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Abstract The count of mitotic figures (MFs) observed in hematoxylin and eosin (H&E)-stained slides is an important prognostic marker, as it is a measure for tumor cell proliferation. However, the identification of MFs has a known low inter-rater agreement. In a computer-aided setting, deep learning algorithms can help to mitigate this, but they require large amounts of annotated data for training and validation. Furthermore, label noise introduced during the annotation process may impede the algorithms’ performance. Unlike H&E, where identification of MFs is based mainly on morphological features, the mitosis-specific antibody phospho-histone H3 (PHH3) specifically highlights MFs. Counting MFs on slides stained against PHH3 leads to higher agreement among raters and has therefore recently been used as a ground truth for the annotation of MFs in H&E. However, as PHH3 facilitates the recognition of cells indistinguishable from H&E staining alone, the use of this ground truth could potentially introduce an interpretation shift and even label noise into the H&E-related dataset, impacting model performance. This study analyzes the impact of PHH3-assisted MF annotation on inter-rater reliability and object level agreement through an extensive multi-rater experiment. Subsequently, MF detectors, including a novel dual-stain detector, were evaluated on the resulting datasets to investigate the influence of PHH3-assisted labeling on the models’ performance. We found that the annotators’ object-level agreement significantly increased when using PHH3-assisted labeling (F1: 0.53 to 0.74). However, this enhancement in label consistency did not translate to improved performance for H&E-based detectors, neither during the training phase nor the evaluation phase. Conversely, the dual-stain detector was able to benefit from the higher consistency. This reveals an information mismatch between the H&E and PHH3-stained images as the cause of this effect, which renders PHH3-assisted annotations not well-aligned for use with H&E-based detectors. Based on our findings, we propose an improved PHH3-assisted labeling procedure.

Abstract Background Hip fracture is very common and it has life-shattering consequences for older persons. After discharge the older persons need help with even basic everyday activities from formal and informal caregivers. In Scandinavia formal care are well-developed however the presence of informal caregivers likely reflect on the amount of formal care and wears on the informal caregivers. This study explore how often and how much informal care (IC) older persons receive after hip fracture. Method We contacted 244 community-dwelling older persons every two weeks the first twelve weeks after discharge after hip fracture and asked them if they received care from family and/or friends and how much. We used non-parametric statistics and level of significance was 95%. Results The proportion of older persons receiving IC was 90% and the median amount of IC was 32 hours (IQR 14-66). The number of older persons who received IC was highest the first four weeks after discharge and so was the amount of hours of IC. The older persons that were high-dependence on IC received a median of 66 (IQR 46-107) hours compared to the low-dependent of 11 hours (IQR 2-20). Conclusion IC is very frequent, especially the first two to four weeks after discharge. The median IC was 32 hours from discharge to the 12-week follow-up. However, this figure tended to rise for persons with, among other, reduced functionality and those residing with a partner. Implications With respect to local differences, the findings in this study are likely applicable to other Scandinavian countries. We strongly suggest that the variation in older person need for informal caregiver be given consideration in the prioritisation of resources. Trial registration This prospective cohort study of informal care, was part of a cluster-randomised stepped-wedge clinical controlled trial. Written consent was obtained required by regional ethics committee S-20200070. Data was collected in accordance with the Danish Data Protection Agency (20-21854).

Abstract The prognostic value of mitotic figures in tumor tissue is well-established for many tumor types and automating this task is of high research interest. However, especially deep learning-based methods face performance deterioration in the presence of domain shifts, which may arise from different tumor types, slide preparation and digitization devices. We introduce the MIDOG++ dataset, an extension of the MIDOG 2021 and 2022 challenge datasets. We provide region of interest images from 503 histological specimens of seven different tumor types with variable morphology with in total labels for 11,937 mitotic figures: breast carcinoma, lung carcinoma, lymphosarcoma, neuroendocrine tumor, cutaneous mast cell tumor, cutaneous melanoma, and (sub)cutaneous soft tissue sarcoma. The specimens were processed in several laboratories utilizing diverse scanners. We evaluated the extent of the domain shift by using state-of-the-art approaches, observing notable differences in single-domain training. In a leave-one-domain-out setting, generalizability improved considerably. This mitotic figure dataset is the first that incorporates a wide domain shift based on different tumor types, laboratories, whole slide image scanners, and species.

