Predicting response to neoadjuvant chemotherapy with liquid biopsies and multiparametric MRI in patients with breast cancer.

Accurate prediction of response to neoadjuvant chemotherapy (NAC) can help tailor treatment to individual patients' needs. Little is known about the combination of liquid biopsies and computer extracted features from multiparametric magnetic resonance imaging (MRI) for the prediction of NAC response in breast cancer. Here, we report on a prospective study with the aim to explore the predictive potential of this combination in adjunct to standard clinical and pathological information before, during and after NAC. The study was performed in four Dutch hospitals. Patients without metastases treated with NAC underwent 3 T multiparametric MRI scans before, during and after NAC. Liquid biopsies were obtained before every chemotherapy cycle and before surgery. Prediction models were developed using penalized linear regression to forecast residual cancer burden after NAC and evaluated for pathologic complete response (pCR) using leave-one-out-cross-validation (LOOCV). Sixty-one patients were included. Twenty-three patients (38%) achieved pCR. Most prediction models yielded the highest estimated LOOCV area under the curve (AUC) at the post-treatment timepoint. A clinical-only model including tumor grade, nodal status and receptor subtype yielded an estimated LOOCV AUC for pCR of 0.76, which increased to 0.82 by incorporating post-treatment radiological MRI assessment (i.e., the "clinical-radiological" model). The estimated LOOCV AUC was 0.84 after incorporation of computer-extracted MRI features, and 0.85 when liquid biopsy information was added instead of the radiological MRI assessment. Adding liquid biopsy information to the clinical-radiological resulted in an estimated LOOCV AUC of 0.86. In conclusion, inclusion of liquid biopsy-derived markers in clinical-radiological prediction models may have potential to improve prediction of pCR after NAC in breast cancer.

Personalized neck irradiation guided by sentinel lymph node biopsy in patients with squamous cell carcinoma of the oropharynx, larynx or hypopharynx with a clinically negative neck: (Chemo)radiotherapy to the PRIMary tumor only. Protocol of the PRIMO study.

Background: Elective neck irradiation (ENI) is performed in head and neck cancer patients treated with definitive (chemo)radiotherapy. The aim is to eradicate nodal metastases that are not detectable by pretreatment imaging techniques. It is conceivable that personalized neck irradiation can be performed guided by the results of sentinel lymph node biopsy (SLNB). It is expected that ENI can be omitted to one or both sides of the neck in 9 out of 10 patients, resulting in less radiation side effects with better quality of life. Methods/design: This is a multicenter randomized controlled trial aiming to compare safety and efficacy of treatment with SLNB guided neck irradiation versus standard bilateral ENI in 242 patients with cN0 squamous cell carcinoma of the oropharynx, larynx or hypopharynx for whom bilateral ENI is indicated. Patients randomized to the experimental-arm will undergo SLNB. Based on the histopathologic status of the SLNs, patients will receive no ENI (if all SLNs are negative), unilateral neck irradiation only (if a SLN is positive at one side of the neck) or bilateral neck irradiation (if SLNs are positive at both sides of the neck). Patients randomized to the control arm will not undergo SLNB but will receive standard bilateral ENI. The primary safety endpoint is the number of patients with recurrence in regional lymph nodes within 2 years after treatment. The primary efficacy endpoint is patient reported xerostomia-related quality of life at 6 months after treatment. Discussion: If this trial demonstrates that the experimental treatment is non-inferior to the standard treatment in terms of regional recurrence and is superior in terms of xerostomia-related quality of life, this will become the new standard of care.

Prediction of continuous and discrete kinetic parameters in horses from inertial measurement units data using recurrent artificial neural networks.

