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Abstract Freehand optical ultrasound (OpUS) imaging is an emerging ultrasound imaging paradigm that uses an array of fibre-optic, photoacoustic ultrasound sources and a single fibre-optic ultrasound detector to perform ultrasound imaging without the need for electrical components in the probe head. Previous freehand OpUS devices have demonstrated capability for real-time, video-rate imaging of clinically relevant targets, but have been hampered by poor ultrasound penetration, significant imaging artefacts and low frame rates, and their designs limited their clinical applicability. In this work we present a novel freehand OpUS imaging platform, including a fully mobile and compact acquisition console and an improved probe design. The novel freehand OpUS probe presented utilises optical waveguides to shape the generated ultrasound fields for improved ultrasound penetration depths, an extended fibre-optic bundle to improve system versatility and an overall ruggedised design with protective elements to improve probe handling and protect the internal optical components. This probe is demonstrated with phantoms and the first multi-participant in vivo imaging study conducted with freehand OpUS imaging probes, this represents several significant steps towards the clinical translation of freehand OpUS imaging.

Abstract In the context of soft matter and cellular mechanics, microrheology - the use of micron-sized particles to probe the frequency-dependent viscoelastic response of materials – is widely used to shed light onto the mechanics and dynamics of molecular structures. Here we present the implementation of active microrheology in an Acoustic Force Spectroscopy setup (AFMR), which combines multiplexing with the possibility of probing a wide range of forces ( ~ pN to ~nN) and frequencies (0.01–100 Hz). To demonstrate the potential of this approach, we perform active microrheology on biological samples of increasing complexity and stiffness: collagen gels, red blood cells (RBCs), and human fibroblasts, spanning a viscoelastic modulus range of five orders of magnitude. We show that AFMR can successfully quantify viscoelastic properties by probing many beads with high single-particle precision and reproducibility. Finally, we demonstrate that AFMR to map local sample heterogeneities as well as detect cellular responses to drugs.

Optical ultrasound (OpUS) imaging is an ultrasound modality that utilizes fiber-optic ultrasound sources and detectors to perform pulse-echo ultrasound imaging. These probes can be constructed entirely from glass optical fibers and plastic components, and as such, these devices have been predicted to be compatible with computed tomography (CT) and magnetic resonance imaging (MRI), modalities that use intense electromagnetic fields for imaging. However, to date, this compatibility has not been demonstrated. In this work, a free-hand OpUS imaging system was developed specifically to investigate the compatibility of OpUS systems with CT and MRI imaging systems. The OpUS imaging platform discussed in this work was used to perform real-time OpUS imaging under (separately) concurrent CT and MRI. CT and MRI imaging of the OpUS probe was used to determine if the probe itself would induce artifacts in the CT and MRI imaging, and ultrasound resolution targets and background measurements were used to assess any impact of CT and MRI on the OpUS signal fidelity. These measurements demonstrate that there was negligible interaction between the OpUS system and both the CT and MRI systems, and to further demonstrate this capability, concurrent OpUS-CT and OpUS-MRI imaging was conducted of a tissue-mimicking phantom and a dynamic motion phantom. This work presents a comprehensive demonstration of an OpUS imaging system operating alongside CT and MRI, which opens up new applications of ultrasound imaging in electromagnetically challenging settings.

Abstract Intraflagellar transport (IFT) orchestrates entry of proteins into primary cilia. At the ciliary base, assembled IFT trains, driven by kinesin-2 motors, can transport cargo proteins into the cilium, across the crowded transition zone. How trains assemble at the base and how proteins associate with them is far from understood. Here, we use single-molecule imaging in the cilia of C. elegans chemosensory neurons to directly visualize the entry of kinesin-2 motors, kinesin-II and OSM-3, as well as anterograde cargo proteins, IFT dynein and tubulin. Single-particle tracking shows that IFT components associate with trains sequentially, both in time and space. Super-resolution maps of IFT components in wild-type and mutant worms reveal ciliary ultrastructure and show that kinesin-II is essential for axonemal organization. Finally, imaging cilia lacking kinesin-II and/or transition zone function uncovers the interplay of kinesin-II and OSM-3 in driving efficient transport of IFT trains across the transition zone.

