Castaways: the Leeward Antilles endemic spider genus Papiamenta (Araneae: Pholcidae).

Ninetinae is a group of small to tiny short-legged spiders largely restricted to arid habitats. Among daddy-long-legs spiders (Pholcidae) this is by far the least diverse subfamily but this may partly be a result of inadequate collecting, poor representation in collections or scientific neglect. We build on a large recent collection of the ninetine genus Papiamenta Huber, 2000 from the Leeward Antilles and use cytochrome oxidase 1 (COI ) sequences, extensive scanning electron microscopy data, transmission electron microscopy data and karyotyping to analyse this geographically isolated and poorly known island genus. COI sequences support the split between the two morphologically distinct species on Curaçao but genetic distances between these are surprisingly low (7.4-9.8%; mean 8.6%). The type species P. levii (Gertsch, 1982) may include more than one species but COI and morphology suggest conflicting clade limits. A third species, P. bonay Huber sp. nov. is newly described from Bonaire. Our data on sperm ultrastructure and karyology are puzzling as these suggest different phylogenetic affinities of Papiamenta to other genera. Males transfer sperm as individual sperm (cleistosperm), agreeing with the putative closest relatives as suggested by molecular data, the North American genera Pholcophora and Tolteca . The sex chromosome system (X 1 X 2 X 3 Y ) of P. levii , however, is as in the South American Ninetinae genera Gertschiola and Nerudia but different from the putative closest relatives. ZooBank: urn:lsid:zoobank.org:pub:7A6A2E84-3A61-4637-AF6F-0E31A9FA79A8.

Thriving in dry conditions: on the Neotropical spider genus Galapa (Araneae: Pholcidae).

The genus Galapa Huber, 2000 includes tiny spiders (body length <1.5 mm) restricted to semi-arid habitats. It has long been thought to be endemic to the Galapagos Islands until G. spiniphila Huber, 2020 was described from the Venezuelan Paraguan Peninsula. Here, we support this generic assignment with molecular (CO1) data and describe two new species from Colombia (G. gabito Huber sp. n.) and Costa Rica (G. murphyi Huber sp. n.), showing that the genus is actually widely distributed. Distribution modelling identifies several high suitability areas for Galapa, all of which are poorly sampled with respect to Pholcidae (ranging from Nicaragua to northern Peru and Guiana). Our results suggest a strong sampling bias against spiders restricted to dry tropical regions and habitats.

Notes on Chisosa (Araneae, Pholcidae), with the description of a new species from Mexico.

The genus Chisosa Huber, 2000 previously included only three species of small to tiny North American and Caribbean spiders that are rare in collections and poorly studied. Originally placed in the subfamily Ninetinae, Chisosa is currently considered a representative of Arteminae, close to the North American genus Physocyclus Simon, 1893. This placement has been suggested by molecular data, and it affects the interpretation of morphological characters that were originally thought to support the monophyly of Chisosa: they are shared with Physocyclus and thus plesiomorphic for Chisosa. Here we describe a new species from Mexico, C. calapa sp. nov., and restudy in detail the morphology (incl. ultrastructure) of the type species C. diluta (Gertsch & Mulaik, 1940) and of C. caquetio Huber, 2019, based on newly collected material. We document further similarities with Physocyclus but find only weak morphological support for the monophyly of Chisosa (body size reduction and short legs). In addition, we document surprisingly large genetic distances among C. caquetio specimens from Curaao (>14% CO1 K2P distances), possibly indicating species limits. Finally, we propose that the Dominican amber genus Serratochorus Wunderlich, 1988, based on a single male specimen, is also phylogenetically close to Chisosa and should be included in future studies on these enigmatic spiders.

Influence of visual acuity, manual dexterity and handgrip strength on oral and denture hygiene ability of non-frail older people: Development of the Gerostomatological Assessment Battery.