Vertical ground reaction force (GRFz) measurements are the best tool for assessing horses' weight-bearing lameness. However, collection of these data is often impractical for clinical use. This study evaluates GRFz predicted using data from body-mounted IMUs and long short-term memory recurrent neural networks (LSTM-RNN). Twenty-four clinically sound horses, equipped with IMUs on the upper-body (UB) and each limb, walked and trotted on a GRFz measuring treadmill (TiF). Both systems were time-synchronised. Data from randomly selected 16, 4, and 4 horses formed training, validation, and test datasets, respectively. LSTM-RNN with different input sets (All, Limbs, UB, Sacrum, or Withers) were trained to predict GRFz curves or peak-GRFz. Our models could predict GRFz shapes at both gaits with RMSE below 0.40 N.kg-1. The best peak-GRFz values were obtained when extracted from the predicted curves by the all dataset. For both GRFz curves and peak-GRFz values, predictions made with the All or UB datasets were systematically better than with the Limbs dataset, showing the importance of including upper-body kinematic information for kinetic parameters predictions. More data should be gathered to confirm the usability of LSTM-RNN for GRFz predictions, as they highly depend on factors like speed, gait, and the presence of weight-bearing lameness.

Correction: Automatic hoof-on and -off detection in horses using hoof-mounted inertial measurement unit sensors.

[This corrects the article DOI: 10.1371/journal.pone.0233266.].

Correction: Automatic detection of break-over phase onset in horses using hoof-mounted inertial measurement unit sensors.

[This corrects the article DOI: 10.1371/journal.pone.0233649.].

Expansion of off-site percutaneous coronary intervention centres significantly reduces ambulance driving time to primary PCI in the Netherlands.

INTRODUCTION: In patients with ST-elevation myocardial infarction (STEMI), percutaneous coronary intervention (PCI)-mediated reperfusion is preferred over pharmacoinvasive reperfusion with fibrinolysis if transfer to a PCI centre can be ensured in ≤120 min. We evaluated the ambulance driving time to primary PCI centres in the Netherlands and assessed to what extent ambulance driving times were impacted by the expansion of off-site PCI centres. METHODS AND RESULTS: We calculated the driving routes from every Dutch postal code to the nearest PCI centre with (on-site) or without (off-site) surgical back-up. We used data from ambulance records to estimate the ambulance driving time on each route. There were 16 on-site and 14 off-site PCI centres. The median (interquartile range) time to on-site PCI centres was 18.8 min (12.2-26.3) compared with 14.9 min (8.9-20.9) to any PCI centre (p < 0.001). In postal code areas that were impacted by the initiation of off-site PCI, the median driving time decreased from 25.4 (18.2-33.1) to 14.7 min (8.9-20.9) (p < 0.001). Ambulance driving times of >120 min were only seen in non-mainland areas. CONCLUSION: Based on a computational model, timely ambulance transfer to a PCI centre within 120 min is available to almost all STEMI patients in the Netherlands. Expansion of off-site PCI has significantly reduced the driving time to PCI centres.

[Artificial intelligence and smartphone program applications (Apps) : Relevance for dermatological practice]. / Künstliche Intelligenz und Smartphone-Programm-Applikationen (Apps) : Bedeutung für die dermatologische Praxis.

ADVANTAGES OF ARTIFICIAL INTELLIGENCE (AI): With responsible, safe and successful use of artificial intelligence (AI), possible advantages in the field of dermato-oncology include the following: (1) medical work can focus on skin cancer patients, (2) patients can be more quickly and effectively treated despite the increasing incidence of skin cancer and the decreasing number of actively working dermatologists and (3) users can learn from the AI results. POTENTIAL DISADVANTAGES AND RISKS OF AI USE: (1) Lack of mutual trust can develop due to the decreased patient-physician contact, (2) additional time effort will be necessary to promptly evaluate the AI-classified benign lesions, (3) lack of adequate medical experience to recognize misclassified AI decisions and (4) recontacting a patient in due time in the case of incorrect AI classifications. Still problematic in the use of AI are the medicolegal situation and remuneration. Apps using AI currently cannot provide sufficient assistance based on clinical images of skin cancer. REQUIREMENTS AND POSSIBLE USE OF SMARTPHONE PROGRAM APPLICATIONS: Smartphone program applications (apps) can be implemented responsibly when the image quality is good, the patient's history can be entered easily, transmission of the image and results are assured and medicolegal aspects as well as remuneration are clarified. Apps can be used for disease-specific information material and can optimize patient care by using teledermatology.

Automatic hoof-on and -off detection in horses using hoof-mounted inertial measurement unit sensors.

