Extracorporeal life support (ECLS) is increasingly used to bridge deteriorating patients awaiting lung transplantation (LTx), however, few systematic descriptions of this practice exist. We therefore ...aimed to review our institutional experience over the past 10 years.
In this case series, we included all adults who received ECLS with the intent to bridge to LTx. Data were retrieved from patient charts and our institutional ECLS and transplant databases.
Between January 2006 and September 2016, 1111 LTx were performed in our institution. ECLS was used in 71 adults with the intention to bridge to LTx; of these, 11 (16%) were bridged to retransplantation. The median duration of ECLS before LTx was 10 days (range, 0-95). We used a single dual-lumen venous cannula in 23 patients (32%). Nine of 13 patients (69%) with pulmonary hypertension were bridged by central pulmonary artery to left atrium Novalung. Twenty-five patients (35%) were extubated while on ECLS and 26 patients (37%) were mobilized. Sixty-three patients (89%) survived to LTx. Survival by intention to treat was 66% (1 year), 58% (3 years) and 48% (5 years). Survival was significantly shorter in patients undergoing ECLS bridge to retransplantation compared with first LTx (median survival, 15 months (95% CI, 0-31) versus 60 months (95% CI, 37-83); P = .041).
In our center experience, ECLS bridge to first lung transplant leads to good short-term and long-term outcomes in carefully selected patients. In contrast, our data suggest that ECLS as a bridge to retransplantation should be used with caution.
Summary
Background
The Ehlers–Danlos syndromes (EDS) consist of 13 subtypes with overlapping features including joint hypermobility, skin and vascular fragility and generalized connective tissue ...friability. As DNA analysis has become the gold standard for investigation of EDS, transmission electron microscopy (TEM) in clinical practice is decreasing. However, owing to the use of next‐generation sequencing, the frequency of variants of uncertain significance (VUS) identified using DNA analysis is increasing. We hypothesized that TEM can provide evidence for or against pathogenicity of VUS.
Objectives
The aim of this study was to evaluate the role of TEM in the diagnosis of EDS subtypes.
Methods
Data were collected from patients who underwent a skin biopsy between October 2012 and March 2017 at the London EDS National Diagnostic Service. TEM biopsies were categorized as ‘normal’ or ‘abnormal’ according to the description and conclusion in the TEM reports. Definitive diagnoses were reached via a combination of clinical features, structural and functional studies and DNA investigations.
Results
The analysis included 177 patients, comprising 30 abnormal and 147 normal TEM reports. A definitive diagnosis of monogenic EDS subtypes was made in 24 patients. Overall, 17 of these 24 patients (71%) had an abnormal biopsy report and seven (29%) had a normal biopsy report. No TEM findings were specifically associated with any EDS subtype, although collagen flowers were present in most patients with a genetically confirmed diagnosis of classical EDS.
Conclusions
TEM analysis of collagen structure may have the potential to provide evidence for or against the pathogenicity of a VUS, but more work is needed to establish a clear role for TEM in this process.
What's already known about this topic?
Collagen fibril abnormalities can be seen in several Ehlers–Danlos syndrome (EDS) subtypes.
What does this study add?
This study provides clinical data, transmission electron microscopy (TEM) data and molecular data of one of the largest groups of patients suspected to have a monogenetic EDS subtype.
No TEM findings were specifically associated with an EDS subtype.
There was a higher percentage (71%) of abnormal biopsy findings in patients with a definitive diagnosis of a monogenetic EDS subtype and where a class 4/5 genetic variant was present.
Linked Editorial: Steele and O’Toole. Br J Dermatol 2020; 182:521–522.
Linked Comment: Hausser. Br J Dermatol 2020; 182:535–536.
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The EQ-5D-Y, an outcome measure of Health Related Quality of Life (HRQoL) in children, was developed by an international task team in 2010. The multinational feasibility, reliability and validity ...study which followed was undertaken with mainly healthy children. The aim of this study was to investigate the psychometric properties of the EQ-5D-Y when used to assess the HRQoL of children with different health states.
A sample of 224 children between eight and twelve years were grouped according to their health state. The groups included 52 acutely ill children, 67 children with either a chronic health condition or disability and 105 mostly healthy, mainstream school children as a comparator. They were assessed at baseline, at three months and at six months. An analysis of the psychometric properties was performed to assess the reliability, validity and responsiveness of the EQ-5D-Y in the different groups of children. Cohen's kappa, the intraclass correlation coefficient, Pearson Chi-square, Kruskal-Wallis ANOVA and effect size of Wilcoxon Signed-rank test were used to determine the reliability, validity and responsiveness of the instrument.
