('cost difference').

Quantitative measurement of patient status in the regular care of patients with rheumatic diseases over 25 years as a continuous quality improvement activity, rather than traditional research.

Patient assessment in rheumatology is characterized by an important paradox: many extensively-characterized quantitative measures and indices have been developed for rheumatoid arthritis (RA), psoriatic arthritis, systemic lupus erythematosus (SLE), ankylosing spondylitis, vasculitis, osteoarthritis, fibromyalgia, and other rheumatic diseases. However, most regular rheumatology care is guided largely by qualitative clinical impressions, without such measures or indices or any quantitative data other than laboratory tests to assess patient status and/or quality of care. This paradox may be explained in part by regarding the development of measures primarily as clinical research activities, while viewing the application of measurements in regular clinical care as continuous quality improvement (CQI) activities.

Blood product support for delivery in severe factor X deficiency: the use of thrombin generation to guide therapy.

Background: Severe FX deficiency is a rare disorder with a variable bleeding tendency but spontaneous life threatening haemorrhage can occur. Treatment for invasive procedures and spontaneous bleeding is with prothrombin complex concentrates (PCC). When used in large or repetitive doses these are associated with a thrombotic tendency.

The tragedy of the commons in microbial populations: insights from theoretical, comparative and experimental studies.

First principles of thermodynamics imply that metabolic pathways are faced with a trade-off between the rate and yield of ATP production. Simple evolutionary models argue that this trade-off generates a fundamental social conflict in microbial populations: average fitness in a population is highest if all individuals exploit common resources efficiently, but individual reproductive rate is maximized by consuming common resources at the highest possible rate, a scenario known as the tragedy of the commons. In this paper, I review studies that have addressed two key questions: What is the evidence that the rate-yield trade-off is an evolutionary constraint on metabolic pathways? And, if so, what determines evolutionary outcome of the conflicts generated by this trade-off? Comparative studies and microbial experiments provide evidence that the rate-yield trade-off is an evolutionary constraint that is driven by thermodynamic constraints that are common to all metabolic pathways and pathway-specific constraints that reflect the evolutionary history of populations.

Responsiveness of patient reported outcomes including fatigue, sleep quality, activity limitation, and quality of life following treatment with abatacept for rheumatoid arthritis.

Objective: To evaluate the responsiveness of patient reported outcomes (PROs), including fatigue, sleep, activity limitation, and quality of life, in patients with rheumatoid arthritis (RA).

Methods: Data were considered from a randomised controlled trial comparing abatacept (n = 258) with placebo (n = 133) on a background of DMARD treatment in RA patients who were inadequate responders to anti-TNF therapy (ATTAIN study). PROs assessed included SF-36, activity limitation, fatigue, and sleep.

Constraints on microbial metabolism drive evolutionary diversification in homogeneous environments.

Understanding the evolution of microbial diversity is an important and current problem in evolutionary ecology. In this paper, we investigated the role of two established biochemical trade-offs in microbial diversification using a model that connects ecological and evolutionary processes with fundamental aspects of biochemistry. The trade-offs that we investigated are as follows:(1) a trade-off between the rate and affinity of substrate transport; and (2) a trade-off between the rate and yield of ATP production.

A proposed continuous quality improvement approach to assessment and management of patients with rheumatoid arthritis without formal joint counts, based on quantitative routine assessment of patient index data (RAPID) scores on a multidimensional health assessment questionnaire (MDHAQ).

A continuous quality improvement approach is proposed for the assessment and management of patients with rheumatoid arthritis (RA) based on scores on a one-page patient self-report multidimensional health assessment questionnaire (MDHAQ), without formal joint counts. The approach includes five simple steps before the patient is seen by the physician: (1) an MDHAQ is completed by every patient at every visit; (2) scores are calculated for patient function, pain, and global estimate, with options for a self-report joint count and other scales; (3) scores are entered on flow sheets with data from prior visits, which might also include laboratory and medication information; (4) scores are compiled into an index termed Routine Assessment of Patient Index Data (RAPID), analogous to a Disease Activity Score (DAS); (5) RAPID scores are classified to guide treatment decisions. RAPID 3 includes the three patient-reported outcome (PRO) measures in the RA Core Data Set - physical function, pain, and global estimate.

Reversal of motility loss in bongo antelope (Tragelaphus eurycerus isaaci) spermatozoa contaminated with hyposmotic urine during electroejaculation.

Semen collected by a combination of ampullary (rectal) massage and electroejaculation of a bongo bull was incidentally contaminated with urine (1:3.7). At 1.

The relationship between anxiety and sleep-wake behavior after stressor exposure in the rat.

Disturbed sleep is a common subjective complaint among individuals diagnosed with anxiety disorders. In rodents, sleep is often recorded after exposure to various foot-shock paradigms designed to induce an anxiety state. Although differences in sleep-wake architecture are noted, the relationship to specific level of anxiety is often assumed or absent.

Pleiotropy and GAL pathway degeneration in yeast.

Traits that do not contribute to fitness are expected to be lost during the course of evolution, either as a result of selection or drift. The Leloir pathway of galactose metabolism (GAL) is an extensively studied metabolic pathway that degenerated on at least three independent occasions during the evolutionary diversification of yeasts, suggesting that the pathway is costly to maintain in environments that lack galactose. Here I test this hypothesis by competing GAL pathway deletion mutants of Saccharomyces cerevisiae against an isogenic strain with an intact GAL pathway under conditions where expression of the pathway is normally induced, repressed, or uninduced.

Multicentre ISI assignment and calibration of the INR measuring range of a new point-of-care system designed for home monitoring of oral anticoagulation therapy.

The new CoaguChek XS system is designed for use in patient selftesting. It is the successor of the current CoaguChek S system. The detection principle is based on the amperometric measurement of the thrombin activity initiated by starting the coagulation cascade using a human recombinant thromboplastin.

Neurobiological mechanisms for the regulation of mammalian sleep-wake behavior: reinterpretation of historical evidence and inclusion of contemporary cellular and molecular evidence.

At its most basic level, the function of mammalian sleep can be described as a restorative process of the brain and body; recently, however, progressive research has revealed a host of vital functions to which sleep is essential. Although many excellent reviews on sleep behavior have been published, none have incorporated contemporary studies examining the molecular mechanisms that govern the various stages of sleep. Utilizing a holistic approach, this review is focused on the basic mechanisms involved in the transition from wakefulness, initiation of sleep and the subsequent generation of slow-wave sleep and rapid eye movement (REM) sleep.