BackgroundDigitally supported self-management tailored to an individual’s need, in addition to usual care, may reduce pain-related disability compared to usual care alone, and patients with low back pain (LBP) using mobile health (mHealth) solutions express positive experiences. Hence, implementing mHealth solutions designed to support self-management is desirable from a clinical and patient perspective. Easily accessible mHealth solutions that can support the self-management of patients with LBP are available, but interest may be subgroup specific. Understanding the characteristics and preferences of patients with LBP labeled as interested may help to reach relevant LBP patient groups and inform the development and implementation of effective interventions with mHealth for patients with LBP. ObjectiveThis study aims to explore the proportion of patients with LBP labeled as interested in testing an mHealth solution designed to support self-management in addition to usual care and to assess how these patients differ from those who were labeled as not interested. MethodsThis exploratory cross-sectional study analyzed demographic and patient-reported outcomes from the SpineData registry, a Danish registry of patients with LBP in an outpatient setting. Between February and December 2019, the SpineData registry was used to assess the preliminary eligibility of patients for a clinical trial (selfBACK). Patients were labeled as interested or uninterested depending on if they responded to an invitation to be tested for eligibility for the trial Outcomes were selected from the International Classification of Functioning core set of LBP using a clinical approach. Associations were assessed in a backward selection process, and the proportion of variance explained was assessed with pseudo-R2 statistic. ResultsThis study included 843 patients, with 181 (21%) individuals labeled as interested in participating in the selfBACK trial. Notably, the cohort labeled as interested differed from their uninterested counterparts in two key aspects: age (36-65 years: 116/181, 64.1% vs 347/662, 52.4%; P=.003) and smoking status (smokers: 22/181, 12.5% vs 174/662, 26.6%; P

Abstract Background A hip fracture is a serious event for older adults, given that approximately 50% do not regain their habitual level of physical function, and the mortality rate is high, as is the number of readmissions. The gap in healthcare delivery, as separated into two financial and self-governing sectors, might be a contributing cause of inferior rehabilitation and care for these patients. Therefore, we aim to assess the effect of continuous and progressive rehabilitation and care across sectors for older adults after hip fracture. Methods/design The project is designed as a stepped-wedge cluster randomised controlled trial. The study population of patients are older adults 65 years of age and above discharged after a hip fracture and healthcare professionals in primary and secondary care (municipalities and hospitals). Healthcare professionals from different sectors (hospital and municipalities) will be engaged in the empowerment-orientated praxis, through a workshop for healthcare professionals with knowledge sharing to the older adults using a digital health application (app). The rehabilitation intervention consists of 12 weeks of progressive resistance exercises initiated 1–2 days after discharge. To improve communication across sectors, a videoconference involving the patient and physiotherapists from both sectors will be conducted. On day, 3 after discharge, an outreach nurse performs a thorough assessment including measurement of vital signs. A hotline to the hospital for medical advice is a part of the intervention. The intervention is delivered as an add-on to the usual rehabilitation and care, and it involves one regional hospital and the municipalities within the catchment area of the hospital. The primary outcome is a Timed Up and Go Test 8 weeks post-surgery. Discussion Using a stepped-wedge design, the intervention will be assessed as well as implemented in hospital and municipalities, hopefully for the benefit of older adults after hip fracture. Furthermore, the collaboration between the sectors is expected to improve. Trial registration The study is approved by the Regional Scientific Ethics Committees of Southern Denmark (S-20200070) and the Danish Data Protection Agency (20-21854). Registered 9 of June 2020 at ClinicalTrials.gov, NCT04424186 .

In this overview, the latest achievements in dietary origins, absorption mechanism, bioavailability assay, health advantages, cutting-edge encapsulation techniques, fortification approaches, and innovative highly sensitive sensor-based detection methods of vitamin B12 (VB12) were addressed. The cobalt-centered vitamin B is mainly found in animal products, posing challenges for strict vegetarians and vegans. Its bioavailability is highly influenced by intrinsic factor, absorption in the ileum, and liver reabsorption. VB12 mainly contributes to blood cell synthesis, cognitive function, and cardiovascular health, and potentially reduces anemia and optic neuropathy. Microencapsulation techniques improve the stability and controlled release of VB12. Co-microencapsulation of VB12 with other vitamins and bioactive compounds enhances bioavailability and controlled release, providing versatile initiatives for improving bio-functionality. Nanotechnology, including nanovesicles, nanoemulsions, and nanoparticles can enhance the delivery, stability, and bioavailability of VB12 in diverse applications, ranging from antimicrobial agents to skincare and oral insulin delivery. Staple food fortification with encapsulated and free VB12 emerges as a prominent strategy to combat deficiency and promote nutritional value. Biosensing technologies, such as electrochemical and optical biosensors, offer rapid, portable, and sensitive VB12 assessment. Carbon dot-based fluorescent nanosensors, nanocluster-based fluorescent probes, and electrochemical sensors show promise for precise detection, especially in pharmaceutical and biomedical applications.