For gait classification, hoof-on and hoof-off events are fundamental locomotion characteristics of interest. These events can be measured with inertial measurement units (IMUs) which measure the acceleration and angular velocity in three directions. The aim of this study was to present two algorithms for automatic detection of hoof-events from the acceleration and angular velocity signals measured by hoof-mounted IMUs in walk and trot on a hard surface. Seven Warmblood horses were equipped with two wireless IMUs, which were attached to the lateral wall of the right front (RF) and hind (RH) hooves. Horses were walked and trotted on a lead over a force plate for internal validation. The agreement between the algorithms for the acceleration and angular velocity signals with the force plate was evaluated by Bland Altman analysis and linear mixed model analysis. These analyses were performed for both hoof-on and hoof-off detection and for both algorithms separately. For the hoof-on detection, the angular velocity algorithm was the most accurate with an accuracy between 2.39 and 12.22 ms and a precision of around 13.80 ms, depending on gait and hoof. For hoof-off detection, the acceleration algorithm was the most accurate with an accuracy of 3.20 ms and precision of 6.39 ms, independent of gait and hoof. These algorithms look highly promising for gait classification purposes although the applicability of these algorithms should be investigated under different circumstances, such as different surfaces and different hoof trimming conditions.

Automatic detection of break-over phase onset in horses using hoof-mounted inertial measurement unit sensors.

A prolonged break-over phase might be an indication of a variety of musculoskeletal disorders and can be measured with optical motion capture (OMC) systems, inertial measurement units (IMUs) and force plates. The aim of this study was to present two algorithms for automatic detection of the break-over phase onset from the acceleration and angular velocity signals measured by hoof-mounted IMUs in walk and trot on a hard surface. The performance of these algorithms was evaluated by internal validation with an OMC system and a force plate separately. Seven Warmblood horses were equipped with two wireless IMUs which were attached to the lateral wall of the right front (RF) and hind (RH) hooves. Horses were walked and trotted over a force plate for internal validation while simultaneously the 3D position of three reflective markers, attached to lateral heel, lateral toe and lateral coronet of each hoof, were measured by six infrared cameras of an OMC system. The performance of the algorithms was evaluated by linear mixed model analysis. The acceleration algorithm was the most accurate with an accuracy between -9 and 23 ms and a precision around 24 ms (against OMC system), and an accuracy between -37 and 20 ms and a precision around 29 ms (against force plate), depending on gait and hoof. This algorithm seems promising for quantification of the break-over phase onset although the applicability for clinical purposes, such as lameness detection and evaluation of trimming and shoeing techniques, should be investigated more in-depth.

Early detection and follow-up of colorectal neoplasia based on faecal volatile organic compounds.

AIM: Early detection and removal of colorectal cancer (CRC) and advanced adenomas (AAs) decreases the incidence of and mortality from the disease. We aimed to evaluate the potential of faecal volatile organic compounds (VOCs) for detection and follow-up of colorectal adenoma using advanced electronic nose technology. METHOD: This was a prospective multi-centre case-control cohort including two district hospitals and one tertiary referral hospital. Patients undergoing colonoscopy were instructed to collect a faecal sample prior to bowel cleansing and were included in the study when CRC, AAs, large adenomas (LAs; 0.5-1.0 cm), small adenomas (SAs; 0.1-0.5 cm) or no endoscopic abnormalities (controls) were observed. Patients undergoing polypectomy and controls were asked for a second sample after 3 months. Faecal VOCs were measured with gas chromatography-ion mobility spectrometry. Random forest, support vector machine, Gaussian process and neural net classification were used to evaluate accuracy. RESULTS: In total, 14 patients with CRC, 64 with AAs, 69 with LAs, 127 with SAs and 227 controls were included. A second sample was collected from 32 polypectomy patients and 32 controls. Faecal VOCs discriminated CRC and adenomas from control [AUC (95% CI): CRC vs control 0.96 (0.89-1); AA vs control 0.96 (0.93-1); LA vs control 0.96 (0.92-0.99); SA vs control 0.96 (0.94-0.99)]. There were no significant differences between CRC and adenoma groups. Patients with adenomas and controls were discriminated prior to polypectomy, whereas 3 months after polypectomy VOC profiles were similar [T0 adenoma vs control 0.98 (0.95-1); T1 adenoma vs control 0.55 (0.40-0.69)]. CONCLUSIONS: Faecal VOC profiles may be useful for early detection of CRC and adenomas and the timing of polyp surveillance as polypectomy led to a normalization of the VOC profile.

