Defining the Genetic Landscape of Congenital Mirror Movements in 80 Affected Individuals.

BACKGROUND: Congenital mirror movements (CMM) is a rare neurodevelopmental disorder characterized by involuntary movements from one side of the body that mirror voluntary movements on the opposite side. To date, five genes have been associated with CMM, namely DCC, RAD51, NTN1, ARHGEF7, and DNAL4. OBJECTIVE: The aim of this study is to characterize the genetic landscape of CMM in a large group of 80 affected individuals. METHODS: We screened 80 individuals with CMM from 43 families for pathogenic variants in CMM genes. In large CMM families, we tested for presence of pathogenic variants in multiple affected and unaffected individuals. In addition, we evaluated the impact of three missense DCC variants on binding between DCC and Netrin-1 in vitro. RESULTS: Causal pathogenic/likely pathogenic variants were found in 35% of probands overall, and 70% with familial CMM. The most common causal gene was DCC, responsible for 28% of CMM probands and 80% of solved cases. RAD51, NTN1, and ARHGEF7 were rare causes of CMM, responsible for 2% each. Penetrance of CMM in DCC pathogenic variant carriers was 68% and higher in males than females (74% vs. 54%). The three tested missense variants (p.Ile164Thr; p.Asn176Ser; and p.Arg1343His) bind Netrin-1 similarly to wild type DCC. CONCLUSIONS: A genetic etiology can be identified in one third of CMM individuals, with DCC being the most common gene involved. Two thirds of CMM individuals were unsolved, highlighting that CMM is genetically heterogeneous and other CMM genes are yet to be discovered. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Improvements in Between-Vendor MRI Harmonization of Renal T2 Mapping using Stimulated Echo Compensation.

BACKGROUND: T2 mapping is valuable to evaluate pathophysiology in kidney disease. However, variations in T2 relaxation time measurements across MR scanners and vendors may occur requiring additional correction. PURPOSE: To harmonize renal T2 measurements between MR vendor platforms, and use an extended-phase-graph-based fitting method ("StimFit") to correct stimulated echoes and reduce between-vendor variations. STUDY TYPE: Prospective. SUBJECTS: 8 healthy "travelling" volunteers (37.5% female, 32 ± 6 years) imaged on four MRI systems across three vendors at four sites, 10 healthy volunteers (50% female, 32 ± 8 years) scanned multiple times on a given MR scanner for repeatability evaluation. ISMRM/NIST system phantom scanned for evaluation of T2 accuracy. FIELD STRENGTH/SEQUENCE: 3T, multiecho spin-echo sequence. ASSESSMENT: T2 images fit using conventional monoexponential fitting and "StimFit." Mean absolute percentage error (MAPE) of phantom measurements with reference T2 values. Average cortex and medulla T2 values compared between MR vendors, with masks obtained from T2-weighted images and T1 maps. Full-width-at-half-maximum (FWHM) T2 distributions to evaluate local homogeneity of measurements. STATISTICAL TESTS: Coefficient of variation (CV), linear mixed-effects model, analysis of variance, student's t-tests, Bland-Altman plots, P-value <0.05 considered statistically significant. RESULTS: In the ISMRM/NIST phantom, "StimFit" reduced the MAPE from 4.9%, 9.1%, 24.4%, and 18.1% for the four sites (three vendors) to 3.3%, 3.0%, 6.6%, and 4.1%, respectively. In vivo, there was a significant difference in kidney T2 measurements between vendors using a monoexponential fit, but not with "StimFit" (P = 0.86 and 0.92, cortex and medulla, respectively). The intervendor CVs of T2 measures were reduced from 8.0% to 2.6% (cortex) and 7.1% to 2.8% (medulla) with StimFit, resulting in no significant differences for the CVs of intravendor repeat acquisitions (P = 0.13 and 0.05). "StimFit" significantly reduced the FWHM of T2 distributions in the cortex and whole kidney. DATA CONCLUSION: Stimulated-echo correction reduces renal T2 variation across MR vendor platforms. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 1.

A retrospective analysis of the need for on-site emergency physician presence and mission characteristics of a rural ground-based emergency medical service.

