Cost of care pathways before and after appropriate and inappropriate transfers to the emergency department among nursing home residents: results from the FINE study.

BACKGROUND: Transfers of nursing home (NH) residents to the emergency department (ED) is frequent. Our main objective was to assess the cost of care pathways 6 months before and after the transfer to the emergency department among NH residents, according to the type of transfer (i.e. appropriate or inappropriate). METHODS: This was a part of an observational, multicenter, case-control study: the Factors associated with INappropriate transfer to the Emergency department among nursing home residents (FINE) study. Sixteen public hospitals of the former Midi-Pyrénées region participated in recruitment, in 2016. During the inclusion period, all NH residents arriving at the ED were included. A pluri-disciplinary team categorized each transfer to the ED into 2 groups: appropriate or inappropriate. Direct medical and nonmedical costs were assessed from the French Health Insurance (FHI) perspective. Healthcare resources were retrospectively gathered from the FHI database and valued using the tariffs reimbursed by the FHI. Costs were recorded over a 6-month period before and after transfer to the ED. Other variables were used for analysis: sex, age, Charlson score, season, death and presence inside the NH of a coordinating physician or a geriatric nursing assistant. RESULTS: Among the 1037 patients initially included in the FINE study, 616 who were listed in the FHI database were included in this economic study. Among them, 132 (21.4%) had an inappropriate transfer to the ED. In the 6 months before ED transfer, total direct costs on average amounted to 8,145€ vs. 6,493€ in the inappropriate and appropriate transfer groups, respectively. In the 6 months after ED transfer, they amounted on average to 9,050€ vs. 12,094€. CONCLUSIONS: Total costs on average are higher after transfer to the ED, but there is no significant increase in healthcare expenditure with inappropriate ED transfer. Support for NH staff and better pathways of care could be necessary to reduce healthcare expenditures in NH residents. TRIAL REGISTRATION: clinicaltrials.gov, NCT02677272.

CRISPR-Cas tools to study gene function in cytokinesis.

Cytokinesis is the process that separates a cell into two daughter cells at the end of mitosis. Most of our knowledge of cytokinesis comes from overexpression studies, which affects our interpretation of protein function. Gene editing can circumvent this issue by introducing functional mutations or fluorescent probes directly into a gene locus. However, despite its potential, gene editing is just starting to be used in the field of cytokinesis. Here, we discuss the benefits of using gene editing tools for the study of cytokinesis and highlight recent studies that successfully used CRISPR-Cas (clustered regularly interspaced short palindromic repeats-CRISPR-associated proteins) technology to answer critical questions regarding the function of cytokinesis proteins. We also present methodologies for editing essential genes and discuss how CRISPR interference (CRISPRi) and activation (CRISPRa) can enable precise control of gene expression to answer important questions in the field. Finally, we address the need for gene editing to study cytokinesis in more physiologically relevant contexts. Therefore, this Review provides a roadmap for gene editing to be used in the study of cytokinesis and other cellular processes.

Neutrophils and IL-1α Regulate Surfactant Homeostasis during Cigarette Smoking.

Cigarette smoke exposure induces inflammation marked by rapid and sustained neutrophil infiltration, IL-1α, release and altered surfactant homeostasis. However, the extent to which neutrophils and IL-1α contribute to the maintenance of pulmonary surfactant homeostasis is not well understood. We sought to investigate whether neutrophils play a role in surfactant clearance as well as the effect of neutrophil depletion and IL-1α blockade on the response to cigarette smoke exposure. In vitro and in vivo administration of fluorescently labeled surfactant phosphatidylcholine was used to assess internalization of surfactant by lung neutrophils and macrophages during or following cigarette smoke exposure in mice. We also depleted neutrophils using anti-Ly-6G or anti-Gr-1 Abs, or we neutralized IL-1α using a blocking Ab to determine their respective roles in regulating surfactant homeostasis during cigarette smoke exposure. We observed that neutrophils actively internalize labeled surfactant both in vitro and in vivo and that IL-1α is required for smoke-induced elevation of surfactant protein (SP)-A and SP-D levels. Neutrophil depletion during cigarette smoke exposure led to a further increase in SP-A levels in the bronchoalveolar lavage and increased IL-1α, CCL2, GM-CSF, and G-CSF release. Finally, macrophage expression of Mmp12, a protease linked to emphysema, was increased in neutrophil-depleted groups and decreased following IL-1α blockade. Taken together, our results indicate that neutrophils and IL-1α signaling are actively involved in surfactant homeostasis and that the absence of neutrophils in the lungs during cigarette smoke exposure leads to an IL-1α-dependent exacerbation of the inflammatory response.

