ABSTRACT
BACKGROUND: It is unknown whether decompressive craniectomy improves clinical outcome for people with spontaneous severe deep intracerebral haemorrhage. The SWITCH trial aimed to assess whether decompressive craniectomy plus best medical treatment in these patients improves outcome at 6 months compared to best medical treatment alone. METHODS: In this multicentre, randomised, open-label, assessor-blinded trial conducted in 42 stroke centres in Austria, Belgium, Finland, France, Germany, the Netherlands, Spain, Sweden, and Switzerland, adults (18-75 years) with a severe intracerebral haemorrhage involving the basal ganglia or thalamus were randomly assigned to receive either decompressive craniectomy plus best medical treatment or best medical treatment alone. The primary outcome was a score of 5-6 on the modified Rankin Scale (mRS) at 180 days, analysed in the intention-to-treat population. This trial is registered with ClincalTrials.gov, NCT02258919, and is completed. FINDINGS: SWITCH had to be stopped early due to lack of funding. Between Oct 6, 2014, and April 4, 2023, 201 individuals were randomly assigned and 197 gave delayed informed consent (96 decompressive craniectomy plus best medical treatment, 101 best medical treatment). 63 (32%) were women and 134 (68%) men, the median age was 61 years (IQR 51-68), and the median haematoma volume 57 mL (IQR 44-74). 42 (44%) of 95 participants assigned to decompressive craniectomy plus best medical treatment and 55 (58%) assigned to best medical treatment alone had an mRS of 5-6 at 180 days (adjusted risk ratio [aRR] 0·77, 95% CI 0·59 to 1·01, adjusted risk difference [aRD] -13%, 95% CI -26 to 0, p=0·057). In the per-protocol analysis, 36 (47%) of 77 participants in the decompressive craniectomy plus best medical treatment group and 44 (60%) of 73 in the best medical treatment alone group had an mRS of 5-6 (aRR 0·76, 95% CI 0·58 to 1·00, aRD -15%, 95% CI -28 to 0). Severe adverse events occurred in 42 (41%) of 103 participants receiving decompressive craniectomy plus best medical treatment and 41 (44%) of 94 receiving best medical treatment. INTERPRETATION: SWITCH provides weak evidence that decompressive craniectomy plus best medical treatment might be superior to best medical treatment alone in people with severe deep intracerebral haemorrhage. The results do not apply to intracerebral haemorrhage in other locations, and survival is associated with severe disability in both groups. FUNDING: Swiss National Science Foundation, Swiss Heart Foundation, Inselspital Stiftung, and Boehringer Ingelheim.
Subject(s)
Cerebral Hemorrhage , Decompressive Craniectomy , Humans , Middle Aged , Male , Decompressive Craniectomy/methods , Female , Cerebral Hemorrhage/surgery , Aged , Adult , Treatment Outcome , Combined Modality TherapyABSTRACT
BACKGROUND: In vitro systems of primary cystic fibrosis (CF) airway epithelial cells are an important tool to study molecular and functional features of the native respiratory epithelium. However, undifferentiated CF airway cell cultures grown under submerged conditions do not appropriately represent the physiological situation. A more advanced CF cell culture system based on airway epithelial cells grown at the air-liquid interface (ALI) recapitulates most of the in vivo-like properties but requires the use of invasive sampling methods. In this study, we describe a detailed characterization of fully differentiated primary CF airway epithelial cells obtained by non-invasive nasal brushing of pediatric patients. METHODS: Differentiated cell cultures were evaluated with immunolabelling of markers for ciliated, mucus-secreting and basal cells, and tight junction and CFTR proteins. Epithelial morphology and ultrastructure was examined by histology and transmission electron microscopy. Ciliary beat frequency was investigated by a video-microscopy approach and trans-epithelial electrical resistance was assessed with an epithelial Volt-Ohm meter system. Finally, epithelial permeability was analysed by using a cell layer integrity test and baseline cytokine levels where measured by an enzyme-linked immunosorbent assay. RESULTS: Pediatric CF nasal cultures grown at the ALI showed a differentiation into a pseudostratified epithelium with a mucociliary phenotype. Also, immunofluorescence analysis revealed the presence of ciliated, mucus-secreting and basal cells and tight junctions. CFTR protein expression was observed in CF (F508del/F508del) and healthy cultures and baseline interleukin (IL)-8 and IL-6 release were similar in control and CF ALI cultures. The ciliary beat frequency was 9.67 Hz and the differentiated pediatric CF epithelium was found to be functionally tight. CONCLUSION: In summary, primary pediatric CF nasal epithelial cell cultures grown at the ALI showed full differentiation into ciliated, mucus-producing and basal cells, which adequately reflect the in vivo properties of the human respiratory epithelium.