BACKGROUND: Due to the heterogeneity of older people, it is difficult to identify reliable factors influencing oral health. OBJECTIVE: The aim was to illustrate the influence of visual acuity, manual dexterity, and handgrip strength on the oral and denture hygiene ability of older non-frail people. METHODS: In a cross-sectional study, conducted at a specialized dental clinic, at baseline, all participants received professional prophylaxis and instruction on daily oral and denture hygiene regimes for a 6-week intervention period. Data on the Quigley and Hein modified plaque index (QHI), respectively, the Denture Hygiene Index (DHI), visual acuity, manual dexterity and handgrip strength in non-frail participants (≥ 65 years) were collected. Recruitment was done within the clinic's patient clientele and within the staff (control cohort). RESULTS: Women showed significantly better manual dexterity than men (Mann-Whitney U, p = .01), while women's mean handgrip strength was significantly lower (Mann-Whitney U, p < .01). Manual dexterity (Mann-Whitney U, p = .003) and handgrip strength (Mann-Whitney U, p = .052) were associated with age. However, visual acuity, manual dexterity and handgrip strength had no influence on oral or denture hygiene. CONCLUSION: Visual acuity, manual dexterity and handgrip strength have no influence on oral and denture hygiene ability in older non-frail people. Further studies should investigate whether these factors also have no influence on oral and denture hygiene in vulnerable older patients. Therefore, an assessment tool for the evaluation of potential influencing factors of oral and denture hygiene is proposed in a dental context. This Gerostomatological Assessment Battery (G-AB) can be used as a helpful tool to check the individual cognitive function and comprehension, dental therapy approaches and their individual adaption.

Combination of computed tomography angiography with coronary artery calcium score for improved diagnosis of coronary artery disease: a collaborative meta-analysis of stable chest pain patients referred for invasive coronary angiography.

OBJECTIVES: Coronary computed tomography angiography (CCTA) has higher diagnostic accuracy than coronary artery calcium (CAC) score for detecting obstructive coronary artery disease (CAD) in patients with stable chest pain, while the added diagnostic value of combining CCTA with CAC is unknown. We investigated whether combining coronary CCTA with CAC score can improve the diagnosis of obstructive CAD compared with CCTA alone. METHODS: A total of 2315 patients (858 women, 37%) aged 61.1 ± 10.2 from 29 original studies were included to build two CAD prediction models based on either CCTA alone or CCTA combined with the CAC score. CAD was defined as at least 50% coronary diameter stenosis on invasive coronary angiography. Models were built by using generalized linear mixed-effects models with a random intercept set for the original study. The two CAD prediction models were compared by the likelihood ratio test, while their diagnostic performance was compared using the area under the receiver-operating-characteristic curve (AUC). Net benefit (benefit of true positive versus harm of false positive) was assessed by decision curve analysis. RESULTS: CAD prevalence was 43.5% (1007/2315). Combining CCTA with CAC improved CAD diagnosis compared with CCTA alone (AUC: 87% [95% CI: 86 to 89%] vs. 80% [95% CI: 78 to 82%]; p < 0.001), likelihood ratio test 236.3, df: 1, p < 0.001, showing a higher net benefit across almost all threshold probabilities. CONCLUSION: Adding the CAC score to CCTA findings in patients with stable chest pain improves the diagnostic performance in detecting CAD and the net benefit compared with CCTA alone. CLINICAL RELEVANCE STATEMENT: CAC scoring CT performed before coronary CTA and included in the diagnostic model can improve obstructive CAD diagnosis, especially when CCTA is non-diagnostic. KEY POINTS: • The combination of coronary artery calcium with coronary computed tomography angiography showed significantly higher AUC (87%, 95% confidence interval [CI]: 86 to 89%) for diagnosis of coronary artery disease compared to coronary computed tomography angiography alone (80%, 95% CI: 78 to 82%, p < 0.001). • Diagnostic improvement was mostly seen in patients with non-diagnostic C. • The improvement in diagnostic performance and the net benefit was consistent across age groups, chest pain types, and genders.

Validation of a New Measuring Instrument for the Assessment of Bite Force.