The EQ-5D-Y dimensions were found to be reliable on test-retest (kappa varying from 0.365 to 0.653), except for the Usual Activities dimension (kappa 0.199). The Visual Analogue Scale (VAS) was also reliable (ICC = 0.77). Post-hoc analysis indicated that dimensions were able to discriminate between acutely ill and healthy children (all differences p < 0.001). The acutely ill children had the lowest ranked VAS (median 50, range 0-100), indicating worst HRQoL and was the only group significantly different from the other three groups (p < 0.001 in all cases). Convergent validity between all similar EQ-5D-Y and PedsQL, WeeFIM and Faces Pain Scale dimensions was only evident in the acutely ill children. As expected the largest treatment effect was also observed in these children (Wilcoxon Signed-rank test for VAS was 0.43). Six of the nine therapists who took part in the study, found the measure quick and easy to apply, used the information in the management of the child and would continue to use it in future.
The EQ-5D-Y could be used with confidence as an outcome measure for acutely-ill children, but demonstrated poorer psychometric properties in children with no health condition or chronic conditions. It appears to be feasible and useful to include the EQ-5D-Y in routine assessments of children.
Excessive respiratory muscle effort during mechanical ventilation may cause patient self-inflicted lung injury and load-induced diaphragm myotrauma, but there are no non-invasive methods to reliably ...detect elevated transpulmonary driving pressure and elevated respiratory muscle effort during assisted ventilation. We hypothesized that the swing in airway pressure generated by respiratory muscle effort under assisted ventilation when the airway is briefly occluded (ΔP
) could be used as a highly feasible non-invasive technique to screen for these conditions.
Respiratory muscle pressure (P
), dynamic transpulmonary driving pressure (ΔP
, the difference between peak and end-expiratory transpulmonary pressure), and ΔP
were measured daily in mechanically ventilated patients in two ICUs in Toronto, Canada. A conversion factor to predict ΔP
and P
from ΔP
was derived and validated using cross-validation. External validity was assessed in an independent cohort (Nanjing, China).
Fifty-two daily recordings were collected in 16 patients. In this sample, P
and ΔP
were frequently excessively high: P
exceeded 10 cm H
O on 84% of study days and ΔP
exceeded 15 cm H
O on 53% of study days. ΔP
measurements accurately detected P
> 10 cm H
O (AUROC 0.92, 95% CI 0.83-0.97) and ΔP
> 15 cm H
O (AUROC 0.93, 95% CI 0.86-0.99). In the external validation cohort (n = 12), estimating P
and ΔP
from ΔP
measurements detected excessively high P
and ΔP
with similar accuracy (AUROC ≥ 0.94).
Measuring ΔP
enables accurate non-invasive detection of elevated respiratory muscle pressure and transpulmonary driving pressure. Excessive respiratory effort and transpulmonary driving pressure may be frequent in spontaneously breathing ventilated patients.
Protein lysine methyltransferases are important regulators of epigenetic signaling. These enzymes catalyze the transfer of donor methyl groups from S-adenosylmethionine to specific acceptor lysines ...on histones, leading to changes in chromatin structure and transcriptional regulation. These enzymes also methylate nonhistone protein substrates, revealing an additional mechanism to regulate cellular physiology. The oncogenic protein SMYD2 represses the functional activities of the tumor suppressor proteins p53 and Rb, making it an attractive drug target. Here we report the discovery of AZ505, a potent and selective inhibitor of SMYD2 that was identified from a high throughput chemical screen. We also present the crystal structures of SMYD2 with p53 substrate and product peptides, and notably, in complex with AZ505. This substrate competitive inhibitor is bound in the peptide binding groove of SMYD2. These results have implications for the development of SMYD2 inhibitors, and indicate the potential for developing novel therapies targeting this target class.
► The oncogenic protein SMYD2 represses the functional activities of the tumor suppressor proteins p53 and Rb, making it an attractive drug target ► We report the discovery of AZ505, a potent and selective inhibitor of SMYD2 that was identified from a high throughput chemical screen. We also present the crystal structures of SMYD2 with p53 substrate and product peptides, and notably, in complex with AZ505 ► This substrate competitive inhibitor is bound in the peptide binding groove of SMYD2 ► These results have implications for the development of SMYD2 inhibitors, and indicate the potential for developing novel therapies targeting this target class
Brain metastasis is the most common type of intracranial tumor. The contemporary management of brain metastasis is a challenging issue and traditionally has carried a poor prognosis as these lesions ...typically occur in the setting of advanced cancer. However, improvement in systemic therapy, advances in radiation techniques and multimodal therapy tailored to the individual patient, has given hope to this patient population. Surgical resection has a well-established role in the management of brain metastasis. Here we discuss the evolving role of surgery in the treatment of this diverse patient population.
