Functional Implication of Dp71 in Osmoregulation and Vascular Permeability of the Retina

Functional alterations of Müller cells, the principal glia of the retina, are an early hallmark of most retina diseases and contribute to their further progression. The molecular mechanisms of these reactive Müller cell alterations, resulting in disturbed retinal homeostasis, remain largely unknown. Here we show that experimental detachment of mouse retina induces mislocation of the inwardly rectifying potassium channels (Kir4.1) and a downregulation of the water channel protein (AQP4) in Müller cells. These alterations are associated with a strong decrease of Dp71, a cytoskeleton protein responsible for the localization and the clustering of Kir4.1 and AQP4. Partial (in detached retinas) or total depletion of Dp71 in Müller cells (in Dp71-null mice) impairs the capability of volume regulation of Müller cells under osmotic stress. The abnormal swelling of Müller cells In Dp71-null mice involves the action of inflammatory mediators. Moreover, we investigated whether the alterations in Müller cells of Dp71-null mice may interfere with their regulatory effect on the blood-retina barrier. In the absence of Dp71, the retinal vascular permeability was increased as compared to the controls. Our results reveal that Dp71 is crucially implicated in the maintenance of potassium homeostasis, in transmembraneous water transport, and in the Müller cell-mediated regulation of retinal vascular permeability. Furthermore, our data provide novel insights into the mechanisms of retinal homeostasis provided by Müller cells under normal and pathological conditions

3 years of liraglutide versus placebo for type 2 diabetes risk reduction and weight management in individuals with prediabetes: a randomised, double-blind trial

Background: Liraglutide 3·0 mg was shown to reduce bodyweight and improve glucose metabolism after the 56-week period of this trial, one of four trials in the SCALE programme. In the 3-year assessment of the SCALE Obesity and Prediabetes trial we aimed to evaluate the proportion of individuals with prediabetes who were diagnosed with type 2 diabetes. Methods: In this randomised, double-blind, placebo-controlled trial, adults with prediabetes and a body-mass index of at least 30 kg/m2, or at least 27 kg/m2 with comorbidities, were randomised 2:1, using a telephone or web-based system, to once-daily subcutaneous liraglutide 3·0 mg or matched placebo, as an adjunct to a reduced-calorie diet and increased physical activity. Time to diabetes onset by 160 weeks was the primary outcome, evaluated in all randomised treated individuals with at least one post-baseline assessment. The trial was conducted at 191 clinical research sites in 27 countries and is registered with ClinicalTrials.gov, number NCT01272219. Findings: The study ran between June 1, 2011, and March 2, 2015. We randomly assigned 2254 patients to receive liraglutide (n=1505) or placebo (n=749). 1128 (50%) participants completed the study up to week 160, after withdrawal of 714 (47%) participants in the liraglutide group and 412 (55%) participants in the placebo group. By week 160, 26 (2%) of 1472 individuals in the liraglutide group versus 46 (6%) of 738 in the placebo group were diagnosed with diabetes while on treatment. The mean time from randomisation to diagnosis was 99 (SD 47) weeks for the 26 individuals in the liraglutide group versus 87 (47) weeks for the 46 individuals in the placebo group. Taking the different diagnosis frequencies between the treatment groups into account, the time to onset of diabetes over 160 weeks among all randomised individuals was 2·7 times longer with liraglutide than with placebo (95% CI 1·9 to 3·9, p<0·0001), corresponding with a hazard ratio of 0·21 (95% CI 0·13–0·34). Liraglutide induced greater weight loss than placebo at week 160 (–6·1 [SD 7·3] vs −1·9% [6·3]; estimated treatment difference −4·3%, 95% CI −4·9 to −3·7, p<0·0001). Serious adverse events were reported by 227 (15%) of 1501 randomised treated individuals in the liraglutide group versus 96 (13%) of 747 individuals in the placebo group. Interpretation: In this trial, we provide results for 3 years of treatment, with the limitation that withdrawn individuals were not followed up after discontinuation. Liraglutide 3·0 mg might provide health benefits in terms of reduced risk of diabetes in individuals with obesity and prediabetes. Funding: Novo Nordisk, Denmark

withdrawn 2017 hrs ehra ecas aphrs solaece expert consensus statement on catheter and surgical ablation of atrial fibrillation

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Geoeconomic variations in epidemiology, ventilation management, and outcomes in invasively ventilated intensive care unit patients without acute respiratory distress syndrome: a pooled analysis of four observational studies