BACKGROUND: This study aimed to address the challenges faced by rural emergency medical services in Europe, due to an increasing number of missions and limited human resources. The primary objective was to determine the necessity of having an on-site emergency physician (EP), while the secondary objectives included analyzing the characteristics of rural EP missions. METHODS: A retrospective study was conducted, examining rural EP missions carried out between January 1st, 2017, and December 2nd, 2021 in Burgenland, Austria. The need for physical presence of an EP was classified based on the National Advisory Committee for Aeronautics (NACA) score into three categories; category A: no need for an EP (NACA 1-3); category B: need for an EP (NACA 1-3 along with additional medical interventions beyond the capabilities of emergency medical technicians); and category C: definite need for an EP (NACA 4-7). Descriptive statistics were used for analysis. RESULTS: Out of 16,971 recorded missions, 15,591 were included in the study. Approximately 32.3% of missions fell into category A, indicating that an EP's physical presence was unnecessary. The diagnoses made by telecommunicators matched those of the EPs in only 52.8% of cases. CONCLUSION: The study suggests that about a third of EP missions carried out in rural areas might not have a solid medical rationale. This underscores the importance of developing an alternative care approach for these missions. Failing to address this could put additional pressure on already stretched EMS systems, risking their collapse.

Functional and Morphological Differences of Muscle Mitochondria in Chronic Fatigue Syndrome and Post-COVID Syndrome.

Patients suffering from chronic fatigue syndrome (CFS) or post-COVID syndrome (PCS) exhibit a reduced physiological performance capability. Impaired mitochondrial function and morphology may play a pivotal role. Thus, we aimed to measure the muscle mitochondrial oxidative phosphorylation (OXPHOS) capacity and assess mitochondrial morphology in CFS and PCS patients in comparison to healthy controls (HCs). Mitochondrial OXPHOS capacity was measured in permeabilized muscle fibers using high-resolution respirometry. Mitochondrial morphology (subsarcolemmal/intermyofibrillar mitochondrial form/cristae/diameter/circumference/area) and content (number and proportion/cell) were assessed via electron microscopy. Analyses included differences in OXPHOS between HC, CFS, and PCS, whereas comparisons in morphology/content were made for CFS vs. PCS. OXPHOS capacity of complex I, which was reduced in PCS compared to HC. While the subsarcolemmal area, volume/cell, diameter, and perimeter were higher in PCS vs. CFS, no difference was observed for these variables in intermyofibrillar mitochondria. Both the intermyofibrillar and subsarcolemmal cristae integrity was higher in PCS compared to CFS. Both CFS and PCS exhibit increased fatigue and impaired mitochondrial function, but the progressed pathological morphological changes in CFS suggest structural changes due to prolonged inactivity or unknown molecular causes. Instead, the significantly lower complex I activity in PCS suggests probably direct virus-induced alterations.

TatA and TatB generate a hydrophobic mismatch important for the function and assembly of the Tat translocon in Escherichia coli.

The twin-arginine translocation (Tat) system serves to translocate folded proteins across energy-transducing membranes in bacteria, archaea, plastids, and some mitochondria. In Escherichia coli, TatA, TatB, and TatC constitute functional translocons. TatA and TatB both possess an N-terminal transmembrane helix (TMH) followed by an amphipathic helix. The TMHs of TatA and TatB generate a hydrophobic mismatch with the membrane, as the helices comprise only 12 consecutive hydrophobic residues; however, the purpose of this mismatch is unclear. Here, we shortened or extended this stretch of hydrophobic residues in either TatA, TatB, or both and analyzed effects on translocon function and assembly. We found the WT length helices functioned best, but some variation was clearly tolerated. Defects in function were exacerbated by simultaneous mutations in TatA and TatB, indicating partial compensation of mutations in each by the other. Furthermore, length variation in TatB destabilized TatBC-containing complexes, revealing that the 12-residue-length is important but not essential for this interaction and translocon assembly. To also address potential effects of helix length on TatA interactions, we characterized these interactions by molecular dynamics simulations, after having characterized the TatA assemblies by metal-tagging transmission electron microscopy. In these simulations, we found that interacting short TMHs of larger TatA assemblies were thinning the membrane and-together with laterally-aligned tilted amphipathic helices-generated a deep V-shaped membrane groove. We propose the 12 consecutive hydrophobic residues may thus serve to destabilize the membrane during Tat transport, and their conservation could represent a delicate compromise between functionality and minimization of proton leakage.

Bounded rational decision-making models suggest capacity-limited concurrent motor planning in human posterior parietal and frontal cortex.

