i-gel™ supraglottic airway in clinical practice: a prospective observational multicentre study

Background The i-gel™ supraglottic airway device has been studied in randomized controlled studies, but it has not been evaluated in a large prospective patient cohort. Therefore, we performed this prospective multicentre observational study to evaluate success rates, airway leak pressure, risk factors for i-gel failure, and adverse events. Methods With Ethics Committee approval and waiver of patients' consent, data about anaesthesia providers, patient characteristics, and the performance of the i-gel were recorded in five independent hospitals in Switzerland over a period of 24 months. We analysed success rates, leak pressures, adverse events, and risk factors for failure. Results Data from 2049 i-gel uses were analysed. Patients' mean age was 47 (range 6-91) yr. The primary i-gel success rate without changing size was 93%; the overall success rate was 96%. Insertion was deemed very easy or easy in 92%. The mean airway leak pressure was 26 (8) cm H2O. The mean anaesthesia time was 67 (42) min. Risk factors associated with i-gel failure were males (P<0.001), impaired mandibular subluxation (P=0.01), poor dentition (P=0.02), and older age (P<0.01). Adverse events recorded were laryngeal spasms (n=25, 1.2%), blood stained airway devices (n=79, 3.9%), transient nerve damage (n=2, 0.1%), one case of transient vasovagal asystole, and one glottic haematoma. Conclusions The i-gel is a reliable supraglottic airway device failing in <5% and providing high airway leak pressures. Males, impaired mandibular subluxation, poor dentition, and older age are risk factors associated with primary device failure. Serious adverse events are rar

Clinical outcome measures in dementia with Lewy bodies trials: critique and recommendations

The selection of appropriate outcome measures is fundamental to the design of any successful clinical trial. Although dementia with Lewy bodies (DLB) is one of the most common neurodegenerative conditions, assessment of therapeutic benefit in clinical trials often relies on tools developed for other conditions, such as Alzheimer's or Parkinson's disease. These may not be sufficiently valid or sensitive to treatment changes in DLB, decreasing their utility. In this review, we discuss the limitations and strengths of selected available tools used to measure DLB-associated outcomes in clinical trials and highlight the potential roles for more specific objective measures. We emphasize that the existing outcome measures require validation in the DLB population and that DLB-specific outcomes need to be developed. Finally, we highlight how the selection of outcome measures may vary between symptomatic and disease-modifying therapy trials

<i>Trypanosoma brucei rhodesiense</i> transmitted by a single tsetse fly bite in vervet monkeys as a model of human African trypanosomiasis

Sleeping sickness is caused by a species of trypanosome blood parasite that is transmitted by tsetse flies. To understand better how infection with this parasite leads to disease, we provide here the most detailed description yet of the course of infection and disease onset in vervet monkeys. One infected tsetse fly was allowed to feed on each host individual, and in all cases infections were successful. The characteristics of infection and disease were similar in all hosts, but the rate of progression varied considerably. Parasites were first detected in the blood 4-10 days after infection, showing that migration of parasites from the site of fly bite was very rapid. Anaemia was a key feature of disease, with a reduction in the numbers and average size of red blood cells and associated decline in numbers of platelets and white blood cells. One to six weeks after infection, parasites were observed in the cerebrospinal fluid (CSF), indicating that they had moved from the blood into the brain; this was associated with a white cell infiltration. This study shows that fly-transmitted infection in vervets accurately mimics human disease and provides a robust model to understand better how sleeping sickness develops

Correction: Clinical outcome measures in dementia with Lewy bodies trials: critique and recommendations.

The selection of appropriate outcome measures is fundamental to the design of any successful clinical trial. Although dementia with Lewy bodies (DLB) is one of the most common neurodegenerative conditions, assessment of therapeutic benefit in clinical trials often relies on tools developed for other conditions, such as Alzheimer's or Parkinson's disease. These may not be sufficiently valid or sensitive to treatment changes in DLB, decreasing their utility. In this review, we discuss the limitations and strengths of selected available tools used to measure DLB-associated outcomes in clinical trials and highlight the potential roles for more specific objective measures. We emphasize that the existing outcome measures require validation in the DLB population and that DLB-specific outcomes need to be developed. Finally, we highlight how the selection of outcome measures may vary between symptomatic and disease-modifying therapy trials

Clinical outcome measures in dementia with Lewy bodies trials: critique and recommendations.

