•Gaze behaviour and EDA are reliable continuous measures of trust in automation.•Gaze behaviour and EDA, when combined, predict trust better than individually.•Automated vehicle behaviour does not ...need to be perfect, but predictable.•Unexpected system failures strongly and negatively impact drivers’ trust.
Studies show that drivers’ intention to use automated vehicles is strongly modulated by trust. It follows that their benefits are unlikely to be achieved if users do not trust them. To date, most studies of trust in automated vehicles have relied on self-reports. However, questionnaires cannot capture real-time changes in drivers’ trust, and are hard to use in applied settings. In previous work, we found evidence that gaze behaviour could provide an effective measure of trust. In this study we tested whether combining gaze behaviour with Electrodermal Activity could provide a stronger metric. The results indicated a strong relationship between self-reported trust, monitoring behaviour and Electrodermal Activity: The higher participants’ self-reported trust, the less they monitored the road, the more attention they paid to a non-driving related secondary task, and the lower their Electrodermal Activity. We also found evidence that combined measures of gaze behaviour and Electrodermal Activity predict self-reported trust better than either of these measures on its own. These findings suggest that such combined measures have the potential to provide a reliable and objective real-time indicator of driver trust.
To determine if mexiletine is safe and effective in reducing myotonia in myotonic dystrophy type 1 (DM1).
Myotonia is an early, prominent symptom in DM1 and contributes to decreased dexterity, gait ...instability, difficulty with speech/swallowing, and muscle pain. A few preliminary trials have suggested that the antiarrhythmic drug mexiletine is useful, symptomatic treatment for nondystrophic myotonic disorders and DM1.
We performed 2 randomized, double-blind, placebo-controlled crossover trials, each involving 20 ambulatory DM1 participants with grip or percussion myotonia on examination. The initial trial compared 150 mg of mexiletine 3 times daily to placebo, and the second trial compared 200 mg of mexiletine 3 times daily to placebo. Treatment periods were 7 weeks in duration separated by a 4- to 8-week washout period. The primary measure of myotonia was time for isometric grip force to relax from 90% to 5% of peak force after a 3-second maximum grip contraction. EKG measurements and adverse events were monitored in both trials.
There was a significant reduction in grip relaxation time with both 150 and 200 mg dosages of mexiletine. Treatment with mexiletine at either dosage was not associated with any serious adverse events, or with prolongation of the PR or QTc intervals or of QRS duration. Mild adverse events were observed with both placebo and mexiletine treatment.
Mexiletine at dosages of 150 and 200 mg 3 times daily is effective, safe, and well-tolerated over 7 weeks as an antimyotonia treatment in DM1.
This study provides Class I evidence that mexiletine at dosages of 150 and 200 mg 3 times daily over 7 weeks is well-tolerated and effective in reducing handgrip relaxation time in DM1.
The development of resistance to chemotherapy is a major obstacle for lasting effective treatment of cancer. Here, we demonstrate that endogenous mesenchymal stem cells (MSCs) become activated during ...treatment with platinum analogs and secrete factors that protect tumor cells against a range of chemotherapeutics. Through a metabolomics approach, we identified two distinct platinum-induced polyunsaturated fatty acids (PIFAs), 12-oxo-5,8,10-heptadecatrienoic acid (KHT) and hexadeca-4,7,10,13-tetraenoic acid (16:4(n-3)), that in minute quantities induce resistance to a broad spectrum of chemotherapeutic agents. Interestingly, blocking central enzymes involved in the production of these PIFAs (cyclooxygenase-1 and thromboxane synthase) prevents MSC-induced resistance. Our findings show that MSCs are potent mediators of resistance to chemotherapy and reveal targets to enhance chemotherapy efficacy in patients.
► Mesenchymal stem cells (MSCs) systemically induce resistance to chemotherapy ► Platinum-activated MSCs release two specific platinum-induced fatty acids (PIFAs) ► At minute quantities PIFAs induce resistance to various chemotherapeutics ► COX-1 and thromboxane synthase inhibition prevents MSC-induced resistance
In spinal muscular atrophy (SMA), weakness, decreased endurance, and fatigue limit mobility. Scales have been developed to measure function across the wide spectrum of disease severity. However, ...these scales typically are observer dependent, and scores are based on sums across Likert-scaled items. The Six-Minute Walk Test (6MWT) is an objective, easily administered, and standardized evaluation of functional exercise capacity that has been proven reliable in other neurologic disorders and in children.
To study the performance of the 6MWT in SMA, 18 ambulatory participants were evaluated in a cross-sectional study. Clinical measures were 6MWT, 10-m walk/run, Hammersmith Functional Motor Scale-Expanded (HFMSE), forced vital capacity, and handheld dynamometry. Associations between the 6MWT total distance and other outcomes were analyzed using Spearman correlation coefficients. A paired t test was used to compare the mean distance walked in the first and sixth minutes.
The 6MWT was associated with the HFMSE score (r = 0.83, p < 0.0001), 10-m walk/run (r = -0.87, p < 0.0001), and knee flexor strength (r = 0.62, p = 0.01). Gait velocity decreased during successive minutes in nearly all participants. The average first minute distance (57.5 m) was significantly more than the sixth minute distance (48 m) (p = 0.0003).