While traditional theories of sensorimotor processing have often assumed a serial decision-making pipeline, more recent approaches have suggested that multiple actions may be planned concurrently and vie for execution. Evidence for the latter almost exclusively stems from electrophysiological studies in posterior parietal and premotor cortex of monkeys. Here we study concurrent prospective motor planning in humans by recording functional magnetic resonance imaging (fMRI) during a delayed response task engaging movement sequences towards multiple potential targets. We find that also in human posterior parietal and premotor cortex delay activity modulates both with sequence complexity and the number of potential targets. We tested the hypothesis that this modulation is best explained by concurrent prospective planning as opposed to the mere maintenance of potential targets in memory. We devise a bounded rationality model with information constraints that optimally assigns information resources for planning and memory for this task and determine predicted information profiles according to the two hypotheses. When regressing delay activity on these model predictions, we find that the concurrent prospective planning strategy provides a significantly better explanation of the fMRI-signal modulations. Moreover, we find that concurrent prospective planning is more costly and thus limited for most subjects, as expressed by the best fitting information capacities. We conclude that bounded rational decision-making models allow relating both behavior and neural representations to utilitarian task descriptions based on bounded optimal information-processing assumptions.

Eye-tracking during simulation-based echocardiography: a feasibility study.

INTRODUCTION: Due to the technical progress point-of-care ultrasound (POCUS) is increasingly used in critical care medicine. However, optimal training strategies and support for novices have not been thoroughly researched so far. Eye-tracking, which offers insights into the gaze behavior of experts may be a useful tool for better understanding. The aim of this study was to investigate the technical feasibility and usability of eye-tracking during echocardiography as well as to analyze differences of gaze patterns between experts and non-experts. METHODS: Nine experts in echocardiography and six non-experts were equipped with eye-tracking glasses (Tobii, Stockholm, Sweden), while performing six medical cases on a simulator. For each view case specific areas of interests (AOI) were defined by the first three experts depending on the underlying pathology. Technical feasibility, participants' subjective experience on the usability of the eye-tracking glasses as well as the differences of relative dwell time (focus) inside the areas of interest (AOI) between six experts and six non-experts were evaluated. RESULTS: Technical feasibility of eye-tracking during echocardiography was achieved with an accordance of 96% between the visual area orally described by participants and the area marked by the glasses. Experts had longer relative dwell time in the case specific AOI (50.6% versus 38.4%, p = 0.072) and performed ultrasound examinations faster (138 s versus 227 s, p = 0.068). Furthermore, experts fixated earlier in the AOI (5 s versus 10 s, p = 0.033). CONCLUSION: This feasibility study demonstrates that eye-tracking can be used to analyze experts and non-experts gaze patterns during POCUS. Although, in this study the experts had a longer fixation time in the defined AOIs compared to non-experts, further studies are needed to investigate if eye-tracking could improve teaching of POCUS.

Comparative Exergy and Environmental Assessment of the Residual Biomass Gasification Routes for Hydrogen and Ammonia Production.

The need to reduce the dependency of chemicals on fossil fuels has recently motivated the adoption of renewable energies in those sectors. In addition, due to a growing population, the treatment and disposition of residual biomass from agricultural processes, such as sugar cane and orange bagasse, or even from human waste, such as sewage sludge, will be a challenge for the next generation. These residual biomasses can be an attractive alternative for the production of environmentally friendly fuels and make the economy more circular and efficient. However, these raw materials have been hitherto widely used as fuel for boilers or disposed of in sanitary landfills, losing their capacity to generate other by-products in addition to contributing to the emissions of gases that promote global warming. For this reason, this work analyzes and optimizes the biomass-based routes of biochemical production (namely, hydrogen and ammonia) using the gasification of residual biomasses. Moreover, the capture of biogenic CO2 aims to reduce the environmental burden, leading to negative emissions in the overall energy system. In this context, the chemical plants were designed, modeled, and simulated using Aspen plus™ software. The energy integration and optimization were performed using the OSMOSE Lua Platform. The exergy destruction, exergy efficiency, and general balance of the CO2 emissions were evaluated. As a result, the irreversibility generated by the gasification unit has a relevant influence on the exergy efficiency of the entire plant. On the other hand, an overall negative emission balance of -5.95 kgCO2/kgH2 in the hydrogen production route and -1.615 kgCO2/kgNH3 in the ammonia production route can be achieved, thus removing from the atmosphere 0.901 tCO2/tbiomass and 1.096 tCO2/tbiomass, respectively.