Abstract Background Nowadays, large benign lateral spreading lesions (LSLs) and sessile polyps in the colorectum are mostly resected by endoscopic mucosal resection (EMR). A major drawback of EMR is the polyp recurrence rate of up to 20%. Snare tip soft coagulation (STSC) is considered an effective technique to reduce recurrence rates. However, clinical trials on STSC have mainly been conducted in expert referral centers. In these studies, polyp recurrence was assessed optically, and additional adjunctive techniques were excluded. In the current trial, we will evaluate the efficacy and safety of STSC in daily practice, by allowing adjunctive techniques during EMR and the use of both optical and histological polyp recurrence to assess recurrences during follow-up. Methods The RESPECT study is a multicenter, parallel-group, international single blinded randomized controlled superiority trial performed in the Netherlands and Germany. A total of 306 patients undergoing piecemeal EMR for LSLs or sessile colorectal polyps sized 20–60 mm will be randomized during the procedure after endoscopic complete polyp resection to the intervention or control group. Post-EMR defects allocated to the intervention group will be treated with thermal ablation with STSC of the entire resection margin. Primary outcome will be polyp recurrence by optical and histological confirmation at the first surveillance colonoscopy after 6 months. Secondary outcomes include technical success and complication rates. Discussion The RESPECT study will evaluate if STSC is effective in reducing recurrence rates after piecemeal EMR of large colorectal lesions in daily clinical practice performed by expert and non-expert endoscopists. Moreover, endoscopists will be allowed to use adjunctive techniques to remove remaining adenomatous tissue during the procedure. Finally, adenomatous polyp recurrence during follow-up will be defined by histologic identification. Trial registration ClinicalTrials.gov NCT05121805. Registered on 16 November 2021. Start recruitment: 17 March 2022. Planned completion of recruitment: 31 April 2025.

Abstract Background The goal is to estimate the additional value of ultrasonographic optic nerve sheath diameter (ONSD) measurement on days 1–3, on top of electroencephalography (EEG), pupillary light reflexes (PLR), and somatosensory evoked potentials (SSEP), for neurological outcome prediction of comatose cardiac arrest patients. We performed a prospective longitudinal cohort study in adult comatose patients after cardiac arrest. ONSD was measured on days 1–3 using ultrasound. Continuous EEG, PLR, and SSEP were acquired as standard care. Poor outcome was defined as cerebral performance categories 3–5 at 3–6 months. Logistic regression models were created for outcome prediction based on the established predictors with and without ONSD. Additional predictive value was assessed by increase in sensitivity for poor (at 100% specificity) and good outcome (at 90% specificity). Results We included 100 patients, 54 with poor outcome. Mean ONSD did not differ significantly between patients with good and poor outcome. Sensitivity for predicting poor outcome increased by adding ONSD to EEG and SSEP from 25% to 41% in all patients and from 27% to 50% after exclusion of patients with non-neurological death. Conclusions ONSD on days 1–3 after cardiac arrest holds potential to add to neurological outcome prediction. Trial registration: clinicaltrials.gov, NCT04084054. Registered 10 September 2019, https://www.clinicaltrials.gov/study/NCT04084054 .

Many studies have been performed in different regions of the world as a result of the COVID-19 pandemic. In this work, we perform a statistical study related to the number of vaccinated cases and the number of deaths due to COVID-19 in ten South American countries. Our objective is to group countries according to the aforementioned variables. Once the groups of countries are built, they are characterized based on common properties of countries in the same group and differences between countries that are in different groups. Countries are grouped using principal component analysis and K-means analysis. These methods are combined in a single procedure that we propose for the classification of the countries. Regarding both variables, the countries were classified into three groups. Political decisions, availability of resources, bargaining power with suppliers and health infrastructure among others are some of the factors that can affect both the vaccination process and the timely care of infected people to avoid death. In general, the countries acted in a timely manner in relation to the vaccination of their citizens with the exception of two countries. Regarding the number of deaths, all countries reached peaks at some point in the study period.

