Automating hybrid collective intelligence in open-ended medical diagnostics.

Collective intelligence has emerged as a powerful mechanism to boost decision accuracy across many domains, such as geopolitical forecasting, investment, and medical diagnostics. However, collective intelligence has been mostly applied to relatively simple decision tasks (e.g., binary classifications). Applications in more open-ended tasks with a much larger problem space, such as emergency management or general medical diagnostics, are largely lacking, due to the challenge of integrating unstandardized inputs from different crowd members. Here, we present a fully automated approach for harnessing collective intelligence in the domain of general medical diagnostics. Our approach leverages semantic knowledge graphs, natural language processing, and the SNOMED CT medical ontology to overcome a major hurdle to collective intelligence in open-ended medical diagnostics, namely to identify the intended diagnosis from unstructured text. We tested our method on 1,333 medical cases diagnosed on a medical crowdsourcing platform: The Human Diagnosis Project. Each case was independently rated by ten diagnosticians. Comparing the diagnostic accuracy of single diagnosticians with the collective diagnosis of differently sized groups, we find that our method substantially increases diagnostic accuracy: While single diagnosticians achieved 46% accuracy, pooling the decisions of ten diagnosticians increased this to 76%. Improvements occurred across medical specialties, chief complaints, and diagnosticians' tenure levels. Our results show the life-saving potential of tapping into the collective intelligence of the global medical community to reduce diagnostic errors and increase patient safety.

Domain-Agnostic Representation of Side-Channels.

Side channels are unintended pathways within target systems that leak internal target information. Side-channel sensing (SCS) is the process of exploiting side channels to extract embedded target information. SCS is well established within the cybersecurity (CYB) domain, and has recently been proposed for medical diagnostics and monitoring (MDM). Remaining unrecognised is its applicability to human-computer interaction (HCI), among other domains (Misc). This article analyses literature demonstrating SCS examples across the MDM, HCI, Misc, and CYB domains. Despite their diversity, established fields of advanced sensing and signal processing underlie each example, enabling the unification of these currently otherwise isolated domains. Identified themes are collating under a proposed domain-agnostic SCS framework. This SCS framework enables a formalised and systematic approach to studying, detecting, and exploiting of side channels both within and between domains. Opportunities exist for modelling SCS as data structures, allowing for computation irrespective of domain. Future methodologies can take such data structures to enable cross- and intra-domain transferability of extraction techniques, perform side-channel leakage detection, and discover new side channels within target systems.

SUsPECT: a pipeline for variant effect prediction based on custom long-read transcriptomes for improved clinical variant annotation.

Our incomplete knowledge of the human transcriptome impairs the detection of disease-causing variants, in particular if they affect transcripts only expressed under certain conditions. These transcripts are often lacking from reference transcript sets, such as Ensembl/GENCODE and RefSeq, and could be relevant for establishing genetic diagnoses. We present SUsPECT (Solving Unsolved Patient Exomes/gEnomes using Custom Transcriptomes), a pipeline based on the Ensembl Variant Effect Predictor (VEP) to predict variant impact on custom transcript sets, such as those generated by long-read RNA-sequencing, for downstream prioritization. Our pipeline predicts the functional consequence and likely deleteriousness scores for missense variants in the context of novel open reading frames predicted from any transcriptome. We demonstrate the utility of SUsPECT by uncovering potential mutational mechanisms of pathogenic variants in ClinVar that are not predicted to be pathogenic using the reference transcript annotation. In further support of SUsPECT's utility, we identified an enrichment of immune-related variants predicted to have a more severe molecular consequence when annotating with a newly generated transcriptome from stimulated immune cells instead of the reference transcriptome. Our pipeline outputs crucial information for further prioritization of potentially disease-causing variants for any disease and will become increasingly useful as more long-read RNA sequencing datasets become available.

Modern Electrochemical Biosensing Based on Nucleic Acids and Carbon Nanomaterials.