Reductive catalytic fractionation of pine wood: elucidating and quantifying the molecular structures in the lignin oil.

In-depth structural analysis of biorefined lignin is imperative to understand its physicochemical properties, essential for its efficient valorization to renewable materials and chemicals. Up to now, research on Reductive Catalytic Fractionation (RCF) of lignocellulose biomass, an emerging biorefinery technology, has strongly focused on the formation, separation and quantitative analysis of the abundant lignin-derived phenolic monomers. However, detailed structural information on the linkages in RCF lignin oligomers, constituting up to 50 wt% of RCF lignin, and their quantification, is currently lacking. This study discloses new detailed insights into the pine wood RCF lignin oil's molecular structure through the combination of fractionation and systematic analysis, resulting in the first assignment of the major RCF-derived structural units in the 1H-13C HSQC NMR spectrum of the RCF oligomers. Specifically, ß-5 γ-OH, ß-5 ethyl, ß-1 γ-OH, ß-1 ethyl, ß-ß 2x γ-OH, ß-ß THF, and 5-5 inter-unit linkages were assigned unambiguously, resulting in the quantification of over 80% of the lignin inter-unit linkages and end-units. Detailed inspection of the native lignin inter-unit linkages and their conversion reveals the occurring hydrogenolysis chemistry and the unambiguous proof of absence of lignin fragment condensation during proper RCF processing. Overall, the study offers an advanced analytical toolbox for future RCF lignin conversion and lignin structural analysis research, and valuable insights for lignin oil valorization purposes.

A "scattered" SCAT in a football goalkeeper: a case report.

Background: In an acute field-side setting, it is often challenging to differentiate benign sports-related concussion (SRC) from potential, more sinister, intracranial pathology. Moreover, recovery in the ensuing days and weeks is often complex as the resolution of classical signs and symptoms does not always follow a standard pattern. Aim: To highlight the value of a structured and repeated thorough clinical assessment approach toward SRC, particularly as atypical and unexpected sequences in patient recovery patterns may require further specialist referral and intervention. Findings: A football goalkeeper sustained a concussion in which symptoms failed to resolve as expected. Deterioration in his clinical condition led to an eventual diagnosis of Chiari malformation (type I), which required surgical intervention. Implications: Non-typical recovery patterns of concussion may be indicative of increased severity when considered retrospectively. However, clinicians should not discount the possibility of underlying conditions.

Between-subject variability in the influence of mental imagery on conscious perception.

Mental imagery and visual perception rely on similar neural mechanisms, but the function of this overlap remains unclear. One idea is that imagery can influence perception. Previous research has shown that imagining a stimulus prior to binocular presentation of rivalling stimuli increases the chance of perceiving the imagined stimulus. In this study we investigated how this effect interacts with bottom-up sensory input by comparing psychometric response curves for congruent and incongruent imagery in humans. A Bayesian hierarchical model was used, allowing us to simultaneously study group-level effects as well as effects for individual participants. We found strong effects of both imagery as well as its interaction with sensory evidence within individual participants. However, the direction of these effects were highly variable between individuals, leading to weak effects at the group level. This highlights the heterogeneity of conscious perception and emphasizes the need for individualized investigation of such complex cognitive processes.

Oral & Maxillofacial surgery is ready for patient-centred eHealth interventions - the outcomes of a scoping review.

Within the field of oral and maxillofacial (OMF) surgery, eHealth is expected to be a tool to improve quality of care. The aim of this study is to map the research of patient-centred eHealth interventions within OMF surgery by means of a scoping review. After a systematic literature search, relevant studies on patient-centred eHealth interventions for OMF-surgery patients were selected. The interventions were mapped based on their key components, target population and outcome measures. To gain insight in the research phase of evaluation, the framework of the Medical Research Council (MRC) was used. Forty-one papers were included, comprising 34 unique interventions. Nineteen interventions were designed for head and neck cancer patients, 11 interventions concernd video-teleconsultation. According to the MRC framework, 26 papers fitted into the feasibility and piloting phase of research, 8 into the evaluation phase, 7 were in the development phase. No implementation studies were found. This scoping review can be a starting point for those who are interested in applying and evaluating eHealth in their practice. Since many feasibility and pilot studies were found on similar interventions, a more extensive collaboration with and connecting to each other is recommended to catalyze the implementation of eHealth in daily practice. Profound involvement of patients in developing and evaluating eHealth interventions is essential to achieve true patient-centred OMF surgery.