Abstract Driving a car requires high cognitive demands, from sustained attention to perception and action planning. Recent research investigated the neural processes reflecting the planning of driving actions, aiming to better understand the factors leading to driving errors and to devise methodologies to anticipate and prevent such errors by monitoring the driver’s cognitive state and intention. While such anticipation was shown for discrete driving actions, such as emergency braking, there is no evidence for robust neural signatures of continuous action planning. This study aims to fill this gap by investigating continuous steering actions during a driving task in a car simulator with multimodal recordings of behavioural and electroencephalography (EEG) signals. System identification is used to assess whether robust neurophysiological signatures emerge before steering actions. Linear decoding models are then used to determine whether such cortical signals can predict continuous steering actions with progressively longer anticipation. Results point to significant EEG signatures of continuous action planning. Such neural signals show consistent dynamics across participants for anticipations up to 1 s, while individual-subject neural activity could reliably decode steering actions and predict future actions for anticipations up to 1.8 s. Finally, we use canonical correlation analysis to attempt disentangling brain and non-brain contributors to the EEG-based decoding. Our results suggest that low-frequency cortical dynamics are involved in the planning of steering actions and that EEG is sensitive to that neural activity. As a result, we propose a framework to investigate anticipatory neural activity in realistic continuous motor tasks.

Objective: To provide a systematic review of the literature and knowledge base of cost per quality-adjusted life year of physical rehabilitation and care of older persons after hip fracture. Material and methods: A research librarian assisted in searching 9 databases (14 May to 27 May 2021), with exclusion of studies on cognitively impaired or institutionalized individuals. A stepwise selection process was conducted by 2 authors, study quality was assessed using Drummond et al.’s checklist, and comparison between different countries was assessed using Welte et al.’s checklist. Results: Three studies were included, which employed 3 different interventions initiated at 3 different postoperative time-points. One high-quality study demonstrated that comprehensive geriatric assessment was cost-effective compared with coordinated care. The other 2 studies did not find the interventions studied to be cost-effective, and both studies were deemed to be of moderate quality. Conclusion: The body of evidence on the cost-effectiveness of physical rehabilitation and care after hip fracture is limited and heterogeneous, with only 1 high-quality study. Thus, stakeholders perform decision-making with a limited knowledge base of the cost-effectiveness of physical rehabilitation and care. We recommend researchers to assess cost-per-QALY. LAY ABSTRACT Hip fractures have severe consequences for older persons and, after surgery, patients need physical rehabilitation and care to recover. Physical rehabilitation and care vary greatly in terms of effectiveness and cost. It is not known what kind of physical rehabilitation and care contribute most to health relative to their costs. This systematic review provides the first comprehensive description of the cost- effectiveness of physical rehabilitation and care of older persons after hip fracture. Nine databases were searched, and 3 economic evaluation studies were identified. One economic study identified comprehensive geriatric care as cost-effective compared with usual coordinated care. The other two studies consisting of an intervention of additional 10 weeks of physical rehabilitation initiated 4 months after discharge and an intervention physical rehabilitation and nutrient management proved not cost-effective compared to usual rehabilitation and care. In conclusion, the number of studies published in this field is very limited and further research is necessary.

Summary: Neutrophils are specialized innate immune cells known for their ability to fight pathogens. However, the mechanisms of neutrophil trafficking to lymph nodes are not fully clear. Using a murine model of dermal infection with Leishmania parasites, we observe a transient neutrophil influx in draining lymph nodes despite sustained recruitment to the infection site. Cell-tracking experiments, together with intravital two-photon microscopy, indicate that neutrophil recruitment to draining lymph nodes occurs minimally through lymphatics from the infected dermis, but mostly through blood vessels via high endothelial venules. Mechanistically, neutrophils do not respond to IL-1β or macrophage-derived molecules. Instead, they are guided by the C5a-C5aR1 axis, using L-selectin and integrins, to extravasate into the draining lymph node parenchyma. We also report that C5, the C5a precursor, is locally produced in the draining lymph node by lymphatic endothelial cells. Our data establish and detail organ-specific mechanisms of neutrophil trafficking.

Nowadays, the growing interest in gathering physiological data and human behavior in everyday life scenarios is paralleled by an increase in wireless devices recording brain and body signals. However, the technical issues that characterize these solutions often limit the full brain-related assessments in real-life scenarios. Here we introduce the Biohub platform, a hardware/software (HW/SW) integrated wearable system for multistream synchronized acquisitions. This system consists of off-the-shelf hardware and state-of-art open-source software components, which are highly integrated into a high-tech low-cost solution, complete, yet easy to use outside conventional labs. It flexibly cooperates with several devices, regardless of the manufacturer, and overcomes the possibly limited resources of recording devices. The Biohub was validated through the characterization of the quality of (i) multistream synchronization, (ii) in-lab electroencephalographic (EEG) recordings compared with a medical-grade high-density device, and (iii) a Brain-Computer-Interface (BCI) in a real driving condition. Results show that this system can reliably acquire multiple data streams with high time accuracy and record standard quality EEG signals, becoming a valid device to be used for advanced ergonomics studies such as driving, telerehabilitation, and occupational safety.

