Adeno-associated virus (AAV) vectors are currently the leading candidates for virus-based gene therapies because of their broad tissue tropism, non-pathogenic nature and low immunogenicity. They have ...been successfully used in clinical trials to treat hereditary diseases such as haemophilia B (ref. 2), and have been approved for treatment of lipoprotein lipase deficiency in Europe. Considerable efforts have been made to engineer AAV variants with novel and biomedically valuable cell tropisms to allow efficacious systemic administration, yet basic aspects of AAV cellular entry are still poorly understood. In particular, the protein receptor(s) required for AAV entry after cell attachment remains unknown. Here we use an unbiased genetic screen to identify proteins essential for AAV serotype 2 (AAV2) infection in a haploid human cell line. The most significantly enriched gene of the screen encodes a previously uncharacterized type I transmembrane protein, KIAA0319L (denoted hereafter as AAV receptor (AAVR)). We characterize AAVR as a protein capable of rapid endocytosis from the plasma membrane and trafficking to the trans-Golgi network. We show that AAVR directly binds to AAV2 particles, and that anti-AAVR antibodies efficiently block AAV2 infection. Moreover, genetic ablation of AAVR renders a wide range of mammalian cell types highly resistant to AAV2 infection. Notably, AAVR serves as a critical host factor for all tested AAV serotypes. The importance of AAVR for in vivo gene delivery is further highlighted by the robust resistance of Aavr(-/-) (also known as Au040320(-/-) and Kiaa0319l(-/-)) mice to AAV infection. Collectively, our data indicate that AAVR is a universal receptor involved in AAV infection.
Summary
What is known and objective
With the emerging and promising role of healthcare professionals in implementing smoking cessation services, community pharmacists, in particular, can play a ...pivotal role. The aim of this meta‐analysis is to evaluate the effectiveness of smoking cessation interventions delivered by community pharmacists in assisting smokers to quit.
Methods
PubMed, EMBASE, Scopus, International Pharmaceutical s and ISI Web of Knowledge were searched from inception to May 2013. Original research articles were selected for review, if they addressed the effectiveness of pharmacy‐based interventions in smokers vs. a control group and reported smoking abstinence rates as an outcome. Obtained studies were assessed for methodological quality using the Cochrane Effective Practice and Organization of Care Group risk of bias tool. The primary outcome of measure was smoking abstinence based on the ‘most rigorous criterion’. Pooled relative risks (RR) with 95% confidence interval (CI) were estimated using the Dersimonian and Laird random‐effects models. Corresponding subgroup met‐analysis was performed.
Results
Of the 1168 articles extracted, five studies (three randomized controlled trials and two controlled before‐after studies) met the inclusion criteria, involving a total of 1426 smokers. Pharmacist interventions showed better abstinence rates as compared with controls (RR 2·21, 95% CI 1·49–3·29). Compared with the control group, the RR (95% CI) in the intervention group was 3·21 (1·81–5·72) for clinically validated abstinence and 1·66 (1·08–2·54) for self‐reported abstinence. In the intervention group, the RR for short‐term and long‐term abstinence was 2·48 (1·15–5·31) and 2·40 (1·37–4·23), respectively.
What is new and conclusions
Pharmacist‐led interventions can significantly impact abstinence rates in smokers. Health policymakers should direct incentives for community pharmacists to provide such services.
The aim of this meta‐analysis is to evaluate the effectiveness of smoking cessation interventions delivered by community pharmacists in assisting smokers to quit. Pharmacist‐led interventions can significantly impact abstinence rates in smokers. Health policymakers should direct incentives for community pharmacists to provide such services.
Lors de bactériémies, la détermination du profil de résistance apparaît comme une étape cruciale. Bien qu’un traitement antibiotique probabiliste soit instauré, les résistances demeurent ...imprévisibles et peuvent être à l’origine d’échecs thérapeutiques. La rapidité de l’obtention de l’antibiogramme conditionne une bonne adaptation du traitement antibiotique et une optimisation de la prise en charge des patients bactériémiques.
Cette étude pilote prospective a été réalisée en routine entre août 2016 et janvier 2017. Les antibiogrammes ont été réalisés directement à partir des flacons d’hémocultures positives sur milieu Mueller Hinton (MH). 86 échantillons, contenant des entérobactéries (79 %) ou des Staphylococcus aureus (21 %) ont été testés en parallèle par deux méthodes : le milieu MH standard (Biorad), incubé 16h et le milieu MHR (MH rapide, i2a), incubé 6 à 8h. Deux panels différents d’antibiotiques ont été testés : 32 disques sur les bacilles à Gram négatif et 16 disques sur les S. aureus. Les diamètres d’inhibition ont tous été lus par le système automatique SIRscan 2000 (i2a) et ont été interprétés en tenant compte des recommandations EUCAST 2016. Pour chaque bactérie et chaque antibiotique testés, nous avons comparé la concordance des interprétations entre les deux méthodes : sensible (S), intermédiaire (I) ou résistant (R).