Despite progress in locoregional and systemic therapies, patient survival from lung cancer remains a challenge. Receptor tyrosine kinases are frequently implicated in lung cancer pathogenesis, and ...some tyrosine kinase inhibition strategies have been effective clinically. The EphB4 receptor tyrosine kinase has recently emerged as a potential target in several other cancers. We sought to systematically study the role of EphB4 in lung cancer. Here, we demonstrate that EphB4 is overexpressed 3-fold in lung tumors compared to paired normal tissues and frequently exhibits gene copy number increases in lung cancer. We also show that overexpression of EphB4 promotes cellular proliferation, colony formation, and motility, while EphB4 inhibition reduces cellular viability in vitro, halts the growth of established tumors in mouse xenograft models when used as a single-target strategy, and causes near-complete regression of established tumors when used in combination with paclitaxel. Taken together, these data suggest an important role for EphB4 as a potential novel therapeutic target in lung cancer. Clinical trials investigating the efficacy of anti-EphB4 therapies as well as combination therapy involving EphB4 inhibition may be warranted.
Carotid-artery stenting and carotid endarterectomy are both options for treating carotid-artery stenosis, an important cause of stroke.
We randomly assigned patients with symptomatic or asymptomatic ...carotid stenosis to undergo carotid-artery stenting or carotid endarterectomy. The primary composite end point was stroke, myocardial infarction, or death from any cause during the periprocedural period or any ipsilateral stroke within 4 years after randomization.
For 2502 patients over a median follow-up period of 2.5 years, there was no significant difference in the estimated 4-year rates of the primary end point between the stenting group and the endarterectomy group (7.2% and 6.8%, respectively; hazard ratio with stenting, 1.11; 95% confidence interval, 0.81 to 1.51; P=0.51). There was no differential treatment effect with regard to the primary end point according to symptomatic status (P=0.84) or sex (P=0.34). The 4-year rate of stroke or death was 6.4% with stenting and 4.7% with endarterectomy (hazard ratio, 1.50; P=0.03); the rates among symptomatic patients were 8.0% and 6.4% (hazard ratio, 1.37; P=0.14), and the rates among asymptomatic patients were 4.5% and 2.7% (hazard ratio, 1.86; P=0.07), respectively. Periprocedural rates of individual components of the end points differed between the stenting group and the endarterectomy group: for death (0.7% vs. 0.3%, P=0.18), for stroke (4.1% vs. 2.3%, P=0.01), and for myocardial infarction (1.1% vs. 2.3%, P=0.03). After this period, the incidences of ipsilateral stroke with stenting and with endarterectomy were similarly low (2.0% and 2.4%, respectively; P=0.85).
Among patients with symptomatic or asymptomatic carotid stenosis, the risk of the composite primary outcome of stroke, myocardial infarction, or death did not differ significantly in the group undergoing carotid-artery stenting and the group undergoing carotid endarterectomy. During the periprocedural period, there was a higher risk of stroke with stenting and a higher risk of myocardial infarction with endarterectomy. (ClinicalTrials.gov number, NCT00004732.)
Relationships between temperament and a range of performance, carcass, and meat quality traits in young cattle were studied in 2 experiments conducted in New South Wales (NSW) and Western Australia ...(WA), Australia. In both experiments, growth rates of cattle were assessed during backgrounding on pasture and grain finishing in a feedlot. Carcass and objective meat quality characteristics were measured after slaughter. Feed intake and efficiency during grain finishing were also determined in NSW. Brahman (n = 82 steers and 82 heifers) and Angus (n = 25 steers and 24 heifers) cattle were used in the NSW experiment. In NSW, temperament was assessed by measuring flight speed FS, m/s on exit from the chute (crush) on 14 occasions, and by assessing agitation score during confinement in the crush (CS; 1 = calm to 5 = highly agitated) on 17 occasions over the course of the experiment. Brahman (n = 173) and Angus (n = 20) steers were used in the WA experiment. In WA, temperament was assessed by measuring FS on 2 occasions during backgrounding and on 2 occasions during grain feeding. At both sites, a hormonal growth promotant (Revalor-H, Virbac, Milperra, New South Wales, Australia) was applied to one-half of the cattle at feedlot entry, and the Brahman cattle were polymorphic for 2 calpain-system markers for beef tenderness. Temperament was not related (most P > 0.05) to tenderness gene marker status in Brahman cattle and was not (all P > 0.26) modified by the growth promotant treatment in either breed. The Brahman cattle had greater individual variation in, and greater correlations within and between, repeated assessments of FS and CS than did the Angus cattle. Correlations for repeated measures of FS were greater than for repeated assessments of CS, and the strength of correlations for both declined over time. Average FS or CS for each experiment and location (NSW or WA x backgrounding or finishing) were more highly correlated than individual measurements, indicating that the average values were a more reliable assessment of cattle temperament than any single measure. In Brahman cattle, increased average FS and CS were associated with significant (P < 0.05) reductions in backgrounding and feedlot growth rates, feed intake and time spent eating, carcass weight, and objective measures of meat quality. In Angus cattle, the associations between temperament and growth rates, feed intake, and carcass traits were weaker than in Brahmans, although the strength of relationships with meat quality were similar.