Catalytic Strategies Towards Lignin-Derived Chemicals.

Lignin valorization represents a crucial, yet underexploited component in current lignocellulosic biorefineries. An alluring opportunity is the selective depolymerization of lignin towards chemicals. Although challenged by lignin's recalcitrant nature, several successful (catalytic) strategies have emerged. This review provides an overview of different approaches to cope with detrimental lignin structural alterations at an early stage of the biorefinery process, thus enabling effective routes towards lignin-derived chemicals. A first general strategy is to isolate lignin with a better preserved native-like structure and therefore an increased amenability towards depolymerization in a subsequent step. Both mild process conditions as well as active stabilization methods will be discussed. An alternative is the simultaneous depolymerization-stabilization of native lignin towards stable lignin monomers. This approach requires a fast and efficient stabilization of reactive lignin intermediates in order to minimize lignin repolymerization and maximize the envisioned production of chemicals. Finally, the obtained lignin-derived compounds can serve as a platform towards a broad range of bio-based products. Their implementation will improve the sustainability of the chemical industry, but equally important will generate opportunities towards product innovations based on unique biobased chemical structures.

Chemicals from lignin: an interplay of lignocellulose fractionation, depolymerisation, and upgrading.

In pursuit of more sustainable and competitive biorefineries, the effective valorisation of lignin is key. An alluring opportunity is the exploitation of lignin as a resource for chemicals. Three technological biorefinery aspects will determine the realisation of a successful lignin-to-chemicals valorisation chain, namely (i) lignocellulose fractionation, (ii) lignin depolymerisation, and (iii) upgrading towards targeted chemicals. This review provides a summary and perspective of the extensive research that has been devoted to each of these three interconnected biorefinery aspects, ranging from industrially well-established techniques to the latest cutting edge innovations. To navigate the reader through the overwhelming collection of literature on each topic, distinct strategies/topics were delineated and summarised in comprehensive overview figures. Upon closer inspection, conceptual principles arise that rationalise the success of certain methodologies, and more importantly, can guide future research to further expand the portfolio of promising technologies. When targeting chemicals, a key objective during the fractionation and depolymerisation stage is to minimise lignin condensation (i.e. formation of resistive carbon-carbon linkages). During fractionation, this can be achieved by either (i) preserving the (native) lignin structure or (ii) by tolerating depolymerisation of the lignin polymer but preventing condensation through chemical quenching or physical removal of reactive intermediates. The latter strategy is also commonly applied in the lignin depolymerisation stage, while an alternative approach is to augment the relative rate of depolymerisation vs. condensation by enhancing the reactivity of the lignin structure towards depolymerisation. Finally, because depolymerised lignins often consist of a complex mixture of various compounds, upgrading of the raw product mixture through convergent transformations embodies a promising approach to decrease the complexity. This particular upgrading approach is termed funneling, and includes both chemocatalytic and biological strategies.

Convolutional neural network-based encoding and decoding of visual object recognition in space and time.

Representations learned by deep convolutional neural networks (CNNs) for object recognition are a widely investigated model of the processing hierarchy in the human visual system. Using functional magnetic resonance imaging, CNN representations of visual stimuli have previously been shown to correspond to processing stages in the ventral and dorsal streams of the visual system. Whether this correspondence between models and brain signals also holds for activity acquired at high temporal resolution has been explored less exhaustively. Here, we addressed this question by combining CNN-based encoding models with magnetoencephalography (MEG). Human participants passively viewed 1,000 images of objects while MEG signals were acquired. We modelled their high temporal resolution source-reconstructed cortical activity with CNNs, and observed a feed-forward sweep across the visual hierarchy between 75 and 200 ms after stimulus onset. This spatiotemporal cascade was captured by the network layer representations, where the increasingly abstract stimulus representation in the hierarchical network model was reflected in different parts of the visual cortex, following the visual ventral stream. We further validated the accuracy of our encoding model by decoding stimulus identity in a left-out validation set of viewed objects, achieving state-of-the-art decoding accuracy.