To meet the requirements of novel therapies, effective treatments should be supported by diagnostic tools characterized by appropriate analytical and working parameters. These are, in particular, fast and reliable responses that are proportional to analyte concentration, with low detection limits, high selectivity, cost-efficient construction, and portability, allowing for the development of point-of-care devices. Biosensors using nucleic acids as receptors has turned out to be an effective approach for meeting the abovementioned requirements. Careful design of the receptor layers will allow them to obtain DNA biosensors that are dedicated to almost any analyte, including ions, low and high molecular weight compounds, nucleic acids, proteins, and even whole cells. The impulse for the application of carbon nanomaterials in electrochemical DNA biosensors is rooted in the possibility to further influence their analytical parameters and adjust them to the chosen analysis. Such nanomaterials enable the lowering of the detection limit, the extension of the biosensor linear response, or the increase in selectivity. This is possible thanks to their high conductivity, large surface-to-area ratio, ease of chemical modification, and introduction of other nanomaterials, such as nanoparticles, into the carbon structures. This review discusses the recent advances on the design and application of carbon nanomaterials in electrochemical DNA biosensors that are dedicated especially to modern medical diagnostics.

Flexible surface-enhanced Raman scatting substrates: recent advances in their principles, design strategies, diversified material selections and applications.

Surface-enhanced Raman scattering (SERS) is widely used as a powerful analytical technology in cutting-edge areas such as food safety, biology, chemistry, and medical diagnosis, providing ultra-fast, ultra-sensitive, nondestructive characterization and achieving ultra-high detection sensitivity even down to the single-molecule level. Development of Raman spectroscopy is strongly dependent on high-performance SERS substrates, which have long evolved from the early days of rough metal electrodes to periodic nanopatterned arrays building on solid supporting substrates. For rigid SERS substrates, however, their applications are restricted by sophisticated pretreatments for detecting solid samples with non-planar surfaces. It is therefore essential to reassert the principles in constructing flexible SERS substrates. Herein, we comprehensively review the state-of-the-art in understanding, preparing and using flexible SERS. The basic mechanisms behind the flexible SERS are briefly outlined, typical design strategies are highlighted and diversified selection of materials in preparing flexible SERS substrates are reviewed. Then the recent achievements of various interdisciplinary applications based on flexible SERS substrates are summarized. Finally, the challenges and perspectives for future evolution of flexible SERS and their applications are demonstrated. We propose new research directions focused on stimulating the real potential of SERS as an advanced analytical technique for commercialization.

Experimental Validation of Shifted Position-Diffuse Reflectance Imaging (SP-DRI) on Optical Phantoms.

Numerous diseases such as hemorrhage, sepsis or cardiogenic shock induce a heterogeneous perfusion of the capillaries. To detect such alterations in the human blood flow pattern, diagnostic devices must provide an appropriately high spatial resolution. Shifted position-diffuse reflectance imaging (SP-DRI) has the potential to do so; it is an all-optical diagnostic technique. So far, SP-DRI has mainly been developed using Monte Carlo simulations. The present study is therefore validating this algorithm experimentally on realistic optical phantoms with thread structures down to 10 µm in diameter; a SP-DRI sensor prototype was developed and realized by means of additive manufacturing. SP-DRI turned out to be functional within this experimental framework. The position of the structures within the optical phantoms become clearly visible using SP-DRI, and the structure thickness is reflected as modulation in the SP-DRI signal amplitude; this performed well for a shift along the x axis as well as along the y axis. Moreover, SP-DRI successfully masked the pronounced influence of the illumination cone on the data. The algorithm showed significantly superior to a mere raw data inspection. Within the scope of the study, the constructive design of the SP-DRI sensor prototype is discussed and potential for improvement is explored.

Ligand-Specific Nano-Contrast Agents Promote Enhanced Breast Cancer CT Detection at 0.5 mg Au.