Subject(s)
Cystic Fibrosis/pathology , Microvilli/pathology , Nasal Mucosa/pathology , Respiratory Mucosa/pathology , Adolescent , Cells, Cultured , Child , Child, Preschool , Cystic Fibrosis/metabolism , Cystic Fibrosis Transmembrane Conductance Regulator/biosynthesis , Epithelial Cells/metabolism , Epithelial Cells/pathology , Female , Humans , Male , Microvilli/metabolism , Nasal Mucosa/metabolism , Respiratory Mucosa/metabolismABSTRACT
RATIONALE: Decompressive craniectomy (DC) is beneficial in people with malignant middle cerebral artery infarction. Whether DC improves outcome in spontaneous intracerebral haemorrhage (ICH) is unknown. AIM: To determine whether DC without haematoma evacuation plus best medical treatment (BMT) in people with ICH decreases the risk of death or dependence at 6 months compared to BMT alone. METHODS AND DESIGN: SWITCH is an international, multicentre, randomised (1:1), two-arm, open-label, assessor-blinded trial. Key inclusion criteria are age ⩽75 years, stroke due to basal ganglia or thalamic ICH that may extend into cerebral lobes, ventricles or subarachnoid space, Glasgow coma scale of 8-13, NIHSS score of 10-30 and ICH volume of 30-100 mL. Randomisation must be performed <66 h after onset and DC <6 h after randomisation. Both groups will receive BMT. Participants randomised to the treatment group will receive DC of at least 12 cm in diameter according to institutional standards. SAMPLE SIZE: A sample of 300 participants randomised 1:1 to DC plus BMT versus BMT alone provides over 85% power at a two-sided alpha-level of 0.05 to detect a relative risk reduction of 33% using a chi-squared test. OUTCOMES: The primary outcome is the composite of death or dependence, defined as modified Rankin scale score 5-6 at 6 months. Secondary outcomes include death, functional status, quality of life and complications at 180 days and 12 months. DISCUSSION: SWITCH will inform physicians about the outcomes of DC plus BMT in people with spontaneous deep ICH, compared to BMT alone. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02258919.
Subject(s)
Cerebral Hemorrhage , Decompressive Craniectomy , Humans , Decompressive Craniectomy/methods , Cerebral Hemorrhage/surgery , Male , Middle Aged , Treatment Outcome , Female , Aged , Switzerland , AdultABSTRACT
Rationale: Direct oral anticoagulants (DOAC) are highly effective in preventing ischaemic strokes in people with atrial fibrillation (AF). However, it is unclear how soon they should be started after acute ischaemic stroke (AIS). Early initiation may reduce early risk of recurrence but might increase the risk of haemorrhagic complications. Aim: To estimate the safety and efficacy of early initiation of DOACs compared to late guideline-based initiation in people with AIS related to AF. Methods and design: An international, multicentre, randomised (1:1) controlled, two-arm, open, assessor-blinded trial is being conducted. Early treatment is defined as DOAC initiation within 48 h of a minor or moderate stroke, or at day 6-7 following major stroke. Late treatment is defined as DOAC initiation after day 3-4 following minor stroke, after day 6-7 following moderate stroke and after day 12-14 following major stroke. Severity of stroke is defined according to imaging assessment of infarct size. Sample size: ELAN will randomise 2000 participants 1:1 to early versus late initiation of DOACs. This assumes a risk difference of 0.5% favouring the early arm, allowing an upper limit of the 95% confidence interval up to 1.5% based on the Miettinen & Nurminen formula. Outcomes: The primary outcome is a composite of symptomatic intracranial haemorrhage, major extracranial bleeding, recurrent ischaemic stroke, systemic embolism or vascular death at 30 ± 3 days after randomisation. Secondary outcomes include the individual components of the primary outcome at 30 ± 3 and 90 ± 7 days and functional status at 90 ± 7 days. Discussion: ELAN will estimate whether there is a clinically important difference in safety and efficacy outcomes following early anticoagulation with a DOAC compared to late guideline-based treatment in neuroimaging-selected people with an AIS due to AF.