[Learning to see things from a different perspective: interns and residents collaborate with artists to become better doctors]. / Anders leren kijken en de ander leren zien.

In 2016 and 2017, we started an innovative learning track in the Radboudumc that combines arts and medical education, and appraised the learning processes involved. The voluntary track was followed by 32 and 30 participants respectively, mostly interns and a few residents. The initiative built upon the ideas of several American educational developments which incorporated museum visits. We extended the format by having participants join artists in their studios, to allow students to have an immersive experience of a different discipline, rather than only observing its end products. The track did not have specific learning objectives. However, participants were encouraged to set personal goals and to reflect on what they learned in terms of observation skills, creative thinking, personalized health care, and frame reflection. Here we report the rationale of the track, and illustrate preliminary conclusions with participants' quotes.

Abscisic acid regulates seed germination of Vellozia species in response to temperature.

The relationship between the phytohormones, gibberellin (GA) and abscisic acid (ABA) and light and temperature on seed germination is still not well understood. We aimed to investigate the role of the ABA and GA on seed germination of Vellozia caruncularis, V. intermedia and V. alutacea in response to light/dark conditions on different temperature. Seeds were incubated in GA (GA3 or GA4 ) or ABA and their respective biosynthesis inhibitors (paclobutrazol - PAC, and fluridone - FLU) solutions at two contrasting temperatures (25 and 40 °C). Furthermore, endogenous concentrations of active GAs and those of ABA were measured in seeds of V. intermedia and V. alutacea during imbibition/germination. Exogenous ABA inhibited the germination of Vellozia species under all conditions tested. GA, FLU and FLU + GA3 stimulated germination in the dark at 25 °C (GA4 being more effective than GA3 ). PAC reduced seed germination in V. caruncularis and V. alutacea, but did not affect germination of V. intermedia at 40 °C either under light or dark conditions. During imbibition in the dark, levels of active GAs decreased in the seeds of V. intermedia, but were not altered in those of V. alutacea. Incubation at 40 °C decreased ABA levels during imbibition in both V. caruncularis and V. alutacea. We conclude that the seeds of Vellozia species studied here require light or high temperature to germinate and ABA has a major role in the regulation of Vellozia seed germination in response to light and temperature.

Validation of distal limb mounted inertial measurement unit sensors for stride detection in Warmblood horses at walk and trot.

BACKGROUND: Inertial measurement unit (IMU) sensor-based techniques are becoming more popular in horses as a tool for objective locomotor assessment. OBJECTIVES: To describe, evaluate and validate a method of stride detection and quantification at walk and trot using distal limb mounted IMU sensors. STUDY DESIGN: Prospective validation study comparing IMU sensors and motion capture with force plate data. METHODS: A total of seven Warmblood horses equipped with metacarpal/metatarsal IMU sensors and reflective markers for motion capture were hand walked and trotted over a force plate. Using four custom built algorithms hoof-on/hoof-off timing over the force plate were calculated for each trial from the IMU data. Accuracy of the computed parameters was calculated as the mean difference in milliseconds between the IMU or motion capture generated data and the data from the force plate, precision as the s.d. of these differences and percentage of error with accuracy of the calculated parameter as a percentage of the force plate stance duration. RESULTS: Accuracy, precision and percentage of error of the best performing IMU algorithm for stance duration at walk were 28.5, 31.6 ms and 3.7% for the forelimbs and -5.5, 20.1 ms and -0.8% for the hindlimbs, respectively. At trot the best performing algorithm achieved accuracy, precision and percentage of error of -27.6/8.8 ms/-8.4% for the forelimbs and 6.3/33.5 ms/9.1% for the hindlimbs. MAIN LIMITATIONS: The described algorithms have not been assessed on different surfaces. CONCLUSIONS: Inertial measurement unit technology can be used to determine temporal kinematic stride variables at walk and trot justifying its use in gait and performance analysis. However, precision of the method may not be sufficient to detect all possible lameness-related changes. These data seem promising enough to warrant further research to evaluate whether this approach will be useful for appraising the majority of clinically relevant gait changes encountered in practice.