Recombinant human ß-defensin 2 delivery improves smoking-induced lung neutrophilia and bacterial exacerbation.

Treatment of the cigarette smoke-associated lung diseases, such as chronic obstructive pulmonary disease (COPD), has largely focused on broad-spectrum anti-inflammatory therapies. However, these therapies, such as high-dose inhaled corticosteroids, enhance patient susceptibility to lung infection and exacerbation. Our objective was to assess whether the cationic host defense peptide, human ß-defensin 2 (hBD-2), can simultaneously reduce pulmonary inflammation in cigarette smoke-exposed mice while maintaining immune competence during bacterial exacerbation. Mice were exposed to cigarette smoke acutely (4 days) or chronically (5 days/wk for 7 wk) and administered hBD-2 intranasally or by gavage. In a separate model of acute exacerbation, chronically exposed mice treated with hBD-2 were infected with nontypeable Haemophilus influenzae before euthanasia. In the acute exposure model, cigarette smoke-associated pulmonary neutrophilia was significantly blunted by both local and systemic hBD-2 administration. Similarly, chronically exposed mice administered hBD-2 therapeutically exhibited reduced pulmonary neutrophil infiltration and downregulated proinflammatory signaling in the lungs compared with vehicle-treated mice. Finally, in a model of acute bacterial exacerbation, hBD-2 administration effectively limited neutrophil infiltration in the lungs while markedly reducing pulmonary bacterial load. This study shows that hBD-2 treatment can significantly attenuate lung neutrophilia induced by cigarette smoke exposure while preserving immune competence and promoting an appropriate host-defense response to bacterial stimuli.

Co-modulation of T cells and B cells enhances the inhibition of inflammation in experimental hypersensitivity pneumonitis.

BACKGROUND: Hypersensitivity pneumonitis (HP) is an interstitial lung disease characterized by antigen-triggered neutrophilic exacerbations. Although CD4+ T cells are sufficient for HP pathogenesis, this never translated into efficient T cell-specific therapies. Increasing evidence shows that B cells also play decisive roles in HP. Here, we aimed to further define the respective contributions of B and T cells in subacute experimental HP. METHODS: Mice were subjected to a protocol of subacute exposure to the archaeon Methanosphaera stadmanae to induce experimental HP. Using models of adoptive transfers of B cells and T cells in Rag1-deficient mice and of B cell-specific S1P1 deletion, we assessed the importance of B cells in the development of HP by evaluating inflammation in bronchoalveolar lavage fluid. We also aimed to determine if injected antibodies targeting B and/or T cells could alleviate HP exacerbations using a therapeutic course of intervention. RESULTS: Even though B cells are not sufficient to induce HP, they strongly potentiate CD4+ T cell-induced HP­associated neutrophilic inflammation in the airways. However, the reduction of 85% of lung B cells in mice with a CD19-driven S1P1 deletion does not dampen HP inflammation, suggesting that lung B cells are not necessary in large numbers to sustain local inflammation. Finally, we found that injecting antibodies targeting B cells after experimental HP was induced does not dampen neutrophilic exacerbation. Yet, injection of antibodies directed against B cells and T cells yielded a potent 76% inhibition of neutrophilic accumulation in the lungs. This inhibition occurred despite partial, sometimes mild, depletion of B cells and T cells subsets. CONCLUSIONS: Although B cells are required for maximal inflammation in subacute experimental HP, partial reduction of B cells fails to reduce HP-associated inflammation by itself. However, co-modulation of T cells and B cells yields enhanced inhibition of HP exacerbation caused by an antigenic rechallenge.

HER2 testing in metastatic breast cancer - Is reflex ISH testing necessary on HER2 IHC-equivocal (2+) cases?