Improved Waste Heat Management and Energy Integration in an Aluminum Annealing Continuous Furnace Using a Machine Learning Approach.

Annealing furnaces are critical for achieving the desired material properties in the production of high-quality aluminum products. In addition, energy efficiency has become more and more important in industrial processes due to increasing decarbonization regulations and the price of natural gas. Thus, the current study aims to determine the opportunities to reduce energy consumption in an annealing continuous furnace and the associated emissions. To this end, the heat transfer phenomenon is modeled and solutions for the decreasing fuel consumption are evaluated so that the overall performance of the process is enhanced. A heat transfer model is developed using the finite difference method, and the heat transfer coefficient is calculated using machine learning regression models. The heat transfer model is able to predict the heat transfer coefficient and calculate the aluminum temperature profile along the furnace and the fuel consumption for any given operating condition. Two solutions for boosting the furnace exergy efficiency are evaluated, including the modulation of the furnace temperature profiles and the energy integration by the recycling of exhaust flue gases. The results show that the advanced energy integration approach significantly reduces fuel consumption by up to 20.7%. Sensitivity analysis demonstrates that the proposed strategy can effectively reduce fuel consumption compared with the business-as-usual scenario for a range of sheet thicknesses and sheet velocities.

Sugar-sweetened beverage tax implementation processes: results of a scoping review.

Taxing sugar-sweetened beverages (SSB) is seen as a win-win situation for governments. It is argued that SSB taxes are relatively easy to implement from a practical perspective compared to for example other nutrition policies. However, the implementation of SSB taxation laws does not happen by itself. Therefore, this work examines implementation processes for SSB taxation in terms of (1) pre-implementation context, (2) taxation instruments used and (3) interactions in the implementation process. Ten databases and grey literature were systematically searched for studies reporting on SSB taxation implementation processes up to February 2020. All studies (N = 1248) were screened independently by two reviewers according to predefined criteria. The selection of variables to be extracted was based on the policy cycle heuristic and informed by intervention implementation research. Information on the process of implementing SSB taxation is limited. Only six cases based on three publications were identified, indicating a gap in this research area. SSB taxation implementation was accomplished by hiring a subcontractor for the implementation or using pre-existing tax collection structures. Political and public support within the implementation process seems to be supportive for the city of Berkeley and for Portugal but was not reported for the Pacific Islands. However, the existing data are very limited, and further research on SSB taxation implementation processes is needed to determine whether the aim of the policy and the envisaged outcome are linked in practice. Registration The protocol was registered with the Open Science Framework (OSF) (osf.io/7w84q/).

SARS-CoV-2 Altered Hemorheological and Hematological Parameters during One-Month Observation Period in Critically Ill COVID-19 Patients.

Hematological and hemorheological parameters are known to be altered in COVID-19; however, the value of combined monitoring in order to deduce disease severity is only scarcely examined. A total of 44 acute SARS-CoV-2-infected patients (aCOV) and 44 age-matched healthy controls (Con) were included. Blood of aCOV was sampled at admission (T0), and at day 2 (T2), day 5 (T5), day 10 (T10), and day 30 (T30) while blood of Con was only sampled once. Inter- and intra-group differences were calculated for hematological and hemorheological parameters. Except for mean cellular volume and mean cellular hemoglobin, all blood cell parameters were significantly different between aCOV and Con. During the acute disease state (T0-T5), hematological and hemorheological parameters were highly altered in aCOV; in particular, anemic conditions and increased immune cell response/inflammation, oxidative/nitrosative stress, decreased deformability, as well as increased aggregation, were observed. During treatment and convalescence until T30, almost all abnormal values of aCOV improved towards Con values. During the acute state of the COVID-19 disease, the hematological, as well as the hemorheological system, show fast and potentially pathological changes that might contribute to the progression of the disease, but changes appear to be largely reversible after four weeks. Measuring RBC deformability and aggregation, as well as oxidative stress induction, may be helpful in monitoring critically ill COVID-19 patients.

Automated renal segmentation in healthy and chronic kidney disease subjects using a convolutional neural network.