Knowing that something is unknown is an important part of human cognition. While Bayesian models of cognition have been successful in explaining many aspects of human learning, current explanations of how humans realise that they need to introduce a new concept are problematic. Bayesian models lack a principled way to describe ignorance, as doing so requires comparing the probabilities of concepts in the model with the probabilities of concepts not present in the model, which is by definition impossible. Formal definitions of uncertainty (e.g. Shannon-entropy) are commonly used as a substitute for ignorance, but we will show that these concepts are fundamentally distinct, and thus that something more is needed. Enhancing probability theory to allow Bayesian agents to conclude that they are ignorant would be an important advance for both cognitive engineering and cognitive science. In this research project, we formally analyse this challenge.

Cutaneous melanoma is the deadliest form of skin neoplasm and its high mortality rates could be averted by early accurate detection. While the detection of melanoma is currently reliant upon melanin visualisation, research into melanosome biogenesis, as a key driver of pathogenesis, has not yielded technology that can reliably distinguish between atypical benign, amelanotic and melanotic lesions. The endosomal-lysosomal system has important regulatory roles in cancer cell biology, including a specific functional role in melanosome biogenesis. Herein, the involvement of the endosomal-lysosomal system in melanoma was examined by pooled secondary analysis of existing gene expression datasets. A set of differentially expressed endosomal-lysosomal genes was identified in melanoma, which were interconnected by biological function. To illustrate the protein expression of the dysregulated genes, immunohistochemistry was performed on samples from patients with cutaneous melanoma to reveal candidate markers. This study demonstrated the dysregulation of Syntenin-1, Sortilin and Rab25 may provide a differentiating feature between cutaneous melanoma and squamous cell carcinoma, while IGF2R may indicate malignant propensity in these skin cancers.

Individuals are readily able to extract and encode statisticalinformation from their environment (or statistical learning).However, the bulk of the literature has primarily focused onconditional statistical learning (i.e. the ability to learn joint andconditional relationships between stimuli), and has largelyneglected distributional statistical learning (i.e. the ability tolearn the frequency and variability of distributions). In thispaper, we investigate how and how well distributional learningcan be measured by exploring the relationship between andpsychometric properties of two measures: discriminationjudgements and frequency estimates. Reliable performancewas observed in both measures across two differentdistributional learning tasks (natural and artificial).Discrimination judgements and frequency estimates alsosignificantly correlated with one another in both tasks, andperformance on all tasks accounted for the majority of varianceacross tasks (55%). These results suggest that distributionallearning can be measured reliably, and may tap into both theability to discriminate between relative frequencies and toexplicitly estimate them.

Abstract Background Chronic pancreatitis (CP) is an inflammatory disease that may be complicated by abdominal pain, pancreatic dysfunction, nutritional deficiencies, and diminished bone density. Importantly, it is also associated with a substantially impaired quality of life and reduced life expectancy. This may partly be explained by suboptimal treatment, in particular the long-term management of this chronic condition, despite several national and international guidelines. Standardization of care through a structured implementation of guideline recommendations may improve the level of care and lower the complication rate of these patients. Therefore, the aim of the present study is to evaluate to what extent patient education and standardization of care, through the implementation of an evidence-based integrated management algorithm, improve quality of life and reduce pain severity in patients with CP. Methods The COMBO trial is a nationwide stepped-wedge cluster-randomized controlled trial. In a stepwise manner, 26 centers, clustered in 6 health regions, cross-over from current practice to care according to an evidence-based integrated management algorithm. During the current practice phase, study participants are recruited and followed longitudinally through questionnaires. Individual patients contribute data to both study periods. Co-primary study endpoints consist of quality of life (assessed by the PANQOLI score) and level of pain (assessed by the Izbicki questionnaire). Secondary outcomes include process measure outcomes, clinical outcomes (e.g., pancreatic function, nutritional status, bone health, interventions, medication use), utilization of healthcare resources, (in) direct costs, and the level of social participation. Standard follow-up is 35 months from the start of the trial. Discussion This is the first stepped-wedge cluster-randomized controlled trial to investigate whether an evidence-based integrated therapeutic approach improves quality of life and pain severity in patients with CP as compared with current practice. Trial registration ISRCTN, ISRCTN13042622. Registered on 5 September 2020.