Current guidelines recommend HER2 testing on all primary invasive breast cancers and re-biopsy at disease relapse. The discordance rate between HER2-negative primaries and HER2 IHC2+ metastases that are ISH-amplified is unknown. We hypothesize that the majority of such cases are non-amplified. ISH testing is time-consuming and resource-intensive, and there may be situations where it is unnecessary. A retrospective review of IHC2+ metastatic lesions assessed with ISH at our center from 2013 to 2021 was undertaken. 105 cases were identified after exclusion of cases missing HER2 results, with primaries of unconfirmed origin, and cases of synchronous primary and metastatic disease. IHC and ISH results were recorded with detailed slide review of discordant cases. 91/105 metastases had HER2-negative primaries (87%). A metastasis was significantly more likely to be HER2-negative when the primary was HER2-negative (93%) versus positive (43%) (p < 0.0001). 54/91 primaries were IHC2+/ISH-non-amplified, and 50/54 (93%) corresponding metastases had identical results. Of the 37 HER2-negative primaries that were IHC0/1+, 35 (95%) corresponding metastases were ISH-non-amplified. Six metastases in cases with HER2-negative primaries were discordant. Characteristics of metastases suggesting ISH testing was warranted to assess for discordance included IHC heterogeneity, morphological discordance, increased staining of moderate intensity, and ER/PR discordance. One or more of these factors were present in all discordant metastases. Our results suggest selective ISH testing on HER2 IHC2+ breast cancer metastases in the context of HER2-negative primary disease may be appropriate when there is careful review of the IHC. Validation of our findings awaits further studies with larger sample sizes.

Adnexectomy by vaginal Natural Orifice Transluminal Endoscopic Surgery versus laparoscopy: results of a first randomised controlled trial (NOTABLE trial).

OBJECTIVE: To compare adnexectomy by vaginal Natural Orifice Transluminal Endoscopic Surgery (vNOTES) versus laparoscopy. DESIGN: Parallel group, 1:1 single-centre single-blinded randomised trial, designed as non-inferiority study with a margin of 15%. SETTING: Belgian teaching hospital. POPULATION: Non-pregnant non-virgin women with an intact uterus and without obliteration of the pouch of Douglas scheduled to undergo removal of an adnexal mass assessed to be benign on ultrasound by IOTA criteria. METHODS: Randomisation to laparoscopy (control group) or vNOTES (experimental group). Stratification according to adnexal size. Blinding of participants and outcome assessors by sham incisions. MAIN OUTCOME MEASURES: The primary outcome measure was adnexectomy by the allocated technique. Secondary outcomes included duration of surgery, pain scores and analgesics used, quality of life and adverse events. RESULTS: We randomly assigned 67 participants (34 to the vNOTES group and 33 to the laparoscopy group). The primary end point was always reached in both groups: there were no conversions. We performed a sensitivity analysis for the primary outcome, assuming one conversion in the vNOTES group and no conversions in the laparoscopy group: the one-sided 95% upper limit for the differences in proportions of conversion was estimated as 13%, which is below the predefined non-inferiority margin of 15%. The secondary outcomes demonstrated a shorter duration of surgery, lower pain scores, lower total dose of analgesics and a trend for more adverse events in the vNOTES group. CONCLUSIONS: vNOTES is non-inferior to laparoscopy for a successful adnexectomy without conversion. vNOTES allowed shorter operating times and less postoperative pain but there was a trend for more adverse events.

Increased mast cell density is associated with decreased fibrosis in human atrial tissue.

Fibrotic remodelling of the atria is poorly understood and can be regulated by myocardial immune cell populations after injury. Mast cells are resident immune sentinel cells present in the heart that respond to tissue damage and have been linked to fibrosis in other settings. The role of cardiac mast cells in fibrotic remodelling in response to human myocardial injury is controversial. In this study, we sought to determine the association between mast cells, atrial fibrosis, and outcomes in a heterogeneous population of cardiac surgical patients, including a substantial proportion of coronary artery bypass grafting patients. Atrial appendage from patients was assessed for collagen and mast cell density by histology and by droplet digital polymerase chain reaction (ddPCR) for mast cell associated transcripts. Clinical variables and outcomes were also followed. Mast cells were detected in human atrial tissue at varying densities. Histological and ddPCR assessment of mast cells in atrial tissue were closely correlated. Patients with high mast cell density had less fibrosis and lower severity of heart failure classification or incidence mortality than patients with low mast cell content. Analysis of a homogeneous population of coronary artery bypass graft patients yielded similar observations. Therefore, evidence from this study suggests that increased atrial mast cell populations are associated with decreased clinical cardiac fibrotic remodelling and improved outcomes, in cardiac surgery patients.