Les 63 souches d’entérobactéries étaient distribuées entre 37 (58,7 %) E. coli, 12 (19,0 %) K. pneumoniae, 7 (11,1 %) E. cloacae, 3 (4,8 %) E. aerogenes, 2 (3,2 %) C. freundii, 1 (1,6 %) P. mirabilis et 1 (1,6 %) S. marcescens. Sur les 1732 tests réalisés, les résultats montraient 1648 (96,8 %) concordances, 33 (2,0 %) différences mineures (dm), 5 (0,3 %) différences majeures (DM) et 16 (0,9 %) différences très majeures (DTM). Les dm étaient majoritairement constatées autour de la pipéracilline. Les DTM observées concernaient principalement les Enterobacter, Citrobacter et Serratia pour la céfalexine. Dans le groupe des 18 S. aureus, nous avons trouvé 259 (89,9 %) concordances, 8 (2,8 %) dm, 21 (7,3 %) DM et aucune DTM. Les différences majeures étaient principalement observées pour la céfoxitine.
Nos résultats montrent une bonne corrélation entre les antibiogrammes réalisés en milieux MH et MHR. Bien que des différences aient été constatées, l’utilisation du MHR est une méthode rapide permettant de prédire la sensibilité aux antibiotiques des entérobactéries et des S. aureus. Il apparaît cependant que la céfalexine n’était pas fiable sur les entérobactéries du groupe 3 en méthode MHR, ce qui n’avait pas d’impact en clinique. De plus, la résistance à la méticilline des S. aureus n’était pas systématiquement prédictible en MHR. Notre étude, qui s’inscrit dans une étude plus globale, montre des résultats très encourageants. L’antibiothérapie peut être adaptée dès le premier jour de positivité de l’hémoculture.
Lors de la réalisation d’un examen cytobactériologique des urines (ECBU), un délai de 48h est requis avant d’obtenir l’identification, la numération de la culture ainsi que l’antibiogramme de la ...bactérie mise en cause lors de l’infection urinaire. Dans le contexte actuel de l’augmentation des bactéries multi-résistantes, le profil de résistance des entérobactéries devient imprévisible, aussi bien en communautaire qu’en milieu hospitalier. Il apparaît donc intéressant de réduire ce délai de 48h à 8h afin d’adapter plus rapidement l’antibiothérapie probabiliste et d’éviter les échecs thérapeutiques.
Cette étude prospective a été réalisée entre août 2016 et janvier 2017. 158 échantillons d’urines ont été sélectionnés sur les critères suivants : franche leucocyturie>50 leucocytes/mm3 et présence de seuls bacilles à Gram négatif à l’examen direct. Les échantillons ont été traités selon deux méthodes : la méthode de référence (48h) consistait à ensemencer une gélose chromogène et réalisation d’un antibiogramme en milieu Mueller Hinton (MH incubé 20h, Biorad). La méthode rapide (8h) consistait à ensemencer directement un antibiogramme en milieu MHR (MH rapide, i2a, incubé 6 à 8h). Un panel de 22 antibiotiques a été testé, les diamètres d’inhibition ont été lus par le système SIRscan 2000 Automatic (i2a) et ont été interprétés selon les recommandations EUCAST 2016. Pour chaque bactérie et chaque antibiotique testés, nous avons comparé la concordance des interprétations entre les deux méthodes : sensible (S), intermédiaire (I) ou résistant (R).
Les 158 souches d’entérobactéries étaient distribuées entre 119 (75 %) Escherichia Coli et 39 (25 %) autres entérobactéries. Sur les 3246 tests réalisés, les résultats montraient 3167 (97,6 %) concordances, 47 (1,4 %) différences mineures (dm), 13 (0,4 %) différences majeures (DM) et 19 (0,6 %) différences très majeures (DTM). Les DTM constatées ont été principalement observées autour de la céfalexine et de la témocilline. Les DM concernaient principalement l’amoxicilline-acide clavulanique en considérant comme diamètres critiques 19–19mm, sans différenciation d’une infection urinaire haute ou basse.
Les résultats de notre étude montrent une bonne corrélation entre les résultats des antibiogrammes obtenus directement à partir de l’urine en milieu MHR et ceux obtenus à partir d’une subculture en milieu MH. Cette technique rapide entraîne un gain de temps important : le délai d’obtention d’un antibiogramme est alors de 8h, contre 48h par rapport à la méthode standard de réalisation d’un ECBU, ce qui permet une adaptation thérapeutique précoce. Cette technique est cependant dépendante d’un inoculum bactérien minimum ainsi que du caractère monomicrobien de l’urine.