Background: Geoeconomic variations in epidemiology, the practice of ventilation, and outcome in invasively ventilated intensive care unit (ICU) patients without acute respiratory distress syndrome (ARDS) remain unexplored. In this analysis we aim to address these gaps using individual patient data of four large observational studies. Methods: In this pooled analysis we harmonised individual patient data from the ERICC, LUNG SAFE, PRoVENT, and PRoVENT-iMiC prospective observational studies, which were conducted from June, 2011, to December, 2018, in 534 ICUs in 54 countries. We used the 2016 World Bank classification to define two geoeconomic regions: middle-income countries (MICs) and high-income countries (HICs). ARDS was defined according to the Berlin criteria. Descriptive statistics were used to compare patients in MICs versus HICs. The primary outcome was the use of low tidal volume ventilation (LTVV) for the first 3 days of mechanical ventilation. Secondary outcomes were key ventilation parameters (tidal volume size, positive end-expiratory pressure, fraction of inspired oxygen, peak pressure, plateau pressure, driving pressure, and respiratory rate), patient characteristics, the risk for and actual development of acute respiratory distress syndrome after the first day of ventilation, duration of ventilation, ICU length of stay, and ICU mortality. Findings: Of the 7608 patients included in the original studies, this analysis included 3852 patients without ARDS, of whom 2345 were from MICs and 1507 were from HICs. Patients in MICs were younger, shorter and with a slightly lower body-mass index, more often had diabetes and active cancer, but less often chronic obstructive pulmonary disease and heart failure than patients from HICs. Sequential organ failure assessment scores were similar in MICs and HICs. Use of LTVV in MICs and HICs was comparable (42\ub74% vs 44\ub72%; absolute difference \u20131\ub769 [\u20139\ub758 to 6\ub711] p=0\ub767; data available in 3174 [82%] of 3852 patients). The median applied positive end expiratory pressure was lower in MICs than in HICs (5 [IQR 5\u20138] vs 6 [5\u20138] cm H2O; p=0\ub70011). ICU mortality was higher in MICs than in HICs (30\ub75% vs 19\ub79%; p=0\ub70004; adjusted effect 16\ub741% [95% CI 9\ub752\u201323\ub752]; p<0\ub70001) and was inversely associated with gross domestic product (adjusted odds ratio for a US$10 000 increase per capita 0\ub780 [95% CI 0\ub775\u20130\ub786]; p<0\ub70001). Interpretation: Despite similar disease severity and ventilation management, ICU mortality in patients without ARDS is higher in MICs than in HICs, with a strong association with country-level economic status. Funding: No funding

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

High frequency stimulation of normal and blind mouse retinas using TiO2 nanotubes

International audienceWith three models in commercial use, artificial retinas are the most concrete hope to restore sight to blind patients, notably those affected with retinitis pigmentosa. However, present architectures are costly to produce, while the restored visual acuity remains below the legal threshold for blindness. Furthermore, the complexity of current systems with tethered application‐specific integrated circuits (asics) requires complex surgeries, with risks of complications and failures. In the search for new nanomaterials, it is demonstrated that, when placed in contact with photoreceptors (control mouse retinas) or directly with bipolar cells (rhodopsinP23H mouse retinas, a model of retinitis pigmentosa), films of vertically aligned anatase titanium dioxide (TiO2) nanotubes can drive the activity of the retinal network for stimulation frequencies up to the video rate (25 Hz), in response to short (5–20 ms), small (50–100 µm) light spots. Acting as continuous arrays of electrodes, these films should allow a fine tuning of prosthetic stimulations, through modulation of the spot size, duration, and precise localization over the implant surface

Discussion concernant le projet de décret, proposé par Petit, qui concerne aussi la publication de l'état de fortune de chaque représentant, en annexe de la séance du 28 fructidor an II (14 septembre 1794)

Pelet Jean, Petit Edme Michel, Cambon Pierre-Joseph, Roux Louis Félix, Pénières-Delzors Jean Augustin, Bourdon François-Louis, Legendre Louis, Girot de Pouzol Jean-Baptiste. Discussion concernant le projet de décret, proposé par Petit, qui concerne aussi la publication de l'état de fortune de chaque représentant, en annexe de la séance du 28 fructidor an II (14 septembre 1794). In: Archives Parlementaires de 1787 à 1860 - Première série (1787-1799) Tome XCVII - Du 23 fructidor an II au 2 vendémiaire an III (9 au 23 septembre 1794) Paris : CNRS éditions, 1993. pp. 176-178

Discussion concernant le projet de décret, proposé par Petit, qui concerne aussi la publication de l'état de fortune de chaque représentant, en annexe de la séance du 28 fructidor an II (14 septembre 1794)

Pelet Jean, Petit Edme-Michel, Cambon Pierre-Joseph, Roux (de la Haute-Marne), Pénières, Bourdon (de l'Oise) François-Louis, Legendre (de Paris) Louis, Girot de Pouzol Jean-Baptiste. Discussion concernant le projet de décret, proposé par Petit, qui concerne aussi la publication de l'état de fortune de chaque représentant, en annexe de la séance du 28 fructidor an II (14 septembre 1794). In: Archives Parlementaires de 1787 à 1860 - Première série (1787-1799) Tome XCVII - Du 23 fructidor an II au 2 vendémiaire an III (9 au 23 septembre 1794) Paris : CNRS éditions, 1993. pp. 176-178

Syndrome ischémique distal sévère après injection intra-artérielle volontaire de buprénorphine

La buprénorphine haut dosage (BHD) est un traitement de substitution de la dépendance aux opiacés (TSO) sublingual aux bénéfices sanitaires démontrés, mais aussi connu pour être fréquemment dévié, notamment par voie intraveineuse, avec des conséquences délétères. L’usage intra-artériel est beaucoup plus rarement décrit avec cette substance, tout comme le traitement de ses complications essentiellement ischémiques, allant parfois jusqu’à la nécrose. Nous rapportons ici un cas de ce type, chez un homme de 30 ans s’étant injecté dans l’artère radiale droite une solution de comprimés écrasés de BHD, et présentant quelques heures plus tard une ischémie sévère du pouce, de l’index et du majeur. Un traitement à la fois chirurgical (sympathectomie thoracique par vidéo-thoracoscopie) et médicamenteux (héparine, iloprost et piribédil mésilate) a permis une récupération digitale quasi complète (persistance d’une nécrose de la pulpe de l’index ayant nécessité une amputation distale) et un retour à domicile après 2 semaines d’hospitalisation