S1P1 Contributes to Endotoxin-enhanced B-Cell Functions Involved in Hypersensitivity Pneumonitis.

In a proportion of patients with hypersensitivity pneumonitis, the biological and environmental factors that sustain inflammation are ill defined, resulting in no effective treatment option. Bioaerosols found in occupational settings are complex and often include Toll-like receptor ligands, such as endotoxins. How Toll-like receptor ligands contribute to the persistence of hypersensitivity pneumonitis, however, remains poorly understood. In a previous study, we found that an S1P1 (sphingosine-1-phosphate receptor 1) agonist prevented the reactivation of antigen-driven B-cell responses in the lung. Here, we assessed the impact of endotoxins on B-cell activation in preexisting hypersensitivity pneumonitis and the role of S1P1 in this phenomenon. The impact of endotoxins on pre-established hypersensitivity pneumonitis was studied in vivo. S1P1 levels were tracked on B cells in the course of the disease using S1P1-eGFP knockin mice, and the role of S1P1 on B-cell functions was assessed using pharmacological tools. S1P1 was found on B cells in experimental hypersensitivity pneumonitis. Endotoxin exposure enhanced neutrophil accumulation in the BAL of mice with experimental hypersensitivity pneumonitis. This was associated with enhanced CD69 cell-surface expression on lymphocytes in the BAL. In isolated B cells, endotoxins increased cell-surface levels of costimulatory molecules and CD69, which was prevented by an S1P1 agonist. S1P1 modulators also reduced TNF production by B cells and their capacity to trigger T-cell cooperation ex vivo. An S1P1 ligand directly inhibited endotoxin-induced B-cell activation.

Exposure to nicotine-free and flavor-free e-cigarette vapors modifies the pulmonary response to tobacco cigarette smoke in female mice.

Most of electronic cigarette (e-cigarette) users are also smoking tobacco cigarettes. Because of the relative novelty of this habit, very little is known on the impact of vaping on pulmonary health, even less on the potential interactions of dual e-cigarette and tobacco cigarette use. Therefore, we used well-established mouse models to investigate the impact of dual exposure to e-cigarette vapors and tobacco cigarette smoke on lung homeostasis. Groups of female BALB/c mice were exposed to room air, tobacco smoke only, nicotine-free flavor-free e-cigarette vapors only or both tobacco smoke and e-cigarette vapors. Moreover, since tobacco smoke and electronic cigarette vapors both affect circadian processes in the lungs, groups of mice were euthanized at two different time points during the day. We found that dual-exposed mice had altered lung circadian gene expression compared with mice exposed to tobacco smoke alone. Dual-exposed mice also had different frequencies of dendritic cells, macrophages, and neutrophils in the lung tissue compared with mice exposed to tobacco smoke alone, an observation also valid for B-lymphocytes and CD4+ and CD8+ T lymphocytes. Exposure to e-cigarette vapors also impacted the levels of immunoglobulins in the bronchoalveolar lavage and serum. Finally, e-cigarette and dual exposures increased airway resistance compared with mice exposed to room air or tobacco smoke alone, respectively. Taken together, these data suggest that e-cigarette vapors, even without nicotine or flavors, could affect how the lungs react to tobacco cigarette smoke exposure in dual users, potentially altering the pathological course triggered by smoking.

Critical importance of dietary methionine and choline in the maintenance of lung homeostasis during normal and cigarette smoke exposure conditions.