The selection of appropriate outcome measures is fundamental to the design of any successful clinical trial. Although dementia with Lewy bodies (DLB) is one of the most common neurodegenerative conditions, assessment of therapeutic benefit in clinical trials often relies on tools developed for other conditions, such as Alzheimer's or Parkinson's disease. These may not be sufficiently valid or sensitive to treatment changes in DLB, decreasing their utility. In this review, we discuss the limitations and strengths of selected available tools used to measure DLB-associated outcomes in clinical trials and highlight the potential roles for more specific objective measures. We emphasize that the existing outcome measures require validation in the DLB population and that DLB-specific outcomes need to be developed. Finally, we highlight how the selection of outcome measures may vary between symptomatic and disease-modifying therapy trials

Feasibility, acceptability and effectiveness of integrated care for COPD patients: a mixed methods evaluation of a pilot community-based programme.

The aim of this study was to assess the feasibility, acceptability and effectiveness of a pilot COPD integrated care programme implemented in Valais, Switzerland. The programme was adapted from the self-management programme Living Well with COPD, and included the following elements: self-management patient-education group sessions, telephone and medical follow-ups, multidisciplinary teams, training of healthcare professionals, and evidence-based COPD care. A process and outcome evaluation of the pilot phase of the programme was conducted by means of qualitative and quantitative methods. Reach (coverage, participation rates), dosage (interventions carried out), fidelity (delivered as intended) and stakeholders' acceptance of the programme were evaluated through data monitoring and conduct of focus groups with patients and healthcare professionals. Effectiveness was assessed with pre-post analyses (before and after the intervention). The primary outcome measures were; (1) generic and disease-specific quality of life (36-Item Short Form Health Survey, Chronic Respiratory Questionnaire); and (2) hospitalisations (all-cause and for acute exacerbations) in the past 12 months. Secondary outcomes included self-efficacy, number of exacerbations and exercise capacity. Finally, controlled pre-post comparisons were also made with patients from the Swiss COPD Cohort for three common outcome measures (dyspnoea [mMRC score], number of exacerbations and smoking status). During the first 2 years of the programme, eight series of group-based education sessions were delivered to 57 patients with COPD in three different locations of the canton of Valais. Coverage objectives were achieved and attendance rate at the education sessions was high (83.6%). Patients' and healthcare professionals' reported a high degree of satisfaction, except for multidisciplinarity and transfer of information. Exploration of the effectiveness of this pilot programme suggested positive pre-post results at 12 months, with improvements in terms of health-related quality of life, self-efficacy, exercise capacity, immunisation coverage and Patient Assessment of Chronic Illness Care score. No other outcome, including the number of hospital admissions, differed significantly after 12 months. We observed no differences from the control group. The evaluation demonstrated the feasibility and acceptability of the programme and confirmed the relevance of mixed method process evaluation to adjust and improve programme implementation. The introduction of multidisciplinary teams in a context characterised by fragmentation of care was identified as the main challenge in the programme implementation and could not be achieved as expected. Despite this area for improvement, patients' feedback and early effectiveness results confirmed the benefits of COPD integrated care programmes emphasising self-management education

Systematic Functional Analysis of Bicaudal-D Serine Phosphorylation and Intragenic Suppression of a Female Sterile Allele of BicD

Protein phosphorylation is involved in posttranslational control of essentially all biological processes. Using mass spectrometry, recent analyses of whole phosphoproteomes led to the identification of numerous new phosphorylation sites. However, the function of most of these sites remained unknown. We chose the Drosophila Bicaudal-D protein to estimate the importance of individual phosphorylation events. Being involved in different cellular processes, BicD is required for oocyte determination, for RNA transport during oogenesis and embryogenesis, and for photoreceptor nuclei migration in the developing eye. The numerous roles of BicD and the available evidence for functional importance of BicD phosphorylation led us to identify eight phosphorylation sites of BicD, and we tested a total of 14 identified and suspected phosphoserine residues for their functional importance in vivo in flies. Surprisingly, all these serines turned out to be dispensable for providing sufficient basal BicD activity for normal growth and development. However, in a genetically sensitized background where the BicDA40V protein variant provides only partial activity, serine 103 substitutions are not neutral anymore, but show surprising differences. The S103D substitution completely inactivates the protein, whereas S103A behaves neutral, and the S103F substitution, isolated in a genetic screen, restores BicDA40V function. Our results suggest that many BicD phosphorylation events may either be fortuitous or play a modulating function as shown for Ser103. Remarkably, amongst the Drosophila serines we found phosphorylated, Ser103 is the only one that is fully conserved in mammalian BicD