PURPOSE: Total kidney volume (TKV) is an important measure in renal disease detection and monitoring. We developed a fully automated method to segment the kidneys from T2 -weighted MRI to calculate TKV of healthy control (HC) and chronic kidney disease (CKD) patients. METHODS: This automated method uses machine learning, specifically a 2D convolutional neural network (CNN), to accurately segment the left and right kidneys from T2 -weighted MRI data. The data set consisted of 30 HC subjects and 30 CKD patients. The model was trained on 50 manually defined HC and CKD kidney segmentations. The model was subsequently evaluated on 50 test data sets, comprising data from 5 HCs and 5 CKD patients each scanned 5 times in a scan session to enable comparison of the precision of the CNN and manual segmentation of kidneys. RESULTS: The unseen test data processed by the 2D CNN had a mean Dice score of 0.93 ± 0.01. The difference between manual and automatically computed TKV was 1.2 ± 16.2 mL with a mean surface distance of 0.65 ± 0.21 mm. The variance in TKV measurements from repeat acquisitions on the same subject was significantly lower using the automated method compared to manual segmentation of the kidneys. CONCLUSION: The 2D CNN method provides fully automated segmentation of the left and right kidney and calculation of TKV in <10 s on a standard office computer, allowing high data throughput and is a freely available executable.

The Use of Multimode Data Collection in Random Digit Dialing Cell Phone Surveys for Young Adults: Feasibility Study.

BACKGROUND: Young adults' early adoption of new cell phone technologies have created challenges to survey recruitment but offer opportunities to combine random digit dialing (RDD) sampling with web mode data collection. The National Young Adult Health Survey was designed to test the feasibility of this methodology. OBJECTIVE: In this study, we compared response rates across the telephone mode and web mode, assessed sample representativeness, examined design effects (DEFFs), and compared cigarette smoking prevalence to a gold standard national survey. METHODS: We conducted a survey experiment where the sampling frame was randomized to single-mode telephone interviews, telephone-to-web sequential mixed mode, and single-mode web survey. A total of 831 respondents aged 18 to 34 years were recruited via RDD at baseline. A soft launch was conducted prior to main launch. We compared the web mode to the telephone modes (ie, single-mode and mixed mode) at wave 1 based on the American Association for Public Opinion Research response rate 3 for screening and extended surveys. Base-weighted demographic distributions were compared to the American Community Survey. The sample was calibrated to the US Census Bureau's American Community Survey to calculate DEFFs and to compare cigarette smoking prevalence to the National Health Interview Survey. Prevalence estimates are estimated with sampling weights and are presented with unweighted sample sizes. Consistency of estimates was judged by 95% CI. RESULTS: The American Association for Public Opinion Research response rate 3 was higher in the telephone mode than in the web mode (24% and 30% vs 6.1% and 12.5%, for soft launch and main launch, respectively), which was reflected in response rate 3 for screening and extended surveys. During the soft launch, the extended survey and eligibility rate were low for respondents pushed to the web mode. To boost productivity and survey completes for the web condition, the main launch used cell phone numbers from the sampling frame where the sample vendor matched the number to auxiliary data, which suggested that the number likely belonged to an adult in the target age range. This increased the eligibility rate, but the screener response rate was lower. Compared to population distribution from the US Census Bureau, the telephone mode overrepresented men (57.1% [unweighted n=412] vs 50.9%) and those enrolled in college (40.3% [unweighted n=269] vs 23.8%); it also underrepresented those with a Bachelor of Arts or Science (34.4% [unweighted n=239] vs 55%). The web mode overrepresented White, non-Latinos (70.7% [unweighted n=90] vs 54.4%) and those with some college education (30.4% [unweighted n=40] vs 7.6%); it also underrepresented Latinos (13.6% [unweighted n=20] vs 20.7%) and those with a high school or General Education Development diploma (15.3% [unweighted n=20] vs 29.3%). The DEFF measure was 1.28 (subpopulation range 0.96-1.93). The National Young Adult Health Survey cigarette smoking prevalence was consistent with the National Health Interview Survey overall (15%, CI 12.4%-18% [unweighted 149/831] vs 13.5%, CI 12.3%-14.7% [unweighted 823/5552]), with notable deviation among 18- to 24-year-olds (15.6%, CI 11.3%-22.2% [unweighted 51/337] vs 8.7%, CI 7.1%-10.6% [unweighted 167/1647]), and those with education levels lower than Bachelor of Arts or Science (24%, CI 19.3%-29.4% [unweighted 123/524] vs 17.1%, CI 15.6%-18.7% [unweighted 690/3493]). CONCLUSIONS: RDD sampling for a web survey is not feasible for young adults due to its low response rate. However, combining this methodology with RDD telephone surveys may have a great potential for including media and collecting autophotographic data in population surveys.