BACKGROUND: this study aims to validate two occlusal-force-measuring devices by comparing them to a universal testing machine and assessing their reliability across various dental and prosthetic groups. The research comprised two parts: part 1 assessed the measurement accuracy of the Occlusal Force Meter GM 10® (OFM) (Morita, Nagano Keiki, Higashimagome, Ohta-ku, Tokyo, Japan) and a prototype (PRO) by comparing them to a calibrated universal testing machine (ZWICK). Part 2 involved analyzing the devices' reliability based on clinical bite force measurements from study participants. RESULTS: both devices become more accurate and reliable compared to the ZWICK over time of usage. Additionally, higher deviation from the ZWICK can be observed for higher values of forces applied and vice versa for both devices. The PRO's intraoral alignment influences its mean values compared to the OFM in different dental and prosthetic groups. CONCLUSION: both devices had limitations and required quadratic function calibration, making them suitable only for progression measurements. The study concludes that both the OFM and PRO devices can measure occlusal forces with improved accuracy over time. Intraoral alignment should be considered. Their easy-to-use clinical application would allow a more widespread use of masticatory function diagnosis, which could indicate the need for treatment and improve treatment planning.

An in silico model of the capturing of magnetic nanoparticles in tumour spheroids in the presence of flow.

One of the main challenges in improving the efficacy of conventional chemotherapeutic drugs is that they do not reach the cancer cells at sufficiently high doses while at the same time affecting healthy tissue and causing significant side effects and suffering in cancer patients. To overcome this deficiency, magnetic nanoparticles as transporter systems have emerged as a promising approach to achieve more specific tumour targeting. Drug-loaded magnetic nanoparticles can be directed to the target tissue by applying an external magnetic field. However, the magnetic forces exerted on the nanoparticles fall off rapidly with distance, making the tumour targeting challenging, even more so in the presence of flowing blood or interstitial fluid. We therefore present a computational model of the capturing of magnetic nanoparticles in a test setup: our model includes the flow around the tumour, the magnetic forces that guide the nanoparticles, and the transport within the tumour. We show how a model for the transport of magnetic nanoparticles in an external magnetic field can be integrated with a multiphase tumour model based on the theory of porous media. Our approach based on the underlying physical mechanisms can provide crucial insights into mechanisms that cannot be studied conclusively in experimental research alone. Such a computational model enables an efficient and systematic exploration of the nanoparticle design space, first in a controlled test setup and then in more complex in vivo scenarios. As an effective tool for minimising costly trial-and-error design methods, it expedites translation into clinical practice to improve therapeutic outcomes and limit adverse effects for cancer patients.

Machine learning instructed microfluidic synthesis of curcumin-loaded liposomes.

The association of machine learning (ML) tools with the synthesis of nanoparticles has the potential to streamline the development of more efficient and effective nanomedicines. The continuous-flow synthesis of nanoparticles via microfluidics represents an ideal playground for ML tools, where multiple engineering parameters - flow rates and mixing configurations, type and concentrations of the reagents - contribute in a non-trivial fashion to determine the resultant morphological and pharmacological attributes of nanomedicines. Here we present the application of ML models towards the microfluidic-based synthesis of liposomes loaded with a model hydrophobic therapeutic agent, curcumin. After generating over 200 different liposome configurations by systematically modulating flow rates, lipid concentrations, organic:water mixing volume ratios, support-vector machine models and feed-forward artificial neural networks were trained to predict, respectively, the liposome dispersity/stability and size. This work presents an initial step towards the application and cultivation of ML models to instruct the microfluidic formulation of nanoparticles.

Harnessing brain plasticity to improve binocular vision in amblyopia: An evidence-based update.

Amblyopia is a developmental visual disorder resulting from atypical binocular experience in early childhood that leads to abnormal visual cortex development and vision impairment. Recovery from amblyopia requires significant visual cortex neuroplasticity, i.e. the ability of the central nervous system and its synaptic connections to adapt their structure and function. There is a high level of neuroplasticity in early development and, historically, neuroplastic responses to changes in visual experience were thought to be restricted to a "critical period" in early life. However, as our review now shows, the evidence is growing that plasticity of the adult visual system can also be harnessed to improve vision in amblyopia. Amblyopia treatment involves correcting refractive error to ensure clear and equal retinal image formation in both eyes, then, if necessary, promoting the use of the amblyopic eye by hindering or reducing visual input from the better eye through patching or pharmacologic therapy. Early treatment in children can lead to visual acuity gains and the development of binocular vision in some cases; however, many children do not respond to treatment, and many adults with amblyopia have historically been untreated or undertreated. Here we review the current evidence on how dichoptic training can be used as a novel binocular therapeutic approach to facilitate visual processing of input from the amblyopic eye and can simultaneously engage both eyes in a training task that requires binocular integration. It is a novel and promising treatment for amblyopia in both children and adults.

