Pharmacokinetics and pharmacodynamics of tiotropium solution and tiotropium powder in chronic obstructive pulmonary disease

The aim of the study was to characterize pharmacokinetics of tiotropium solution 5 µg compared to powder 18 µg and assess dose-dependency of tiotropium solution pharmacodynamics in comparison to placebo. In total 154 patients with chronic obstructive pulmonary disease (COPD) were included in this multicenter, randomized, double-blind within-solution (1.25, 2.5, 5 µg, and placebo), and open-label powder 18 µg, crossover study, including 4-week treatment periods. Primary end points were peak plasma concentration (Cmax,ss ), and area under the plasma concentration-time profile (AUC0-6h,ss ), both at steady state. The pharmacodynamic response was assessed by serial spirometry (forced expiratory volume in 1 second/forced vital capacity). Safety was evaluated as adverse events and by electrocardiogram/Holter. Tiotropium was rapidly absorbed with a median tmax,ss of 5-7 minutes postdosing for both devices. The gMean ratio of solution 5 µg over powder 18 µg was 81% (90% confidence interval, 73-89%) for Cmax,ss and 76% (70-82%) for AUC0-6h,ss , indicating that bioequivalence was not established. Dose ordering for bronchodilation was observed. Powder 18 µg and solution 5 µg were most effective, providing comparable bronchodilation. All treatments were well tolerated with no apparent relation to dose or device. Comparable bronchodilator efficacy to powder18 µg at lower systemic exposure supports tiotropium solution 5 µg for maintenance treatment of COPD

Assessing Competence of NHS Consultants: Challenges and Possible Solutions

Even a mention of formal assessment of senior clinicians can be a contentious issue, to say least, when revalidation is said to be firmly in place in NHS-UK for almost half a decade. Since revalidation is accepted as a standard modality of assessment of performance, some colleagues in NHS wonder ‘stir up a hornets’ nest,’ when the authors allude to limitations of revalidation because poorly performing senior NHS clinicians may ‘slip through the net.’ NHS consultants have clinical as well as training roles. Fundamentally, this assessment (revalidation) is meant to ensure the safety of the public and mitigates the risk of disciplinary action by the GMC. Unfortunately, a disciplinary action is often the first sign of underperformance. In fact, the Bristol and Shipman inquiries have underscored the importance of the non-clinical and behavioural skills like communication, teamworking, personal organization and leadership are as important as clinical skills. Rather than considered an assessment tool, an annual appraisal is aimed to facilitate and improve the way NHS consultants work and provide services. The authors have to wait for five years, to assess the efficacy of the system that was introduced with much ‘fanfare’ since it was projected as a panacea for poor performance by ’bad doctors.’ The objectives of this article are to contextualize the issue of the underperformance among senior clinicians in the current NHS environment and to conceptualize the idea that their performance as trainers is directly related to their performance as clinicians. It is worth identifying the underlying factors of that are related to, or even better, can predict underperformance and will help evolve a strategy to help those consultants who are underperforming

The Role of Astrocytes in Remyelination.

Remyelination is the regeneration of myelin sheaths following demyelination. This regenerative process is critical for the re-establishment of axonal conduction velocity and metabolic support to the axons. Successful remyelination in the CNS generally depends on the activation, proliferation, and differentiation of oligodendrocyte progenitor cells (OPCs). However, other cell types play critical roles in establishing where a lesion is conducive for regeneration. In the last few years, several studies have described beneficial and detrimental roles played by astrocytes in remyelination. This review will discuss recent developments in the concept of astrocyte reactivity, what is known about the astrocytic contribution to remyelination, and highlight future avenues of investigation.The authors’ laboratory is supported by funding from the UK Multiple Sclerosis Society (MS50), The Adelson Medical Research Foundation, and a core support grant from the Wellcome and MRC to the Wellcome-Medical Research Council Cambridge Stem Cell Institute (203151/Z/16/Z). KSR is supported by a postdoctoral fellowship from the Multiple Sclerosis Society of Canad

The age of anxiety? It depends where you look: changes in STAI trait anxiety, 1970–2010

Purpose Population-level surveys suggest that anxiety has been increasing in several nations, including the USA and UK. We sought to verify the apparent anxiety increases by looking for systematic changes in mean anxiety questionnaire scores from research publications. Methods We analyzed all available mean State–Trait Anxiety Inventory scores published between 1970 and 2010. We collected 1703 samples, representing more than 205,000 participants from 57 nations. Results Results showed a significant anxiety increase worldwide, but the pattern was less clear in many individual nations. Our analyses suggest that any increase in anxiety in the USA and Canada may be limited to students, anxiety has decreased in the UK, and has remained stable in Australia. Conclusions Although anxiety may have increased worldwide, it might not be increasing as dramatically as previously thought, except in specific populations, such as North American students. Our results seem to contradict survey results from the USA and UK in particular. We do not claim that our results are more reliable than those of large population surveys. However, we do suggest that mental health surveys and other governmental sources of disorder prevalence data may be partially biased by changing attitudes toward mental health: if respondents are more aware and less ashamed of their anxiety, they are more likely to report it to survey takers. Analyses such as ours provide a useful means of double-checking apparent trends in large population surveys

A Combination of Teacher-Led Assessment and Self-Assessment Drives the Learning Process in Online Master Degree in Transplantation