Genetic predispositions and environmental exposures are regarded as the main predictors of respiratory disease development. Although the impact of dietary essential nutrient deficiencies on cardiovascular disease, obesity, and type II diabetes has been widely studied, it remains poorly explored in chronic respiratory diseases. Dietary choline and methionine deficiencies are common in the population, and their impact on pulmonary homeostasis is currently unknown. Mice were fed choline- and/or methionine-deficient diets while being exposed to room-air or cigarette smoke for up to 4 wk. Lung functions were assessed using the FlexiVent. Pulmonary transcriptional activity was assessed using gene expression microarrays and quantitative PCR. Immune cells, cytokines, and phosphatidylcholine were quantified in the bronchoalveolar lavage. In this study, we found that short-term dietary choline and/or methionine deficiencies significantly affect lung function in mice in a reversible manner. It also reduced transcriptional levels of collagens and elastin as well as pulmonary surfactant phosphatidylcholine levels. We also found that dietary choline and/or methionine deficiencies markedly interfered with the pulmonary response to cigarette smoke exposure, modulating lung function and dampening inflammation. These findings clearly show that dietary choline and/or methionine deficiencies can have dramatic pathophysiological effects on the lungs and can also affect the pathobiology of cigarette smoke-induced pulmonary alterations. Expanding our knowledge in the field of "nutri-respiratory research" may reveal a crucial role for essential nutrients in pulmonary health and disease, which may prove to be as relevant as genetic predispositions and environmental exposures.

Sildenafil Prevents Marfan-Associated Emphysema and Early Pulmonary Artery Dilation in Mice.

Marfan syndrome (MFS) is a connective tissue disorder caused by mutations in fibrillin-1 (Fbn1). Although aortic rupture is the major cause of mortality in MFS, patients also experience pulmonary complications, which are poorly understood. Loss of basal nitric oxide (NO) production and vascular integrity has been implicated in MFS aortic root disease, yet their contribution to lung complications remains unknown. Because of its capacity to potentiate the vasodilatory NO/cyclic guanylate monophosphate signaling pathway, we assessed whether the phosphodiesterase-5 inhibitor, sildenafil (SIL), could attenuate aortic root remodeling and emphysema in a mouse model of MFS. Despite increasing NO-dependent vasodilation, SIL unexpectedly elevated mean arterial blood pressure, failed to inhibit MFS aortic root dilation, and exacerbated elastic fiber fragmentation. In the lung, early pulmonary artery dilation observed in untreated MFS mice was delayed by SIL treatment, and the severe emphysema-like alveolar destruction was prevented. In addition, improvements in select parameters of lung function were documented. Subsequent microarray analyses showed changes to gene signatures involved in the inflammatory response in the MFS lung treated with SIL, without significant down-regulation of connective tissue or transforming growth factor-ß signaling genes. Because phosphodiesterase-5 inhibition leads to improved lung histopathology and function, the effects of SIL against emphysema warrant further investigation in the settings of MFS despite limited efficacy on aortic root remodeling.

Are newer insulin analogues better for people with Type 1 diabetes?

Achieving optimal blood glucose control in Type 1 diabetes is a delicate balance between ensuring tight glycaemic control and achieving this without the expense of hypoglycaemia and weight gain, two major factors impacting quality of life. This is a real challenge for people with Type 1 diabetes and underpins many of the struggles they face in self-managing on a day-to-day basis. The main goals of insulin delivery are to try to simulate the physiology of ß-cell insulin secretion as closely as possible and to overcome the challenges of peripheral insulin administration by achieving rapidity of onset with mealtime insulins and stability of the glucose-lowering effects of long-acting insulins. Since the early days of human insulin use, there have been many developments in insulin formulations that aim to achieve these goals as much as possible, thus contributing to better glycaemic control whilst minimizing hypoglycaemia. In the present review we discuss the currently available insulin analogues and the challenges of achieving glucose control using current analogues in those on multiple daily injections, and appraise the evidence base for newer-generation insulin analogues, such as insulin degludec, glargine U300, faster-acting insulin aspart and BioChaperone lispro. We also highlight new insulins in development and unmet needs in people with Type 1 diabetes.

How GDPR Enhances Transparency and Fosters Pseudonymisation in Academic Medical Research.