Iterative Indirect Immunofluorescence Imaging (4i) on Adherent Cells and Tissue Sections.

Highly multiplexed protein measurements from multiple spatial scales using fluorescence microscopy recently emerged as a powerful way to investigate tumor microenvironments in biomedicine and the multivariate nature of complex systems' interactions. A range of methods for this exist, which either rely on directly labeling the primary antibody with oligonucleotides/rare metals or employing methods to remove fluorescence for cyclic acquisition. Here, we describe a protocol that uses off-the-shelf primary and secondary antibodies without further need for modification and only commonly available chemical reagents. The method harnesses the observation that antibodies can crosslink to bound epitopes during light exposure, thus preventing elution. By utilizing a simple oxygen radical scavenging buffer during imaging and by blocking free sulfhydryl groups before antibody incubation, the presented method can employ comparably mild conditions to remove bound antibodies from epitopes, which preserves sample integrity. Thus, with the stated minor modifications, it allows for a standard immunofluorescence imaging protocol in cyclic fashion, currently permitting staining of up to ~80 unique epitopes.

Tumour growth: An approach to calibrate parameters of a multiphase porous media model based on in vitro observations of Neuroblastoma spheroid growth in a hydrogel microenvironment.

To unravel processes that lead to the growth of solid tumours, it is necessary to link knowledge of cancer biology with the physical properties of the tumour and its interaction with the surrounding microenvironment. Our understanding of the underlying mechanisms is however still imprecise. We therefore developed computational physics-based models, which incorporate the interaction of the tumour with its surroundings based on the theory of porous media. However, the experimental validation of such models represents a challenge to its clinical use as a prognostic tool. This study combines a physics-based model with in vitro experiments based on microfluidic devices used to mimic a three-dimensional tumour microenvironment. By conducting a global sensitivity analysis, we identify the most influential input parameters and infer their posterior distribution based on Bayesian calibration. The resulting probability density is in agreement with the scattering of the experimental data and thus validates the proposed workflow. This study demonstrates the huge challenges associated with determining precise parameters with usually only limited data for such complex processes and models, but also demonstrates in general how to indirectly characterise the mechanical properties of neuroblastoma spheroids that cannot feasibly be measured experimentally.

Vascular dysregulation in glaucoma: retinal vasoconstriction and normal neurovascular coupling in altitudinal visual field defects.

Purpose: Vision loss in glaucoma is not only associated with elevated intraocular pressure and neurodegeneration, but vascular dysregulation (VD) is a major factor. To optimize therapy, an improved understanding of concepts of predictive, preventive, and personalized medicine (3PM) is needed which is based on a more detailed understanding of VD pathology. Specifically, to learn if the root cause of glaucomatous vision loss is of neuronal (degeneration) or vascular origin, we now studied neurovascular coupling (NVC) and vessel morphology and their relationship to vision loss in glaucoma. Methods: In patients with primary open angle glaucoma (POAG) (n = 30) and healthy controls (n = 22), NVC was studied using dynamic vessel analyzer to quantify retinal vessel diameter before, during, and after flicker light stimulation to evaluate the dilation response following neuronal activation. Vessel features and dilation were then related to branch level and visual field impairment. Results: Retinal arterial and venous vessels had significantly smaller diameters in patients with POAG in comparison to controls. However, both arterial and venous dilation reached normal values during neuronal activation despite their smaller diameters. This was largely independent of visual field depth and varied among patients. Conclusions: Because dilation/constriction is normal, VD in POAG can be explained by chronic vasoconstriction which limits energy supply to retinal (and brain) neurons with subsequent hypo-metabolism ("silent" neurons) or neuronal cell death. We propose that the root cause of POAG is primarily of vascular and not neuronal origin. This understanding can help to better personalize POAG therapy of not only targeting eye pressure but also vasoconstriction to prevent low vision, slowing its progression and supporting recovery and restoration. Trial registration: ClinicalTrials.gov, # NCT04037384 on July 3, 2019.

