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Abstract Whispering gallery mode (WGM) microtoroid resonators are one of the most sensitive biochemical sensors in existence, capable of detecting single molecules. The main barrier for translating these devices out of the laboratory is that light is evanescently coupled into these devices though a tapered optical fiber. This hinders translation of these devices as the taper is fragile, suffers from mechanical vibration, and requires precise positioning. Here, we eliminate the need for an optical fiber by coupling light into and out from a toroid via free-space coupling and monitoring the scattered resonant light. A single long working distance objective lens combined with a digital micromirror device (DMD) was used for light injection, scattered light collection, and imaging. We obtain Q-factors as high as $$1.6\times {10}^{8}$$ 1.6 × 10 8 with this approach. Electromagnetically induced transparency (EIT)-like and Fano resonances were observed in a single cavity due to indirect coupling in free space. This enables improved sensing sensitivity. The large effective coupling area (~10 μm in diameter for numerical aperture = 0.14) removes the need for precise positioning. Sensing performance was verified by combining the system with the frequency locked whispering evanescent resonator (FLOWER) approach to perform temperature sensing experiments. A thermal nonlinear optical effect was examined by tracking the resonance through FLOWER while adjusting the input power. We believe that this work will be a foundation for expanding the implementation of WGM microtoroid resonators to real-world applications.

Fluorescence and, more generally, photoluminescence enable high contrast imaging of targeted regions of interest through the use of photoluminescent probes with high specificity for different targets. Fluorescence can be used for rare cell imaging; however, this often requires a high space-bandwidth product: simultaneous high resolution and large field of view. With bulky traditional microscopes, high space-bandwidth product images require time-consuming mechanical scanning and stitching. Lensfree imaging can compactly and cost-effectively achieve a high space-bandwidth product in a single image through computational reconstruction of images from diffraction patterns recorded over the full field of view of standard image sensors. Many methods of lensfree photoluminescent imaging exist, where the excitation light is filtered before the image sensor, often by placing spectral filters between the sample and sensor. However, the sample-to-sensor distance is one of the limiting factors on resolution in lensfree systems and so more competitive performance can be obtained if this distance is reduced. Here, we show a time-gated lensfree photoluminescent imaging system that can achieve a resolution of 8.77 µm. We use europium chelate fluorophores because of their long lifetime (642 µs) and trigger camera exposure ∼50 µs after excitation. Because the excitation light is filtered temporally, there is no need for physical filters, enabling reduced sample-to-sensor distances and higher resolutions.

Abstract This cohort analysis investigated the prevalence of nonalcoholic fatty liver disease (NAFLD) and NAFLD with fibrosis at different stages, associated clinical characteristics, and comorbidities in the general United States population and a subpopulation with type 2 diabetes mellitus (T2DM), using the National Health and Nutrition Examination Survey (NHANES) database (2017–2018). Machine learning was explored to predict NAFLD identified by transient elastography (FibroScan®). Adults ≥20 years of age with valid transient elastography measurements were included; those with high alcohol consumption, viral hepatitis, or human immunodeficiency virus were excluded. Controlled attenuation parameter ≥302 dB/m using Youden’s index defined NAFLD; vibration‐controlled transient elastography liver stiffness cutoffs were ≤8.2, ≤9.7, ≤13.6, and >13.6 kPa for F0–F1, F2, F3, and F4, respectively. Predictive modeling, using six different machine‐learning approaches with demographic and clinical data from NHANES, was applied. Age‐adjusted prevalence of NAFLD and of NAFLD with F0–F1 and F2–F4 fibrosis was 25.3%, 18.9%, and 4.4%, respectively, in the overall population and 54.6%, 32.6%, and 18.3% in those with T2DM. The highest prevalence was among Mexican American participants. Test performance for all six machine‐learning models was similar (area under the receiver operating characteristic curve, 0.79–0.84). Machine learning using logistic regression identified male sex, hemoglobin A1c, age, and body mass index among significant predictors of NAFLD (P ≤ 0.01). Conclusion: Data show a high prevalence of NAFLD with significant fibrosis (≥F2) in the general United States population, with greater prevalence in participants with T2DM. Using readily available, standard demographic and clinical data, machine‐learning models could identify subjects with NAFLD across large data sets.