Left Ventricular Torsion Obtained Using Equilibrated Warping in Patients with Repaired Tetralogy of Fallot.

Patients after surgical repair of Tetralogy of Fallot (rTOF) may suffer a decrease in left ventricular (LV) function. The aim of our study is to evaluate a novel method of assessing LV torsion in patients with rTOF, as an early indicator of systolic LV dysfunction. Motion tracking based on image registration regularized by the equilibrium gap principle, known as equilibrated warping, was employed to assess LV torsion. Seventy-six cases of rTOF and ten normal controls were included. The group of controls was assessed for reproducibility using both equilibrated warping and standard clinical tissue tracking software (CVI42, version 5.10.1, Calgary, Canada). Patients were dichotomized into two groups: normal vs. loss of torsion. Torsion by equilibrated warping was successfully obtained in 68 of 76 (89%) patients and 9 of 10 (90%) controls. For equilibrated warping, the intra- and interobserver coefficients of variation were 0.095 and 0.117, respectively, compared to 0.260 and 0.831 for tissue tracking by standard clinical software. The intra- and inter-observer intraclass correlation coefficients for equilibrated warping were 0.862 and 0.831, respectively, compared to 0.992 and 0.648 for tissue tracking. Loss of torsion was noted in 32 of the 68 (47%) patients with rTOF. There was no difference in LV or RV volumes or ejection fraction between these groups. The assessment of LV torsion by equilibrated warping is feasible and shows good reliability. Loss of torsion is common in patients with rTOF and its robust assessment might contribute into uncovering heart failure in an earlier stage.

MicroRNA-155-5p Plays a Critical Role in Transient Leukemia of Down Syndrome by Targeting Tumor Necrosis Factor Receptor Superfamily Members.

BACKGROUND/AIMS: Down syndrome associated disorders are caused by a complex genetic context where trisomy 21 is a central component in relation to other changes involving epigenetic regulators and signaling molecules. This unique genetic context is responsible for the predisposition of people with Down syndrome to acute leukemia. Although, the research in this field has discovered some important pathogenic keys, the exact mechanism of this predisposition is not known. METHODS: In this study we applied functional enrichment analysis to evaluate the interactions between genes localized on chromosome 21, genes already identify as having a key role in acute leukemia of Down syndrome, miRNAs and signaling pathways implicated in cancer and cell development and found that miR-155 has a high impact in genes present on chromosome 21. Forward, we performed next generation sequencing on DNA samples from a cohort of patients diagnosed with acute leukemia of Down syndrome and in vitro functional assay using a CMK-86 cell line, transfected with either mimic or inhibitor of the microRNA-155-5p. RESULTS: Our results show that the epigenetic alteration of the TNF superfamily receptors in Down syndrome, which can be correlated to microRNA-155-5p aberrant activity, may play an important role in cell signaling and thus be linked to acute myeloid leukemia. CONCLUSION: Some genes, already shown to be mutated in AML-DS, are potential targets for miR-155. Our results show that the epigenetic alteration of the TNF superfamily receptors in Down syndrome may play an important role in cell signaling and thus be linked to acute myeloid leukemia.

Plasma HER2ECD a promising test for patient prognosis and prediction of response in HER2 positive breast cancer: results of a randomized study - SAKK 22/99.