Background: Good performance in a summative assessment does not always equate to educational gain following acourse. An educational programme may focus on improving student’s performance on a particular test instrument.For example, practicing multiple choice questions may lead to mastery of the instrument itself rather than testing theknowledge and its application. We designed an assessment strategy that consistently valid and reliable that would fitwith the students with a range of 27 nationalities with a different institutional, cultural and educational background inthis totally online masters programme in transplantation.Methods: Based on the published evidence, we analyzed 2 main assessment domains: (a) self-assessment and (b)peer-assessment. We compared them with traditional teacher-led assessment considering the diversity of students.Conclusion: We conclude that traditional teacher-led assessment supplemented by self-assessment is a strong drivein the learning process in this on-line course, whilst peer-assessment is challenging and associated with many flawsgiving the diversity of our students. Peer-assessment may be unreliable and not valid due to the difference in theinstitutional background and variation in experience between the students.</jats:p

Combining Donor and Recipient Age With Preoperative MELD and UKELD Scores for Predicting Survival After Liver Transplantation

Objectives: The end-stage liver disease scoring systems MELD, UKELD, and D-MELD (donor age × MELD) have had mediocre results for survival assessment after orthotopic liver transplant. Here, we introduced new indices based on preoperative MELD and UKELD scores and assessed their predictive ability on survival posttransplant. Materials and Methods: We included 1017 deceased donor orthotopic liver transplants that were performed between 2008 (the year UKELD was introduced) and 2019. Donor and recipient characteristics, liver disease scores, transplant characteristics, and outcomes were collected for analyses. D-MELD, D-UKELD (donor age × UKELD), DR-MELD [(donor age + recipient age) × MELD], and DR-UKELD [(donor age + recipient age) × UKELD] were calculated. Results: No score had predictive value for graft survival. For patient survival, DR-MELD and DR-UKELD provided the best results but with low accuracy. The highest accuracy was observed at 1 year posttransplant (areas under the curve of 0.598 [95% CI, 0.529-0.667] and 0.609 [95% CI, 0.549-0.67] for DR-MELD and DR-UKELD). Addition of donor and recipient age significantly improved the predictive abilities of MELD and UKELD for patient survival, but addition of donor age alone did not. For 1-year mortality (using receiver operating characteristic curves), optimal cut-off points were DR-MELD >2345 and DR-UKELD >5908. Recipients with DR-MELD >2345 (P 5908 (P = .002) had worse patient survival within the first year, but only DR-MELD >2345 remained significant after multiva­riable analysis (P = .007). Conclusions: DR-MELD and DR-UKELD scores provided the best, albeit mediocre, predictive ability among the 6 tested models, especially at 1 year after posttransplant, although only for patient but not for graft survival. A DR-MELD >2345 was considered to be an additional independent risk factor for worse recipient survival within the first postoperative year

The Usefulness of the APACHE II Score in Obstetric Critical Care: A Structured Review.

OBJECTIVE: To assess the performance of the Acute Physiology and Chronic Health Evaluation II (APACHE II) mortality prediction model in pregnant and recently pregnant women receiving critical care in low-, middle-, and high-income countries during the study period (1985-2015), using a structured literature review. DATA SOURCES: Ovid MEDLINE, Embase, Web of Science, and Evidence-Based Medicine Reviews, searched for articles published between 1985 and 2015. STUDY SELECTION: Twenty-five studies (24 publications), of which two were prospective, were included in the analyses. Ten studies were from high-income countries (HICs), and 15 were from low- and middle-income countries (LMICs). Median study duration and size were six years and 124 women, respectively. DATA SYNTHESIS: ICU admission complicates 0.48% of deliveries, and pregnant and recently pregnant women account for 1.49% of ICU admissions. One quarter were admitted while pregnant, three quarters of these for an obstetric indication and for a median of three days. The median APACHE II score was 10.9, with a median APACHE II-predicted mortality of 16.6%. Observed mortality was 4.6%, and the median standardized mortality ratio was 0.36 (interquartile range 0.23 to 0.73). The standardized mortality ratio was < 0.9 in 24 of 25 studies. Women in HICs were more frequently admitted with a medical comorbidity but were less likely to die than were women in LMICs. CONCLUSION: The APACHE II score consistently overestimates mortality risks for pregnant and recently pregnant women receiving critical care, whether they reside in HICs or LMICs. There is a need for a pregnancy-specific outcome prediction model for these women

Donor-Recipient Body Surface Area Mismatch and the Outcome of Liver Transplantation in the UK

Introduction: Too small or too big liver grafts for recipient's size has detrimental effects on transplant outcomes. Research Questions: The purpose was to correlate donor-recipient body surface area (BSA) ratio or BSA index (BSAi) with recipient survival, graft survival, hepatic artery or portal vein, or vena cava thrombosis. High and low BSAi cut-off points were determined. Design: There were 11,245 adult recipients of first deceased donor whole liver-only grafts performed in the UK from January 2000 until June 2020. The transplants were grouped according to the BSAi and compared to complications, graft and recipient survival. Results: The BSAi ranged from 0.491 to 1.691 with a median of 0.988. The BSAi > 1.3 was associated with a higher rate of portal vein thrombosis within the first 3 months (5.5%). This risk was higher than size-matched transplants (OR: 2.878, 95% CI: 1.292-6.409, P = 0.01). Overall graft survival was worse in transplants with BSAi ≤ 0.85 (HR: 1.254, 95% CI: 1.051-1.497, P = 0.012) or BSAi > 1.4 (HR: 3.704, 95% CI: 2.029-6.762, P 1.4. These findings were confirmed by bootstrap internal validation. No statistically significant differences were detected for hepatic artery thrombosis, occlusion of hepatic veins/inferior vena cava or recipient survival. Conclusions: Donor-recipient size mismatch affects the rates of portal vein thrombosis within the first 3 months and overall graft survival in deceased-donor liver transplants