Abstract The fabrication of three-dimensional (3D) microscale structures is critical for many applications, including strong and lightweight material development, medical device fabrication, microrobotics, and photonic applications. While 3D microfabrication has seen progress over the past decades, complex multicomponent integration with small or hierarchical feature sizes is still a challenge. In this study, an optical positioning and linking (OPAL) platform based on optical tweezers is used to precisely fabricate 3D microstructures from two types of micron-scale building blocks linked by biochemical interactions. A computer-controlled interface with rapid on-the-fly automated recalibration routines maintains accuracy even after placing many building blocks. OPAL achieves a 60-nm positional accuracy by optimizing the molecular functionalization and laser power. A two-component structure consisting of 448 1-µm building blocks is assembled, representing the largest number of building blocks used to date in 3D optical tweezer microassembly. Although optical tweezers have previously been used for microfabrication, those results were generally restricted to single-material structures composed of a relatively small number of larger-sized building blocks, with little discussion of critical process parameters. It is anticipated that OPAL will enable the assembly, augmentation, and repair of microstructures composed of specialty micro/nanomaterial building blocks to be used in new photonic, microfluidic, and biomedical devices.

Abstract Caused by the herpes simplex virus (HSV), herpes is a viral infection that is one of the most widespread diseases worldwide. Here we present a computational sensing technique for specific detection of HSV using both viral immuno-specificity and the physical size range of the viruses. This label-free approach involves a compact and cost-effective holographic on-chip microscope and a surface-functionalized glass substrate prepared to specifically capture the target viruses. To enhance the optical signatures of individual viruses and increase their signal-to-noise ratio, self-assembled polyethylene glycol based nanolenses are rapidly formed around each virus particle captured on the substrate using a portable interface. Holographic shadows of specifically captured viruses that are surrounded by these self-assembled nanolenses are then reconstructed, and the phase image is used for automated quantification of the size of each particle within our large field-of-view, ~30 mm2. The combination of viral immuno-specificity due to surface functionalization and the physical size measurements enabled by holographic imaging is used to sensitively detect and enumerate HSV particles using our compact and cost-effective platform. This computational sensing technique can find numerous uses in global health related applications in resource-limited environments.

Whispering gallery mode resonators such as silica microtoroids can be used as sensitive biochemical sensors. One sensing modality is mode-splitting, where the binding of individual targets to the resonator breaks the degeneracy between clockwise and counter-clockwise resonant modes. Compared to other sensing modalities, mode-splitting is attractive because the signal shift is theoretically insensitive to the polar coordinate where the target binds. However, this theory relies on several assumptions, and previous experimental and numerical results have shown some discrepancies with analytical theory. More accurate numerical modeling techniques could help to elucidate the underlying physics, but efficient 3D electromagnetic finite-element method simulations of large microtoroid (diameter ~90 µm) and their resonance features have previously been intractable. In addition, applications of mode-splitting often involve bacteria or viruses, which are too large to be accurately described by the existing analytical dipole approximation theory. A numerical simulation approach could accurately explain mode splitting induced by these larger particles. Here, we simulate mode-splitting in a large microtoroid using a beam envelope method with periodic boundary conditions in a wedge-shaped domain. We show that particle sizing is accurate to within 11% for radii a<λ/7, where the dipole approximation is valid. Polarizability calculations need only be based on the background media and need not consider the microtoroid material. This modeling approach can be applied to other sizes and shapes of microresonators in the future.