BACKGROUND: The HER2 extracellular domain shed in blood (HER2ECD) is reported to rise and fall in parallel with HER2+ breast cancer behavior. In this study, we evaluated the clinical relevance of plasma HER2ECD values in patients with metastatic breast cancer treated in the SAKK22/99 trial comparing trastuzumab monotherapy followed by trastuzumab-chemotherapy combination at progression versus upfront combination therapy. METHODS: Quantitative assessment of plasma HER2ECD was performed in 133 patients at baseline; after 2-24 h; at 3 weeks; at first response evaluation (8-9 weeks); and at tumor progression. Associations with tumor characteristics, disease course and trial treatment were evaluated. RESULTS: Baseline HER2ECD levels were stable within 24 h after the first trastuzumab injection. These plasma values correlated positively with the HER2 gene ratio (rs = 0.39, P < 0.001) and HER2 protein expression levels (rs = 0.36, P < 0.001) but not with ER/PR status of the primary tumor. HER2ECD baseline levels were positively associated with the presence of visceral disease (P = 0.05) and poor patients' outcome (Cox-regression: P = 0.009). Patients with high baseline levels (> 35 ng/ml) had the worst overall survival (P = 0.03) if treated with upfront combination therapy. Conversely, patients with low HER2ECD baseline values (< 15 ng/ml) had longer time to progression on combined trastuzumab-chemotherapy when first treated with trastuzumab monotherapy (P = 0.02). Monitoring HER2ECD levels during the course of the trial revealed significant time (P = 0.001) and time-treatment arm interactions (P = 0.0007). Under upfront trastuzumab alone, the HER2ECD levels remained stable until just before disease progression. In patients responding to combination treatment HER2ECD levels decreased to > 20%. CONCLUSIONS: Plasma HER2ECD levels in patients with metastatic breast cancer reflect HER2 disease status. This robust biomarker might help identifying patients without visceral disease profiting from a sequential treatment's modality. Monitoring HER2ECD levels during trastuzumab monotherapy could help defining the optimal time to introduce chemotherapy. TRIAL REGISTRATION: Registration Number by ClinicalTrials.gov: NCT00004935, Trial number: SAKK22/99. Registered on 27 January 2003.

Vitamin K2 Status and Arterial Stiffness Among Untreated Migraine Patients: A Case-Control Study.

OBJECTIVE: We aimed to examine arterial stiffness and vitamin K2 status in migraine subjects by comparison to controls. BACKGROUND: Migraine is a primary headache disorder that has been associated with an increased risk of cardiovascular events. Mechanisms underlying this increased risk, however, remain unclear. Vitamin K2 deficiency emerged as a cardiovascular risk factor, but vitamin K2 status has never been explored in migraine subjects. DESIGN AND METHODS: This is a case-control, single-center, observational study that includes a cohort of subjects with migraine and their age- and sex-matched controls. Arterial stiffness was measured using carotid-femoral pulse wave velocity (cfPWV). Dephosphorylated-uncarboxylated matrix-Gla-protein (dp-ucMGP) was used as a marker for vitamin K2 status. A propensity-matched scoring method was used. RESULTS: A total of 146 patients (73 matched pairs) were included in this study, of whom 89% were women with a mean age of 31.9 ± 8.4 years. Compared with controls, migraine patients had statistically significantly higher mean cfPWV (7.2 ± 1.1 vs 6.4 ± 0.8 m/s, 95% confidence interval (CI) of mean difference [0.45, 1.08], P < .001), as well as higher dp-ucMGP (454.3 ± 116.7 pmol/L vs 379.8 ± 126.6 pmol/L, 95% CI of mean difference [34.63, 114.31], P < .001). Higher cfPWV was associated with higher dp-ucMGP concentrations only in the migraine with aura (MWA) group. Moreover, migraine subjects had a higher frequency of vitamin K2 deficiency (dp-ucMGP ≥ 500 pmol/L) compared to controls, but this association was not statistically significant (23/73 [31.5%] vs 16/73 [21.9%], P = .193). CONCLUSIONS: Individuals with migraine have worse indices of arterial stiffness as compared with their age- and sex-matched control subjects. This increase in arterial stiffness is associated with an increase in markers of vitamin K2 deficiency in the MWA group.

Exploring the relative efficacy of motion artefact correction techniques for EEG data acquired during simultaneous fMRI.

Simultaneous EEG-fMRI allows multiparametric characterisation of brain function, in principle enabling a more complete understanding of brain responses; unfortunately the hostile MRI environment severely reduces EEG data quality. Simply eliminating data segments containing gross motion artefacts [MAs] (generated by movement of the EEG system and head in the MRI scanner's static magnetic field) was previously believed sufficient. However recently the importance of removal of all MAs has been highlighted and new methods developed. A systematic comparison of the ability to remove MAs and retain underlying neuronal activity using different methods of MA detection and post-processing algorithms is needed to guide the neuroscience community. Using a head phantom, we recorded MAs while simultaneously monitoring the motion using three different approaches: Reference Layer Artefact Subtraction (RLAS), Moiré Phase Tracker (MPT) markers and Wire Loop Motion Sensors (WLMS). These EEG recordings were combined with EEG responses to simple visual tasks acquired on a subject outside the MRI environment. MAs were then corrected using the motion information collected with each of the methods combined with different analysis pipelines. All tested methods retained the neuronal signal. However, often the MA was not removed sufficiently to allow accurate detection of the underlying neuronal signal. We show that the MA is best corrected using the RLAS combined with post-processing using a multichannel, recursive least squares (M-RLS) algorithm. This method needs to be developed further to enable practical utility; thus, WLMS combined with M-RLS currently provides the best compromise between EEG data quality and practicalities of motion detection.