Comparing Temporary Immobilization Using Cast and External Fixator in Unimalleolar Ankle Fracture Dislocations: A Retrospective Case Series.

Studies have reported a high percentage of ankle fracture dislocations with secondary loss of reduction during primary treatment with a splint or cast. This study aimed to assess the rate of secondary loss of reduction in unimalleolar ankle fracture dislocations treated primarily with a cast or external fixator, identify the potential influence of fracture morphology, and investigate the potential implications. Unimalleolar ankle fracture dislocations with and without posterior malleolar fracture between 2011 and 2020 were included. Patients were categorized into two groups, depending on the method of temporary treatment. Fracture morphology, time to definitive surgery, and soft-tissue complications were compared. Of 102 patients, loss of reduction tended to occur more often in the cast group (17.3%) than in the external fixator group (6.0%). The presence of a posterior malleolar fracture did not have a significant influence on loss of reduction in cast immobilization; however, the fragment proved to be significantly bigger in cases with loss of reduction. No statistically significant differences in soft tissue complications or time to definitive surgery were found. Surgeons should consider the application of interval external fixation in the primary treatment of unimalleolar ankle fracture dislocations with additional posterior malleolar fractures.

Global sensitivity analysis based on Gaussian-process metamodelling for complex biomechanical problems.

Biomechanical models often need to describe very complex systems, organs or diseases, and hence also include a large number of parameters. One of the attractive features of physics-based models is that in those models (most) parameters have a clear physical meaning. Nevertheless, the determination of these parameters is often very elaborate and costly and shows a large scatter within the population. Hence, it is essential to identify the most important parameters (worth the effort) for a particular problem at hand. In order to distinguish parameters which have a significant influence on a specific model output from non-influential parameters, we use sensitivity analysis, in particular the Sobol method as a global variance-based method. However, the Sobol method requires a large number of model evaluations, which is prohibitive for computationally expensive models. We therefore employ Gaussian processes as a metamodel for the underlying full model. Metamodelling introduces further uncertainty, which we also quantify. We demonstrate the approach by applying it to two different problems: nanoparticle-mediated drug delivery in a complex, multiphase tumour-growth model, and arterial growth and remodelling. Even relatively small numbers of evaluations of the full model suffice to identify the influential parameters in both cases and to separate them from non-influential parameters. The approach also allows the quantification of higher-order interaction effects. We thus show that a variance-based global sensitivity analysis is feasible for complex, computationally expensive biomechanical models. Different aspects of sensitivity analysis are covered including a transparent declaration of the uncertainties involved in the estimation process. Such a global sensitivity analysis not only helps to massively reduce costs for experimental determination of parameters but is also highly beneficial for inverse analysis of such complex models.

RoCS: Robotic Curriculum for young Surgeons.

Robotic-assisted procedures gain increasing acceptance for daily surgical routine. However, structured training programs are designed for surgeons with high expertise. Hence, a comprehensive training curriculum was established to ensure a basic competence in robotic abdominal surgery for young surgeons during their residency. The aim of the current work is to propose a feasible and effective training concept. The development process of this training curriculum is based on a comprehensive literature review which led to the concept of "robotic curriculum for young surgeons" (RoCS). It was implemented in the daily routine of a German university hospital starting in 2020. The robotic assessment questionnaire (RAQ) was used for electronic data collection. After the initial phase adjustments, it led to an improvement of the initial version of the curriculum. RoCS is a multimodal training program containing basic training through assistance at the operation table during robotic-assisted operations and basic console training. Key elements are the robotic team time-out (rTTO), perioperative process standardization including feasible personnel scheduling and useful procedure clustering into organ systems, procedural steps and procedural step complexity. Evaluation of standardized communication, performance assessment, patient factors and individual overall workload using NASA Task Load Index is realizable. Flexibility and adaptability to internal organization processes of surgical departments are the main advantages of the concept. RoCS is a strong training tool to meet the specific needs of young surgeons and evaluate their learning success of robotic procedural training. Furthermore, comparison within the different robotic systems should be considered. Further studies are needed to validate a multicenter concept design.