The Six-Minute Walk Test (6MWT) can be safely performed in ambulatory patients with spinal muscular atrophy (SMA), correlates with established outcome measures, and is sensitive to fatigue-related changes. The 6MWT is a promising candidate outcome measure for clinical trials in ambulatory subjects with SMA.
To compare outcomes after endovascular treatment (EVT) for acute ischemic stroke with 3 different types of anesthetic management in clinical practice, as anesthetic management may influence ...functional outcome.
Data of patients with an anterior circulation occlusion, included in the Dutch nationwide, prospective Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands (MR CLEAN) Registry between March 2014 and June 2016, were analyzed. Patients were divided into 3 groups defined by anesthetic technique performed during EVT: local anesthesia only (LA), general anesthesia (GA), or conscious sedation (CS). Primary outcome was the modified Rankin Scale score at 90 days. To compare functional outcome between groups, we estimated a common odds ratio (OR) with ordinal logistic regression, adjusted for age, sex, prestroke modified Rankin Scale score, baseline NIH Stroke Scale score, collaterals, and time from onset to arrival at intervention center.
A total of 1,376 patients were included. Performed anesthetic technique was LA in 821 (60%), GA in 381 (28%), and CS in 174 (13%) patients. Compared to LA, both GA and CS were associated with worse functional outcome on the modified Rankin Scale score at 90 days (GA cOR
0.75; 95% confidence interval CI 0.58-0.97; CS cOR
0.45; 95% CI 0.33-0.62). CS was associated with worse functional outcome than GA (cOR
0.60; 95% CI 0.42-0.87).
LA is associated with better functional outcome than systemic sedation in patients undergoing EVT for acute ischemic stroke. Whereas LA had a clear advantage over CS, this was less prominent compared to GA.
This study provides Class III evidence that for patients with acute ischemic stroke undergoing EVT, LA improves functional outcome compared to GA or CS.
Acute myeloid leukemia (AML) is a highly heterogeneous disease showing dynamic clonal evolution patterns over time. Various subclones may be present simultaneously and subclones may show a different ...expansion pattern and respond differently to applied therapies. It is already clear that immunophenotyping and genetic analyses may yield overlapping, but also complementary information. Detailed information on the genetic make-up of immunophenotypically defined subclones is however scarce. We performed error-corrected sequencing for 27 myeloid leukemia driver genes in 86, FACS-sorted immunophenotypically characterized normal and aberrant subfractions in 10 AML patients. We identified three main scenarios. In the first group of patients, the two techniques were equally well characterizing the malignancy. In the second group, most of the isolated populations did not express aberrant immunophenotypes but still harbored several genetic aberrancies, indicating that the information obtained only by immunophenotyping would be incomplete. Vice versa, one patient was identified in which genetic mutations were found only in a small fraction of the immunophenotypically defined malignant populations, indicating that the genetic analysis gave an incomplete picture of the disease. We conclude that currently, characterization of leukemic cells in AML by molecular and immunophenotypic techniques is complementary, and infer that both techniques should be used in parallel in order to obtain the most complete view on the disease.
Acute ischemic stroke due to large vessel occlusion is uncommon in young adults. We assessed stroke cause in young patients and compared their outcomes after endovascular thrombectomy with older ...patients.
We used data (March 2014 until November 2017) of patients with an anterior circulation large vessel occlusion stroke from the MR CLEAN (Multicenter Randomized Controlled Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands) Registry, a nationwide, prospective study on endovascular thrombectomy in the Netherlands. We compared young patients (18-49 years) with older patients (≥50 years). Outcomes included modified Rankin Scale score after 90 days (both shift and dichotomized analyses), expanded Thrombolysis in Cerebral Infarction score, and symptomatic intracranial hemorrhage. Analyses were adjusted for confounding.
We included 3256 patients, 310 (10%) were 18 to 49 years old. Young patients had lower median National Institutes of Health Stroke Scale scores (14 versus 16,
<0.001) and less cardiovascular comorbidities than older patients. Stroke etiologies in young patients included carotid dissection (16%), cardio-embolism (15%), large artery atherosclerosis (10%), and embolic stroke of undetermined source (31%). Clinical outcome was better in young than older patients (acOR for modified Rankin Scale shift: 1.8 95% CI, 1.5-2.2; functional independence modified Rankin Scale score 0-2 61 versus 39% adjusted odds ratio, 2.1 95% CI, 1.6-2.8); mortality 7% versus 32%, adjusted odds ratio, 0.2 95% CI, 0.1-0.3). Symptomatic intracranial hemorrhage occurred less frequently in young patients (3% versus 6%, adjusted odds ratio, 0.5 95% CI, 0.2-1.00). Successful reperfusion (expanded Thrombolysis in Cerebral Infarction Score 2b-3) did not differ between groups. Onset to reperfusion time was shorter in young patients (253 versus 255 minutes, adjusted B in minutes 12.4 95% CI, 2.4-22.5).