For many cancer types, being undetectable from early symptoms or blood tests, or often detected at late stages, medical imaging emerges as the most efficient tool for cancer screening. MRI, ultrasound, X-rays (mammography), and X-ray CT (CT) are currently used in hospitals with variable costs. Diagnostic materials that can detect breast tumors through molecular recognition and amplify the signal at the targeting site in combination with state-of-the-art CT techniques, such as dual-energy CT, could lead to a more precise detection and assist significantly in image-guided intervention. Herein, we have developed a ligand-specific X-ray contrast agent that recognizes α5ß1 integrins overexpressed in MDA-MB-231 breast cancer cells for detection of triple (-) cancer, which proliferates very aggressively. In vitro studies show binding and internalization of our nanoprobes within those cells, towards uncoated nanoparticles (NPs) and saline. In vivo studies show high retention of ~3 nm ligand-PEG-S-AuNPs in breast tumors in mice (up to 21 days) and pronounced CT detection, with statistical significance from saline and iohexol, though only 0.5 mg of metal were utilized. In addition, accumulation of ligand-specific NPs is shown in tumors with minimal presence in other organs, relative to controls. The prolonged, low-metal, NP-enhanced spectral-CT detection of triple (-) breast cancer could lead to breakthrough advances in X-ray cancer diagnostics, nanotechnology, and medicine.

Mechanisms of sampling interstitial fluid from skin using a microneedle patch.

Although interstitial fluid (ISF) contains biomarkers of physiological significance and medical interest, sampling of ISF for clinical applications has made limited impact due to a lack of simple, clinically useful techniques that collect more than nanoliter volumes of ISF. This study describes experimental and theoretical analysis of ISF transport from skin using microneedle (MN) patches and demonstrates collection of >1 µL of ISF within 20 min in pig cadaver skin and living human subjects using an optimized system. MN patches containing arrays of submillimeter solid, porous, or hollow needles were used to penetrate superficial skin layers and access ISF through micropores (µpores) formed upon insertion. Experimental studies in pig skin found that ISF collection depended on transport mechanism according to the rank order diffusion < capillary action < osmosis < pressure-driven convection, under the conditions studied. These findings were in agreement with independent theoretical modeling that considered transport within skin, across the interface between skin and µpores, and within µpores to the skin surface. This analysis indicated that the rate-limiting step for ISF sampling is transport through the dermis. Based on these studies and other considerations like safety and convenience for future clinical use, we designed an MN patch prototype to sample ISF using suction as the driving force. Using this approach, we collected ISF from human volunteers and identified the presence of biomarkers in the collected ISF. In this way, sampling ISF from skin using an MN patch could enable collection of ISF for use in research and medicine.

From Small Molecules Toward Whole Cells Detection: Application of Electrochemical Aptasensors in Modern Medical Diagnostics.

This paper focuses on the current state of art as well as on future trends in electrochemical aptasensors application in medical diagnostics. The origin of aptamers is presented along with the description of the process known as SELEX. This is followed by the description of the broad spectrum of aptamer-based sensors for the electrochemical detection of various diagnostically relevant analytes, including metal cations, abused drugs, neurotransmitters, cancer, cardiac and coagulation biomarkers, circulating tumor cells, and viruses. We described also possible future perspectives of aptasensors development. This concerns (i) the approaches to lowering the detection limit and improvement of the electrochemical aptasensors selectivity by application of the hybrid aptamer-antibody receptor layers and/or nanomaterials; and (ii) electrochemical aptasensors integration with more advanced microfluidic devices as user-friendly medical instruments for medical diagnostic of the future.

Smartphone-Based Device for Colorimetric Detection of MicroRNA Biomarkers Using Nanoparticle-Based Assay.

The detection of microRNAs (miRNAs) is emerging as a clinically important tool for the non-invasive detection of a wide variety of diseases ranging from cancers and cardiovascular illnesses to infectious diseases. Over the years, miRNA detection schemes have become accessible to clinicians, but they still require sophisticated and bulky laboratory equipment and trained personnel to operate. The exceptional computing ability and ease of use of modern smartphones coupled with fieldable optical detection technologies can provide a useful and portable alternative to these laboratory systems. Herein, we present the development of a smartphone-based device called Krometriks, which is capable of simple and rapid colorimetric detection of microRNA (miRNAs) using a nanoparticle-based assay. The device consists of a smartphone, a 3D printed accessory, and a custom-built dedicated mobile app. We illustrate the utility of Krometriks for the detection of an important miRNA disease biomarker, miR-21, using a nanoplasmonics-based assay developed by our group. We show that Krometriks can detect miRNA down to nanomolar concentrations with detection results comparable to a laboratory-based benchtop spectrophotometer. With slight changes to the accessory design, Krometriks can be made compatible with different types of smartphone models and specifications. Thus, the Krometriks device offers a practical colorimetric platform that has the potential to provide accessible and affordable miRNA diagnostics for point-of-care and field applications in low-resource settings.