The European General Data Protection Regulation (GDPR) has dotted the i's and crossed the t's in the context of academic medical research. One year into GDPR, it is clear that a change of mind and the uptake of new procedures is required. Research organisations have been looking at the possibility to establish a code-of-conduct, good practices and/or guidelines for researchers that translate GDPR's abstract principles to concrete measures suitable for implementation. We introduce a proposal for the implementation of GDPR in the context of academic research which involves the processing of health related data, as developed by a multidisciplinary team at the University Hospitals Leuven. The proposal is based on three elements, three stages and six specific safeguards. Transparency and pseudonymisation are considered key to find a balance between the need for researchers to collect and analyse personal data and the increasing wish of data subjects for informational control.

Pharmacological activation of liver X receptor during cigarette smoke exposure adversely affects alveolar macrophages and pulmonary surfactant homeostasis.

Smoking alters pulmonary reverse lipid transport and leads to intracellular lipid accumulation in alveolar macrophages. We investigated whether stimulating reverse lipid transport with an agonist of the liver X receptor (LXR) would help alveolar macrophages limit lipid accumulation and dampen lung inflammation in response to cigarette smoke. Mice were exposed to cigarette smoke and treated intraperitoneally with the LXR agonist T0901317. Expression of lipid capture and lipid export genes was assessed in lung tissue and alveolar macrophages. Pulmonary inflammation was assessed in the bronchoalveolar lavage (BAL). Finally, cholesterol efflux capacity and pulmonary surfactant levels were determined. In room air-exposed mice, T0901317 increased the expression of lipid export genes in macrophages and the whole lung and increased cholesterol efflux capacity without inducing inflammation or affecting the pulmonary surfactant. However, cigarette smoke-exposed mice treated with T0901317 showed a marked increase in BAL neutrophils, IL-1α, C-C motif chemokine ligand 2, and granulocyte-colony-stimulating factor levels. T0901317 treatment in cigarette smoke-exposed mice failed to increase the ability of alveolar macrophages to export cholesterol and markedly exacerbated IL-1α release. Finally, T0901317 led to pulmonary surfactant depletion only in cigarette smoke-exposed mice. This study shows that hyperactivation of LXR and the associated lipid capture/export mechanisms only have minor pulmonary effects on the normal lung. However, in the context of cigarette smoke exposure, where the pulmonary surfactant is constantly oxidized, hyperactivation of LXR has dramatic adverse effects, once again showing the central role of lipid homeostasis in the pulmonary response to cigarette smoke exposure.

Integration of World-to-Chip Interfaces with Digital Microfluidics for Bacterial Transformation and Enzymatic Assays.

Digital microfluidics (DMF) represents an alternative to the conventional microfluidic paradigm of transporting fluids in enclosed channels. One of the major benefits of DMF is that fluid motion and control is achieved without external pumps. The automation component of DMF have pushed the barriers of this "lab-on-chip" technology. However, integration with external components (i.e., "world-to-chip") interfaces have been a challenge. Two common "world-to-chip" challenges are (1) delivering biological samples to DMF devices and (2) accurately controlling temperatures on device. To address these challenges, this work describes two "world-to-chip" interface features that have been integrated on a DMF platform: a reagent delivery system and a thermal control apparatus. This platform enables a variety of biological or chemical experiments to be conducted on-chip while reducing manual intervention. Specifically, our platform increases reagent volumes available to device reservoirs volume by at least 50-fold eliminating the need to manually refill reservoirs while improving droplet dispensing reproducibility. In addition, we have integrated a closed-loop temperature control system that offers precise temperature control on-chip. To validate our "world-to-chip" interface, we have automated bacterial transformation and enzymatic assay protocols, showing that such a system enhances DMF performance. Overall, we propose that this system will improve biological experimentation which requires fluidic and temperature control integrated on DMF platforms.

Evidence for the Regulation of Gynoecium Morphogenesis by ETTIN via Cell Wall Dynamics.