Ten percent of patients with acute ischemic stroke undergoing endovascular thrombectomy were younger than 50. Cardioembolism and carotid dissection were common underlying causes in young patients. In one-third of cases, no cause was identified, indicating the need for more research on stroke cause in young patients. Young patients had better prognosis and lower risk of symptomatic intracranial hemorrhage than older patients.
Despite the fact that loss of E-cadherin is causal to the development and progression of invasive lobular carcinoma (ILC), options to treat this major breast cancer subtype are limited if tumours ...develop resistance to anti-oestrogen treatment regimens. This study aimed to identify clinically targetable pathways that are aberrantly active downstream of E-cadherin loss in ILC. Using a combination of reverse-phase protein array (RPPA) analyses, mRNA sequencing, conditioned medium growth assays and CRISPR/Cas9-based knock-out experiments, we demonstrate that E-cadherin loss causes increased responsiveness to autocrine growth factor receptor (GFR)-dependent activation of phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/Akt signalling. Autocrine activation of GFR signalling and its downstream PI3K/Akt hub was independent of oncogenic mutations in PIK3CA, AKT1 or PTEN. Analyses of human ILC samples confirmed growth factor production and pathway activity. Pharmacological inhibition of Akt using AZD5363 or MK2206 resulted in robust inhibition of cell growth and survival of ILC cells, and impeded tumour growth in a mouse ILC model. Because E-cadherin loss evokes hypersensitisation of PI3K/Akt activation independent of oncogenic mutations in this pathway, we propose clinical intervention of PI3K/Akt in ILC based on functional E-cadherin inactivation, irrespective of activating pathway mutations.
Background and purpose
Recent studies have suggested a possible excess risk of skin neoplasms in patients with myotonic dystrophy (DM). Risk factors related to this observation have not been defined.
...Method
Information regarding personal history of skin tumors, pigmentation phenotype, and skin reaction to sun exposure were collected from 266 DM patients who were enrolled in the US National Institutes of Health National Registry of Myotonic Dystrophy and Facioscapulohumeral Muscular Dystrophy Patients and Family Members.
Results
Seventy‐seven subjects reported having skin tumors that were either benign (n = 31), malignant (n = 32) or both (n = 14). Female gender odds ratio (OR) = 2.27, 95% confidence interval (CI) 1.02–5.05, P = 0.04, older age (OR = 1.10, 95% CI 1.05–1.16, P < 0.001) and DM1 subtype (OR = 3.42, 95% CI 1.27–9.26, P = 0.02) were associated with a malignant skin tumor. The associations between malignant skin tumors and known risk factors light eye color (OR = 1.62, 95% CI 0.78–3.39, P = 0.20), light skin complexion (OR = 1.31, 95% CI 0.63–2.73, P = 0.48) and moderate/extensive face freckles (OR = 1.47, 95% CI 0.50–4.34, P = 0.49) were modest. Strong, but not statistically significant, associations were noted with sunburn reactions when exposed to sunlight (OR = 4.28, 95% CI 0.91–19.95, P = 0.06, and OR = 2.19, 95% CI 0.67–7.09, P = 0.19, for sunburn with and without blistering, respectively).
Conclusions
Although our study was limited by small sample size, the risk factors for malignant skin tumors in DM strongly resemble the general population. It is recommended that DM patients adhere to sun exposure protective behavior.
Purpose
We aimed to study the association of non-contrast CT (NCCT) thrombus density with procedural and clinical outcomes in patients with acute ischemic stroke who underwent endovascular treatment ...(EVT). Since thrombus density is associated with thrombus location, we focused on M1 occlusions only.
Methods
Patients with available thin-slice (< 2.5 mm) NCCT were included from a nationwide registry. Regression models were used to assess the relation between thrombus density (per Hounsfield unit HU) and the following outcomes. For reperfusion grade, adjusted common odds ratios (acOR) indicated a 1-step shift towards improved outcome per HU increase in thrombus density. For the binary outcomes of first-pass reperfusion (first-pass extended thrombolysis in cerebral infarction eTICI 2C-3, FPR), functional independence 90-day modified Rankin Scale (mRS) score of 0–2 and mortality), aORs were reported. Adjusted
β
coefficients (a
β
) were reported for 24-h NIHSS and procedure duration in minutes. Outcome differences between first-line treatment devices (stent retriever versus aspiration) were assessed with interaction terms.
Results
In 566 patients with M1 occlusions, thrombus density was not associated with reperfusion (acOR 1.01, 95% CI 0.99–1.02), FPR (aOR 1.01, 95% CI 0.99–1.03), mortality (aOR 0.98, 95% CI 0.95–1.00), 24-h NIHSS (a
β
− 0.7%, 95% CI − 1.4–0.2), or procedure duration (a
β
0.27, 95% CI − 0.05–0.58). In multivariable analysis, thrombus density was associated with functional independence (aOR 1.02, 95% CI 1.00–1.05). No interaction was found between thrombus density and first-line treatment device for any outcome.
Conclusion
In patients with M1 occlusions, thrombus density was not clearly associated with procedural and clinical outcomes after EVT.
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