Recent Advancements in Receptor Layer Engineering for Applications in SPR-Based Immunodiagnostics.

The rapid progress in the development of surface plasmon resonance-based immunosensing platforms offers wide application possibilities in medical diagnostics as a label-free alternative to enzyme immunoassays. The early diagnosis of diseases or metabolic changes through the detection of biomarkers in body fluids requires methods characterized by a very good sensitivity and selectivity. In the case of the SPR technique, as well as other surface-sensitive detection strategies, the quality of the transducer-immunoreceptor interphase is crucial for maintaining the analytical reliability of an assay. In this work, an overview of general approaches to the design of functional SPR-immunoassays is presented. It covers both immunosensors, the design of which utilizes well-known and often commercially available substrates, as well as the latest solutions developed in-house. Various approaches employing chemical and passive binding, affinity-based antibody immobilization, and the introduction of nanomaterial-based surfaces are discussed. The essence of their influence on the improvement of the main analytical parameters of a given immunosensor is explained. Particular attention is paid to solutions compatible with the latest trends in the development of label-free immunosensors, such as platforms dedicated to real-time monitoring in a quasi-continuous mode, the use of in situ-generated receptor layers (elimination of the regeneration step), and biosensors using recombinant and labelled protein receptors.

A comparative study on the use of selective media for the enumeration of Clostridium perfringens in poultry faeces.

Isolation and fast detection of Clostridium perfringens is essential in veterinary medical diagnostics and veterinary research, as it allows to recommend suitable treatment options after antimicrobial resistance determination, and is essential to study pathogenesis. In this study four selective media were tested for the enumeration of, and selectivity towards C. perfringens in faecal samples from poultry. The routinely used Columbia agar with 5% sheep (CBA), Shahidi-Ferguson-perfringens agar (SFP), tryptose sulphite cycloserine agar (TSC), and a novel chromogenic medium, CHROMagar™ C. perfringens (CHCP), were tested. Overall, no difference in C. perfringens recovery could be observed between the selective media. The limit of quantification was 103 CFU/mL for all agars. CHCP showed the highest specificity, especially when low C. perfringens loads were present in the faeces, with TSC being the second most specific selective medium. Both CBA and SFP allowed considerable growth of other faecal microbiota and were not specific for C. perfringens. On CHCP, differentiation of C. perfringens from other faecal bacteria was straightforward due to the appearance of C. perfringens as orange colonies, with other bacteria being absent or appearing as blue/green colonies. On TSC, C. perfringens appeared as black colonies, but longer incubation periods were sometimes needed for the black colour to develop. Therefore, CHCP can be recommended when timely and easy identification and enumeration of C. perfringens from complex samples, such as faeces, is needed.

Strong rotating flow in stationary droplets in low power budget using wire electrode configuration.

We explore a simple strategy of generating strong rotating flow in a stationary surface-droplet, using an intricate interplay of local electrical and thermal fields. Wire electrodes are employed to generate on-spot heating without necessitating any elaborate micro-fabrication, which causes strong local gradients in electrical properties to induce mobile charges into the droplet. Applying a low voltage (∼10 V), strong rotational velocity of the order of mm/s can be achieved in the system, within the standard operating ranges of operating and geometrical parameters. Further, altering the diameter of the electrode, vortices can be tuned locally or globally in low power budget, without incurring any droplet oscillations. These results may turn out to be of immense consequence in enhancing micromixing in a plethora of droplet based applications ranging from thermal management to medical diagnostics to be potentially employed in resource-limited settings.

Boosting medical diagnostics by pooling independent judgments.