ETTIN (ETT) is an atypical member of the AUXIN RESPONSE FACTOR family of transcription factors that plays a crucial role in tissue patterning in the Arabidopsis (Arabidopsis thaliana) gynoecium. Though recent insights have provided valuable information on ETT's interactions with other components of auxin signaling, the biophysical mechanisms linking ETT to its ultimate effects on gynoecium morphology were until now unknown. Here, using techniques to assess cell-wall dynamics during gynoecium growth and development, we provide a coherent body of evidence to support a model in which ETT controls the elongation of the valve tissues of the gynoecium through the positive regulation of pectin methylesterase (PME) activity in the cell wall. This increase in PME activity results in an increase in the level of demethylesterified pectins and a consequent reduction in cell wall stiffness, leading to elongation of the valves. Though similar biophysical mechanisms have been shown to act in the stem apical meristem, leading to the expansion of organ primordia, our findings demonstrate that regulation of cell wall stiffness through the covalent modification of pectin also contributes to tissue patterning within a developing plant organ.

CD34 regulates the skeletal muscle response to hypoxia.

Chronic obstructive pulmonary disease (COPD) can sometimes be associated with skeletal muscle atrophy. Hypoxemic episodes, which occur during disease exacerbation and daily physical activity, are frequent in COPD patients. However, the link between hypoxemia and muscle atrophy remains unclear, along with mechanisms of muscle hypoxic stress response. Myogenic progenitors (MPs) and fibro/adipogenic progenitors (FAPs) express CD34 and participate to muscle mass maintenance. Although there is evidence linking CD34 expression and muscle repair, the link between CD34 expression, muscle wasting and the hypoxic stress observed in COPD has never been studied. Using a 2-day model of exposure to hypoxic conditions, we investigated the impact of hypoxia on skeletal muscle wasting and function, and elucidated the importance of CD34 expression in that response. A 2-day exposure to hypoxic conditions induces muscle atrophy, which was significantly worse in Cd34-/- mice compared to wild type (WT). Moreover, the lack of CD34 expression negatively impacts the maximal strength of the extensor digitorum longus muscle in response to hypoxia. Following exposure to hypoxic conditions, FAPs (which support MPs differentiation and myogenesis) are significantly lower in Cd34-/- mice compared to WT animals while the expression of myogenic regulatory factors and degradation factors (Atrogin) are similar. CD34 expression is important in the maintenance of muscle mass and function in response to hypoxic stress. These results highlight a new potential role for CD34 in muscle mass maintenance in hypoxic stress such as observed in COPD.

Hysterectomy by transvaginal natural orifice transluminal endoscopic surgery versus laparoscopy as a day-care procedure: a randomised controlled trial.

OBJECTIVE: To compare hysterectomy by transvaginal natural orifice transluminal endoscopic surgery (vNOTES) versus total laparoscopic hysterectomy (TLH) as a day-care procedure. DESIGN: Parallel group, 1:1 randomised single-centre single-blinded trial, designed as a non-inferiority study with a margin of 15%. SETTING: Belgian teaching hospital. POPULATION: Women aged 18-70 years scheduled to undergo hysterectomy for benign indications. METHODS: Randomisation to TLH (control group) or vNOTES (experimental group). Stratification according to uterine volume. Blinding of participants and outcome assessors. MAIN OUTCOME MEASURES: The primary outcome was hysterectomy by the allocated technique. We measured the proportion of women leaving within 12 hours after hysterectomy and the length of hospital stay as secondary outcomes. RESULTS: We randomly assigned 70 women to vNOTES (n = 35) or TLH (n = 35). The primary endpoint was always reached in both groups: there were no conversions. We performed a sensitivity analysis for the primary outcome, assuming one conversion in the vNOTES group and no conversions in the TLH group: the one-sided 95% upper limit for the differences in proportions of conversion was estimated as 7.5%, which is below the predefined non-inferiority margin. More women left the hospital within 12 hours after surgery after vNOTES: 77 versus 43%, difference 34% (95% CI 13-56%), P = 0.007. The hospital stay was shorter after vNOTES: 0.8 versus 1.3 days, mean difference -0.5 days, (95% CI -0.98 to -0.02), P = 0.004. CONCLUSIONS: vNOTES is non-inferior to TLH for successfully performing hysterectomy without conversion. Compared with TLH, vNOTES may allow more women to be treated in a day-care setting. TWEETABLE ABSTRACT: RCT: vNOTES is just as good as laparoscopy for successful hysterectomy without conversion but allows more day-care surgery.