Cryopreservation of red blood cells: Effect on rheologic properties and associated metabolic and nitric oxide related parameters.

AIM: High glycerol cryopreservation of red blood cells (RBCs) reduces metabolic processes at ultralow temperatures but less is known regarding the effect of cryopreservation on RBC nitric oxide (NO) metabolism, haemorheological properties, structural behaviour and membrane fragility. METHODS: Blood from ten healthy participants was sampled, glycerolized and stored at -80 °C (SB). Aliquots were thawed and further processed after 4, 8 and 12 weeks, respectively. At these time points, fresh blood (FB) was additionally sampled from each participant. FB/SB mixtures were prepared corresponding to transfusion of 1-3 blood bags. Additionally, mixtures were exposed to shear stress similar to that found in the circulation and deformability was measured to estimate possible behaviour of cryopreserved RBC in vivo. RESULTS: Ageing of RBC was reduced during cryopreservation. Markers for RBC metabolism (ATP, 2,3-DPG) were not altered but RBC sodium levels increased and potassium and calcium decreased, respectively. Mean cellular volume was higher and accordingly, mean cellular haemoglobin concentration was lower in SB. Deformability was altered during storage with less shear stress necessary to deform RBCs. Changes were also detectable in blood mixtures. Deformability remained unaltered in shear stress settings in FB and SB. RBC viscosity was reduced in SB. RBC-NOS content and phosphorylation sites as well as nitrite and RxNO levels seem not to be affected by the intervention. CONCLUSION: Cryopreservation maintains RBC metabolic function in vitro, but structure and function of cryopreserved RBC seems to be altered. Impact of these alterations in vivo seems to be less but needs further investigation.

Development of VariLeg, an exoskeleton with variable stiffness actuation: first results and user evaluation from the CYBATHLON 2016.

BACKGROUND: Powered exoskeletons are a promising approach to restore the ability to walk after spinal cord injury (SCI). However, current exoskeletons remain limited in their walking speed and ability to support tasks of daily living, such as stair climbing or overcoming ramps. Moreover, training progress for such advanced mobility tasks is rarely reported in literature. The work presented here aims to demonstrate the basic functionality of the VariLeg exoskeleton and its ability to enable people with motor complete SCI to perform mobility tasks of daily life. METHODS: VariLeg is a novel powered lower limb exoskeleton that enables adjustments to the compliance in the leg, with the objective of improving the robustness of walking on uneven terrain. This is achieved by an actuation system with variable mechanical stiffness in the knee joint, which was validated through test bench experiments. The feasibility and usability of the exoskeleton was tested with two paraplegic users with motor complete thoracic lesions at Th4 and Th12. The users trained three times a week, in 60 min sessions over four months with the aim of participating in the CYBATHLON 2016 competition, which served as a field test for the usability of the exoskeleton. The progress on basic walking skills and on advanced mobility tasks such as incline walking and stair climbing is reported. Within this first study, the exoskeleton was used with a constant knee stiffness. RESULTS: Test bench evaluation of the variable stiffness actuation system demonstrate that the stiffness could be rendered with an error lower than 30 Nm/rad. During training with the exoskeleton, both users acquired proficient skills in basic balancing, walking and slalom walking. In advanced mobility tasks, such as climbing ramps and stairs, only basic (needing support) to intermediate (able to perform task independently in 25% of the attempts) skill levels were achieved. After 4 months of training, one user competed at the CYBATHLON 2016 and was able to perform 3 (stand-sit-stand, slalom and tilted path) out of 6 obstacles of the track. No adverse events occurred during the training or the competition. CONCLUSION: Demonstration of the applicability to restore ambulation for people with motor complete SCI was achieved. The CYBATHLON highlighted the importance of training and gaining experience in piloting an exoskeleton, which were just as important as the technical realization of the robot.