The post-transcriptional trans-acting regulator, TbZFP3, co-ordinates transmission-stage enriched mRNAs in Trypanosoma brucei

Post-transcriptional gene regulation is essential to eukaryotic development. This is particularly emphasized in trypanosome parasites where genes are co-transcribed in polycistronic arrays but not necessarily co-regulated. The small CCCH protein, TbZFP3, has been identified as a trans-acting post-transcriptional regulator of Procyclin surface antigen expression in Trypanosoma brucei. To investigate the wider role of TbZFP3 in parasite transmission, a global analysis of associating transcripts was carried out. Examination of a subset of the selected transcripts revealed their increased abundance through mRNA stabilization upon TbZFP3 ectopic overexpression, dependent upon the integrity of the CCCH zinc finger domain. Reporter assays demonstrated that this regulation was mediated through 3′-UTR sequences for two target transcripts. Global developmental expression profiling of the cohort of TbZFP3-selected transcripts revealed their significant enrichment in transmissible stumpy forms of the parasite. This analysis of the specific mRNAs selected by the TbZFP3mRNP provides evidence for a developmental regulon with the potential to co-ordinate genes important in parasite transmission

European Malignant Hyperthermia Group guidelines for investigation of malignant hyperthermia susceptibility

It is 30 yr since the British Journal of Anaesthesia published the first consensus protocol for the laboratory diagnosis of malignant hyperthermia susceptibility from the European Malignant Hyperthermia Group. This has subsequently been used in more than 10 000 individuals worldwide to inform use of anaesthetic drugs in these patients with increased risk of developing malignant hyperthermia during general anaesthesia, representing an early and successful example of stratified medicine. In 2001, our group also published a guideline for the use of DNA-based screening of malignant hyperthermia susceptibility. We now present an updated and complete guideline for the diagnostic pathway for patients potentially at increased risk of developing malignant hyperthermia. We introduce the new guideline with a narrative commentary that describes its development, the changes to previously published protocols and guidelines, and new sections, including recommendations for patient referral criteria and clinical interpretation of laboratory finding

Repeated administration of the GABAB receptor positive modulator BHF177 decreased nicotine self-administration, and acute administration decreased cue-induced reinstatement of nicotine seeking in rats

Abstract: Rationale $\gamma$-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the brain and is implicated in the modulation of central reward processes. Acute or chronic administration of GABA$_B$ receptor agonists or positive modulators decreased self-administration of various drugs of abuse. Furthermore, GABA$_B$ receptor agonists inhibited cue-induced reinstatement of nicotine- and cocaine-seeking behavior. Because of their fewer adverse side effects compared with GABA$_B$ receptor agonists, GABA$_B$ receptor positive modulators are potentially improved therapeutic compounds for the treatment of drug dependence compared with agonists. Objectives and methods: We examined whether the acute effects of the GABA$_B$ receptor positive modulator N-[(1R,2R,4S)-bicyclo[2.2.1]hept-2-yl]-2-methyl-5-[4-(trifluoromethyl)phenyl]-4-pyrimidinamine (BHF177) on nicotine self- administration and food-maintained responding under a fixed-ratio 5 schedule of reinforcement were maintained after repeated administration. The effects of acute BHF177 administration on cue-induced nicotine- and food-seeking behavior, a putative animal model of relapse, were also examined. Results: Repeated administration of BHF177 for 14 days decreased nicotine self-administration, with small tolerance observed during the last 7 days of treatment, whereas BHF177 minimally affected food-maintained responding. Acute BHF177 administration dose-dependently blocked cue-induced reinstatement of nicotine-, but not food-, seeking behavior after a 10-day extinction period. Conclusions: These results showed that BHF177 selectively blocked nicotine self-administration and prevented cueinduced reinstatement of nicotine seeking, with minimal effects on responding for food and no effect on cue-induced reinstatement of food seeking. Thus, GABA$_B$ receptor positive modulators could be useful therapeutics for the treatment of different aspects of nicotine dependence by facilitating smoking cessation by decreasing nicotine intake and preventing relapse to smoking in humans