Collective intelligence refers to the ability of groups to outperform individual decision makers when solving complex cognitive problems. Despite its potential to revolutionize decision making in a wide range of domains, including medical, economic, and political decision making, at present, little is known about the conditions underlying collective intelligence in real-world contexts. We here focus on two key areas of medical diagnostics, breast and skin cancer detection. Using a simulation study that draws on large real-world datasets, involving more than 140 doctors making more than 20,000 diagnoses, we investigate when combining the independent judgments of multiple doctors outperforms the best doctor in a group. We find that similarity in diagnostic accuracy is a key condition for collective intelligence: Aggregating the independent judgments of doctors outperforms the best doctor in a group whenever the diagnostic accuracy of doctors is relatively similar, but not when doctors' diagnostic accuracy differs too much. This intriguingly simple result is highly robust and holds across different group sizes, performance levels of the best doctor, and collective intelligence rules. The enabling role of similarity, in turn, is explained by its systematic effects on the number of correct and incorrect decisions of the best doctor that are overruled by the collective. By identifying a key factor underlying collective intelligence in two important real-world contexts, our findings pave the way for innovative and more effective approaches to complex real-world decision making, and to the scientific analyses of those approaches.

Metasurfaces for Advanced Sensing and Diagnostics.

Interest in sensors and their applications is rapidly evolving, mainly driven by the huge demand of technologies whose ultimate purpose is to improve and enhance health and safety. Different electromagnetic technologies have been recently used and achieved good performances. Despite the plethora of literature, limitations are still present: limited response control, narrow bandwidth, and large dimensions. MetaSurfaces, artificial 2D materials with peculiar electromagnetic properties, can help to overcome such issues. In this paper, a generic tool to model, design, and manufacture MetaSurface sensors is developed. First, their properties are evaluated in terms of impedance and constitutive parameters. Then, they are linked to the structure physical dimensions. Finally, the proposed method is applied to realize devices for advanced sensing and medical diagnostic applications: glucose measurements, cancer stage detection, water content recognition, and blood oxygen level analysis. The proposed method paves a new way to realize sensors and control their properties at will. Most importantly, it has great potential to be used for many other practical applications, beyond sensing and diagnostics.

The rheumatoid hand in the light of fluorescence: a diagnostic technique of the future?

Fluorescence spectroscopy is usually applied in physics, chemistry and related sciences. However, in recent years we can observe a growing interest in fluorescence spectroscopy for medical diagnostics. Currently, it is beginning to be used in the monitoring of rheumatoid arthritis (RA) activity. As the knowledge on RA increases, growing importance is being placed on the evaluation of synovitis. Today, it is difficult to imagine contemporary rheumatology without ultrasound (US) and magnetic resonance imaging (MRI). However, it turns out that these are not the only methods allowing one to visualise subclinical lesions, particularly synovitis. Fluorescence optical imaging (FOI) is also useful for the evaluation of inflammatory lesions in the joints. In the future, FOI may become competitive with "traditional" imaging studies. It is characterised by low cost, short duration and similar sensitivity to US.

Anti-ganglioside antibodies: experience from the Italian Association of Neuroimmunology external quality assessment scheme.

Background Anti-ganglioside antibodies are currently used in the differential diagnosis of suspected immune-mediated neuropathies. In-house and increasingly used commercial assays seem to perform suboptimally, and comparative information on their analytical performance are essentially lacking. Born within the frame of guidelines and standardization activities by the Italian Association of Neuroimmunology, this external quality assessment scheme (EQAS) is a real-life snapshot of the laboratory diagnostics in this field. Methods The EQAS consisted of five surplus, anonymized serum samples from patients with clinically-defined neuropathies and two serum samples from healthy blood donors. Eight laboratories used commercial line-/dot-blots, seven in-house/commercial ELISAs (in addition, 13 laboratories tested a recently released ELISA by Bühlmann). Only high anti-ganglioside antibody reactivities were considered, in accordance with consolidated recommendations. Results Large variations in anti-ganglioside antibody profiles were observed, even, although to a lesser extent, within homogeneous classes of assays. Concordance between the profiles and clinical phenotypes was also partial. Conclusions Although conducted on a relatively small, but representative number of Italian laboratories, this EQAS shows a critical between-laboratory disagreement in the test results of anti-ganglioside antibodies. Also considering the trend for using certified assays in generalist laboratories, strong efforts toward standardization and the identification of the best method(s) for their determinations are compellingly needed.

Smartphone Spectrometers.