The volume sensitive residence time distribution method is ideally suited for the study of liquid water and ice formation within operating proton exchange membrane fuel cells. Sensitivity was ...demonstrated with the use of simulated water drops within the flow field channel (machined obstructions) yielding a linear correlation in the 0–20% volume obstruction range between measured and theoretical hydraulic volumes. The correlation was independent of obstruction spatial distribution but dependent on gas flow rate. Sensitivity was also demonstrated by varying the amount of liquid water within a gas diffusion electrode resulting in a linear correlation in the 7–44% void volume obstruction range between normalized time difference between the points at which the tracer concentration has decayed by 20 and 90% of the steady-state value prior to the tracer injection interruption and measured gas diffusion electrode liquid water content. Sensitivity to liquid water obstructions was maintained using an operating fuel cell and two different gas diffusion media with relatively similar transport properties but further work is needed to separate flow field from gas diffusion electrode contributions. The usefulness of the residence time distribution is also demonstrated for other applications, including gas crossover through the proton exchange membrane, flow distribution uniformity and gas diffusion electrode compressibility/deformation.
New in situ and minimally invasive methods are needed to quantify the presence of liquid water and ice within operating proton exchange membrane fuel cells. A volume sensitive residence time ...distribution technique was developed based on
CO
2
tracer and infrared detection. The method, components and operation are detailed (tracer injection and detection, data scaling, calibration, and pressure correction). The measurement system was characterized by an electronic signal processing response time of 43
ms, accuracy and repeatability better than 0.5–5% error in transit time measurement and sufficient sensitivity to detect less than 10% changes in flow field channel and gas diffusion electrode void volumes. Results obtained with a simplified model fuel cell (single flow field channel, absence and presence of a gas diffusion layer) revealed the presence of two time resolved mechanistic steps for negative tracer step cases (convective tracer removal from flow field channel, diffusive tracer removal from gas diffusion layer). A one-dimensional model was derived using convective diffusion in flow field channels and cross-flow tracer exchange proportional to the concentration difference between flow field channel and gas diffusion electrode. Numerical computations showed good agreement with the model fuel cell experimental results.
Abstract
Funding Acknowledgements
Type of funding sources: None.
Background
Patients with anomalous aortic origin of a coronary artery (AAOCA) present with a wide range of clinical manifestations, ...including ischemic symptoms (chest pain or dyspnea) and sudden cardiac death (SCD). Studies have identified coronary anatomic characteristics associated with a higher risk of SCD. However, most of the published literature consists of studies in adolescents and young adults. There is a paucity of data regarding outcomes in middle-aged patients. Current guidelines reveal gaps in evidence for identification of adults are at risk for SCD, and for whom surgery is beneficial.
Purpose
To study the clinical course and rate of major adverse cardiac events (MACE) in middle-aged adults with AAOCA based on presenting symptoms, coronary anatomy on coronary computed tomography angiography (CCTA), stress test results, and surgical management.
Methods
We included all patients from January 2013 to December 2019 age > 18 at our institution who were found to have AAOCA. Patients with the following were excluded to minimize confounding factors which could cause MACE: coronary artery disease (CAD) with >50% stenosis in any coronary vessel, CAD requiring revascularization, heart failure with ejection fraction <40%, history of heart transplant, and non-AAOCA congenital heart disease. All patient charts were reviewed for demographics, coronary anatomy on CCTA, presenting symptoms, rationale for pursuing stress testing and CCTA, nature of surgical interventions, post-surgical course, and MACE (cardiovascular death, myocardial infarction, and need for coronary revascularization). All patients underwent PET as well as treadmill stress testing.
Results
Of 19,367 patients who underwent CCTA, 47 met inclusion criteria, with median age at diagnosis of 54 and median follow-up of 48 months. No patients suffered MACE. Twenty-five patients had AAORCA and 22 had AAOLCA (Table 1). Ten patients with AAORCA and 8 patients with AAOLCA presented with ischemic symptoms and had coronary anatomy characteristics associated with higher risk of SCD, as well as ischemia corresponding to the anomalous artery on stress testing and did not undergo surgery due to personal preference. Five symptomatic patients with stress-induced ischemia corresponding to the anomalous artery underwent surgery and all achieved symptom relief over a median follow up of 5 years.
Conclusion
As AAOCA is a significant cause of SCD in young adults, it is compelling to observe this adult cohort in which no patients experienced MACE, including 18 symptomatic patients with high-risk anatomy and stress-induced ischemia, as well as a Class I recommendations for surgery. The results suggest that although surgery may be beneficial for symptom relief, it does not necessarily improve mortality over an intermediate follow-up period. Future studies should examine surgical outcomes in middle-aged cohorts with larger sample sizes.
Kratom is an herb indigenous to Southeast Asia with psychoactive opioid compounds, often used as a treatment for chronic pain or opiate withdrawal symptoms. It is legally and readily available via ...Internet sales and has been identified as an emerging drug of abuse in the United States. Kratom use has been associated with psychosis, seizures, and even death. At lower doses, kratom acts as a stimulant, while at higher doses, it produces analgesia and euphoria. Here, we describe the successful management of kratom overdose and withdrawal in a young man with negative toxicology screens.
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