Six different flexible stereocontrolled oligo(triazole-urethane)s substituted by precise sequences of nucleobases or analogs are synthesized. Molecular dynamics simulations indicate that the flexibility of the backbone leads to unspecific complexation of pairs of oligomers, irrespective of the complementarity of their sequences. This is ascribed to the existence of other interactions between pairs of oligomers, as well as to the spatial blurring of the sequence order encoded in the chemical structure of the chain due to its flexibility. The same conclusions are drawn when investigating the irreversible adsorption of different probe oligomers onto a layer of target oligomers grafted by click chemistry in a mushroom configuration on a silicon substrate. In contrast, when the target oligomers are grafted in denser brush configurations, irreversible adsorption becomes more specific, with it being twice as probable that probe chains of complementary sequence would be irreversibly-bound to the layer of target chains than those of non-complementary sequence. This is ascribed to lateral excluded volume interactions between chains in the brush, leading to partial chain stretching and increased spatial preservation of the information contained in the monomer sequence of the chains. At even higher grafting densities, however, the penetration of the probe chains in the brush becomes increasingly difficult, resulting in a loss of binding efficiency. Our work thus demonstrates the adverse role of chain flexibility in the specificity of complexation between nucleobase-functionalized oligomers and provides directions for an improvement of specificity by tuning the grafting density of target chains on a substrate.

Here, we report on the synthesis of discrete oligomers of alkyl-bridged naphthalenediimides (NDIs) and study their molecular nanostructures both in bulk, in solution, and at the liquid-solid interface. Via an iterative synthesis method, multiple NDI cores were bridged with short and saturated alkyl-diamines (C 3 and C 12 ) or long and unsaturated alkyl-diamines (u 2 C 33 to u 8 C 100 ) at their imide termini. The strong intermolecular interaction between the NDI cores was observed by probing their photophysical properties in solution. In bulk, the discrete NDI oligomers preferentially ordered in lamellar morphologies, irrespective of whether a saturated or unsaturated spacer was employed. Moreover, both the molecular architecture as well as the crystallization conditions play a significant role in the nanoscale ordering. The long unsaturated alkyl chains lead preferably to folded-chain conformations while their saturated analogues form stretched arrangements. At the solution-solid interface, well-defined lamellar regions were observed. These results show that precision in chemical structure alone is not sufficient to reach well-defined structures of discrete oligomers, but that it must be combined with precision in processing conditions., (© 2023 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.)

We show the emergence of strong catalytic activity at low concentrations in dynamic libraries of complementary sequence-defined oligomeric chains comprising pendant functional catalytic groups and terminal recognition units. In solution, the dynamic constitutional library created from pairs of such complementary oligomers comprises free oligomers, self-assembled di(oligomeric) macrocycles, and a virtually infinite collection of linear poly(oligomeric) chains. We demonstrate, on an exemplary catalytic system requiring the cooperation of no less than five chemical groups, that supramolecular di(oligomeric) macrocycles exhibit a catalytic turnover frequency ca. 20 times larger than the whole collection of linear poly(oligomers) and free chains. Molecular dynamics simulations and network analysis indicate that self-assembled supramolecular di(oligomeric) macrocycles are stabilized by different interactions, among which chain end pairing. We mathematically model the catalytic properties of such complex dynamic libraries with a small set of physically relevant parameters, which provides guidelines for the synthesis of oligomers capable to self-assemble into functionally-active supramolecular macrocycles over a larger range of concentrations., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Similar to biological macromolecules such as DNA and proteins, the precise control over the monomer position in sequence-defined polymers is of paramount importance for tuning their structures and properties toward achieving specific functions. Here, we apply molecular network analysis on three-dimensional structures issued from molecular dynamics simulations to decipher how the chain organization of trifunctional catalytic oligomers is influenced by the oligomer sequence and the length of oligo(ethylene oxide) spacers. Our findings demonstrate that the tuning of their primary structures is crucial for favoring cooperative interactions between the catalytic units and thus higher catalytic activities. This combined approach can assist in establishing structure-property relationships, leading to a more rational design of sequence-defined catalytic oligomers via computational chemistry.