Smartphones are playing an increasing role in the sciences, owing to the ubiquitous proliferation of these devices, their relatively low cost, increasing processing power and their suitability for integrated data acquisition and processing in a 'lab in a phone' capacity. There is furthermore the potential to deploy these units as nodes within Internet of Things architectures, enabling massive networked data capture. Hitherto, considerable attention has been focused on imaging applications of these devices. However, within just the last few years, another possibility has emerged: to use smartphones as a means of capturing spectra, mostly by coupling various classes of fore-optics to these units with data capture achieved using the smartphone camera. These highly novel approaches have the potential to become widely adopted across a broad range of scientific e.g., biomedical, chemical and agricultural application areas. In this review, we detail the exciting recent development of smartphone spectrometer hardware, in addition to covering applications to which these units have been deployed, hitherto. The paper also points forward to the potentially highly influential impacts that such units could have on the sciences in the coming decades.

Raman spectroscopic analysis of oral cells in the high wavenumber region.

Raman spectroscopy can provide a molecular-level signature of the biochemical composition and structure of cells with submicrometer spatial resolution and could be useful to monitor changes in composition for early stage and non-invasive cancer diagnosis, both ex-vivo and in vivo. In particular, the fingerprint spectral region (400-1800cm-1) has been shown to be very promising for optical biopsy purposes. However, limitations for discrimination of dysplastic and inflammatory processes based on the fingerprint region have been demonstrated. In addition, the Raman spectral signal of dysplastic cells is one important source of misdiagnosis of normal versus pathological tissues. The high wavenumber region (2800-3600cm-1) provides more specific information based on NH, OH and CH vibrations and can be used to identify the subtle changes which could be important for discrimination of samples. In this study, we demonstrate the potential of the high-wavenumber spectral region in this context by collecting Raman spectra of nucleolus, nucleus and cytoplasm from oral epithelial cancer (SCC-4) and dysplastic (DOK) cell lines and from normal oral epithelial primary cells, in vitro, in water immersion, which were then analyzed by principal components analysis as a method to discriminate the spectra. Analysis was performed before and after digital subtraction of the bulk water signal. In the normal cell line, the three subcellular regions are well differentiated before water subtraction, although the discrimination of the two nuclear regions is less well defined after water subtraction. Comparing the respective subcellular regions of the three cell lines, before water subtraction, the cell lines can be discriminated using sequential PCA and Feature Discriminant Analysis with up to ~100% sensitivity and 97% specificity for the cytoplasm, which is improved to 100% sensitivity and 99% specificity for the nucleus. The results are discussed in terms of discrimination comparing the CH vibrational modes of nucleic acids, proteins and lipids. The potential role of the OH vibrations, considering free water and confined water, in the discrimination of cell cultures and pathological processes are also discussed.

[PET-CT and PET-MRI of the prostate : From 18F-FDG to 68Ga-PSMA]. / PET-CT/-MRT der Prostata : Von 18F-FDG zu 68Ga-PSMA.

CLINICAL/METHODICAL ISSUE: In the last few years nuclear medical diagnostics have experienced a unprecedented renaissance in the diagnostics of prostate cancer, due to the availability of hybrid imaging with positron emission tomography computed tomography (PET/CT), PET magnetic resonance imaging (PET/MRI) and single photon emission computed tomography (SPECT) CT as well as the development of prostate-specific radiopharmaceuticals. METHODICAL INNOVATIONS: The use of fluorodeoxyglucose (FDG), which has been successfully implemented for many years in PET diagnostics, is only helpful in dedifferentiated tumors due to the biological characteristics of prostate cancer. New specific radiopharmaceuticals, such as choline-derivatives, which are incorporated into the prostate cancer cell and built into the cell membrane as well as the recently developed highly specific ligands for prostate-specific membrane antigen (PSMA) are revolutionizing prostate cancer imaging and (re-) staging. PRACTICAL RECOMMENDATIONS: The 68 Ga-labeled PSMA ligands for PET-CT and PET-MRI are highly specific tracers for primary diagnostics and detection of metastases of prostate carcinoma. In risk patients, which includes patients with intermediate and high-risk tumors, they have largely replaced choline-based PET-CT, especially in the case of very low PSA values <0.5 ng/ml in the diagnostics of recurrence. The use in the primary diagnostics as PET-MRI, also in combination with multiparametric MRI (mpMRI), is promising with respect to early diagnostics and image fusion-assisted biopsy as well as surgery and irradiation planning.