Global brain network modularity dynamics after local optic nerve damage following noninvasive brain stimulation: an EEG-tracking study.

Tightly connected clusters of nodes, called communities, interact in a time-dependent manner in brain functional connectivity networks (FCN) to support complex cognitive functions. However, little is known if and how different nodes synchronize their neural interactions to form functional communities ("modules") during visual processing and if and how this modularity changes postlesion (progression or recovery) following neuromodulation. Using the damaged optic nerve as a paradigm, we now studied brain FCN modularity dynamics to better understand module interactions and dynamic reconfigurations before and after neuromodulation with noninvasive repetitive transorbital alternating current stimulation (rtACS). We found that in both patients and controls, local intermodule interactions correlated with visual performance. However, patients' recovery of vision after treatment with rtACS was associated with improved interaction strength of pathways linked to the attention module, and it improved global modularity and increased the stability of FCN. Our results show that temporal coordination of multiple cortical modules and intermodule interaction are functionally relevant for visual processing. This modularity can be neuromodulated with tACS, which induces a more optimal balanced and stable multilayer modular structure for visual processing by enhancing the interaction of neural pathways with the attention network module.

Nanomedicine and drug delivery to the retina: current status and implications for gene therapy.

Blindness affects more than 60 million people worldwide. Retinal disorders, including age-related macular degeneration (AMD), diabetic retinopathy (DR), and glaucoma, are the leading causes of blindness. Finding means to optimize local and sustained delivery of drugs or genes to the eye and retina is one goal to advance the development of new therapeutics. Despite the ease of accessibility of delivering drugs via the ocular surface, the delivery of drugs to the retina is still challenging due to anatomic and physiologic barriers. Designing a suitable delivery platform to overcome these barriers should enhance drug bioavailability and provide a safe, controlled, and sustained release. Current inventions for posterior segment treatments include intravitreal implants and subretinal viral gene delivery that satisfy these criteria. Several other novel drug delivery technologies, including nanoparticles, micelles, dendrimers, microneedles, liposomes, and nanowires, are now being widely studied for posterior segment drug delivery, and extensive research on gene delivery using siRNA, mRNA, or aptamers is also on the rise. This review discusses the current state of retinal drug/gene delivery and highlights future therapeutic opportunities.

A continuum mechanical framework for modeling tumor growth and treatment in two- and three-phase systems.

The growth and treatment of tumors is an important problem to society that involves the manifestation of cellular phenomena at length scales on the order of centimeters. Continuum mechanical approaches are being increasingly used to model tumors at the largest length scales of concern. The issue of how to best connect such descriptions to smaller-scale descriptions remains open. We formulate a framework to derive macroscale models of tumor behavior using the thermodynamically constrained averaging theory (TCAT), which provides a firm connection with the microscale and constraints on permissible forms of closure relations. We build on developments in the porous medium mechanics literature to formulate fundamental entropy inequality expressions for a general class of three-phase, compositional models at the macroscale. We use the general framework derived to formulate two classes of models, a two-phase model and a three-phase model. The general TCAT framework derived forms the basis for a wide range of potential models of varying sophistication, which can be derived, approximated, and applied to understand not only tumor growth but also the effectiveness of various treatment modalities.

Multimodal perception links cellular state to decision-making in single cells.

Individual cells make decisions that are adapted to their internal state and surroundings, but how cells can reliably do this remains unclear. To study the information processing capacity of human cells, we conducted multiplexed quantification of signaling responses and markers of the cellular state. Signaling nodes in a network displayed adaptive information processing, which led to heterogeneous growth factor responses and enabled nodes to capture partially nonredundant information about the cellular state. Collectively, as a multimodal percept this gives individual cells a large information processing capacity to accurately place growth factor concentration within the context of their cellular state and make cellular state-dependent decisions. Heterogeneity and complexity in signaling networks may have coevolved to enable specific and context-aware cellular decision-making in a multicellular setting.