ABSTRACT
With substantial progress of nanotechnology, there is rising concern about possible adverse health effects related to inhalation of nanomaterials, such as multi-walled carbon nanotubes (MWCNT). In particular, individuals with chronic respiratory disorders, such as chronic obstructive pulmonary disease (COPD), may potentially be more susceptible to adverse health effects related to inhaled MWCNT. Hazard assessment of such inhaled nanomaterials therefore requires timely clarification. This was assessed in this study using a mouse model of COPD by exposing animals to 0.08 µg/cm2 of MWCNT administered by intratracheal instillation. Treatment with MWCNT induced an accumulation of alveolar macrophages (AMφ) in bronchoalveolar lavage fluid (BALF) in COPD mice that increased from 24 h to 7 d. In COPD mice, MWCNT induced a dynamic shift in macrophage polarization as measured by expression of CD38 and CD206, and increased AMφ and lung parenchyma macrophage (LPMΦ) activation with upregulation of co-stimulatory markers CD40 and CD80. Moreover, MWCNT treatment increased the frequencies of pulmonary dendritic cells (DC), leading to an expansion of the CD11b+CD103- DC subset. Although MWCNT did not trigger lung functional or structural changes, they induced an increased expression of the muc5AC transcript in mice with COPD. Our data provide initial evidence that inhaled MWCNT affect the pulmonary mucosal immune system by altering the numbers, phenotype, and activation status of antigen-presenting cell populations. Extrapolating these in vivo mouse findings to human pulmonary MWCNT exposure, caution is warranted in limiting exposure when handling inhalable nanofibers.
Subject(s)
Dendritic Cells/drug effects , Lung/drug effects , Macrophages, Alveolar/drug effects , Nanotubes, Carbon/toxicity , Pulmonary Disease, Chronic Obstructive/chemically induced , Animals , Bronchoalveolar Lavage Fluid/chemistry , Bronchoalveolar Lavage Fluid/cytology , Dendritic Cells/immunology , Disease Models, Animal , Female , Inhalation Exposure , Lung/immunology , Lung/pathology , Macrophages, Alveolar/immunology , Male , Mice, Inbred C57BL , Nanotubes, Carbon/chemistry , Pulmonary Disease, Chronic Obstructive/immunologyABSTRACT
Compartmentalisation of the respiratory tract microbiota in patients with different chronic obstructive pulmonary disease (COPD) severity degrees needs to be systematically investigated. In addition, it is unknown if the inflammatory and emphysematous milieux in patients with COPD are associated with changes in the respiratory tract microbiota and host macrophage gene expression. We performed a cross-sectional study to compare non-COPD controls (n=10) to COPD patients (n=32) with different disease severity degrees. Samples (n=187) were obtained from different sites of the upper and lower respiratory tract. Microbiota analyses were performed by 16S ribosomal RNA gene sequencing and host gene expression analyses by quantitative real-time PCR of distinct markers of bronchoalveolar lavage cells. Overall, the microbial communities of severe COPD (Global Initiative for Chronic Obstructive Lung Disease (GOLD) grade 3/4) patients clustered significantly differently to controls and less severe COPD (GOLD 1/2) patients (permutational multivariate ANOVA (MANOVA), p=0.001). However, we could not detect significant associations between the different sampling sites in the lower airways. In addition, the chosen set of host gene expression markers significantly separated COPD GOLD 3/4 patients, and we found correlations between the composition of the microbiota and the host data. In conclusion, this study demonstrates associations between host gene expression and microbiota profiles that may influence the course of COPD.
ABSTRACT
The risks of occupational exposure during handling of multi-walled carbon nanotubes (MWCNTs) have received limited attention to date, in particular for potentially susceptible individuals with highly prevalent chronic obstructive pulmonary disease (COPD). In this in vitro study, we simulated acute inhalation of MWCNTs employing an air-liquid interface cell exposure (ALICE) system: primary human bronchial epithelial cells from COPD patients and healthy donors (controls), cultured at the air-liquid interface (ALI) were exposed to MWCNTs. To study acute health effects on the respiratory epithelium, two different concentrations (0.16; 0.34 µg/cm2) of MWCNTs were aerosolized onto cell cultures followed by analysis after 24 h. Following MWCNT exposure, epithelial integrity and differentiation remained intact. Electron microscopy analyses identified MWCNTs both extra- and intracellular within vesicles of mucus producing cells. In both COPD and healthy control cultures, MWCNTs neither caused increased release of lactate dehydrogenase (LDH), nor alterations in inflammatory responses, as measured by RNA expression and protein secretion of the cytokines IL-6, IL-8, CXCL10, IL-1ß and TGF-ß and oxidative stress markers HMOX-1 and SOD-2. No short-term alteration of epithelial cell function, as determined by ciliary beating frequency (CBF), occurred in any of the conditions tested. In conclusion, the present study provided a reliable and realistic in vitro acute-exposure model of the respiratory tract, responsive to positive controls such as Dörentruper Quartz (DQ12) and asbestos. Acute exposure to MWCNTs did not affect epithelial integrity, nor induce increased cell death, apoptosis or inflammatory changes.