Introduction and Aims: To project the long-term cost-effectiveness of treating non-valvular atrial fibrillation (AF) patients for stroke prevention with rivaroxaban compared to warfarin in Portugal. Methods: A Markov model was used that included health and treatment states describing the management and consequences of AF and its treatment. The model's time horizon was set at a patient's lifetime and each cycle at three months. The analysis was conducted from a societal perspective and a 5% discount rate was applied to both costs and outcomes. Treatment effect data were obtained from the pivotal phase III ROCKET AF trial. The model was also populated with utility values obtained from the literature and with cost data derived from official Portuguese sources. The outcomes of the model included life-years, quality-adjusted life-years (QALYs), incremental costs, and associated incremental cost-effectiveness ratios (ICERs). Extensive sensitivity analyses were undertaken to further assess the findings of the model. As there is evidence indicating underuse and underprescription of warfarin in Portugal, an additional analysis was performed using a mixed comparator composed of no treatment, aspirin, and warfarin, which better reflects real-world prescribing in Portugal. Results: This cost-effectiveness analysis produced an ICER of €3895/QALY for the base-case analysis (vs. warfarin) and of €6697/QALY for the real-world prescribing analysis (vs. mixed comparator). The findings were robust when tested in sensitivity analyses. Conclusion: The results showed that rivaroxaban may be a cost-effective alternative compared with warfarin or real-world prescribing in Portugal. Resumo: Introdução e objetivos: Estimar o rácio custo-efetividade a longo-prazo associados à utilização de rivaroxabano na prevenção de acidente vascular cerebral em doentes com fibrilhação auricular (FA) não-valvular relativamente a varfarina em Portugal. Métodos: Foi utilizado um modelo de Markov que representa os estádios representativos da progressão da FA e do seu tratamento. O horizonte temporal modelizado descreve o tempo de vida dos doentes e cada ciclo tem a duração de três meses. A análise foi desenvolvida na perspetiva da sociedade, tendo sido aplicada uma taxa de atualização de cinco por cento para custos e consequências. Os efeitos do tratamento foram obtidos no ensaio clínico de fase III ROCKET AF. Adicionalmente, no modelo foram incluídos valores de utilidade provenientes da literatura e estimativas de custos nacionais. Os outcomes avaliados no modelo incluem anos de vida incrementais, anos de vida ajustados pela qualidade de vida incrementais (AVAQ), custos incrementais e rácio custo-efetividade incremental (RCEI). Foram desenvolvidas análises de sensibilidade com o objetivo de avaliar os resultados do modelo. A evidência existente indica subutilização e subprescrição de varfarina em Portugal e, por esta razão, foi desenvolvida uma análise adicional com um comparador misto, constituído por não tratamento, ácido acetilsalicílico e varfarina, o que reflete melhor o «mundo real de prescrição». Resultados: RCEI obtido varia entre 3 895€/AVAQ para o cenário-base (relativamente varfarina) e 6 697€/AVAQ para o «mundo real de prescrição» (relativamente comparador misto). As análises de sensibilidade demonstraram que os resultados são robustos. Conclusão: Os resultados sugerem que rivaroxabano pode constituir uma alternativa custo-efetiva comparativamente a varfarina ou «mundo real de prescrição» em Portugal. Keywords: Atrial fibrillation, Cost-effectiveness, Portugal, Rivaroxaban, Stroke, Palavras-chave: Fibrilhação Auricular, Custo-efetividade, Portugal, Rivaroxabano, AVC

Introduction: Venous thromboembolism is a burden on healthcare systems. The aim of this analysis was to project the long-term costs and outcomes for rivaroxaban compared to standard of care (enoxaparin/warfarin) in Portugal for the treatment and secondary prevention of venous thromboembolism. Material and Methods: A Markov model was developed using event rates extracted from the EINSTEIN trials supplemented with literature-based estimates of longer-term outcomes. Core outcomes included per patient costs and quality-adjusted life years reported separately per treatment arm and incrementally, as well as cost per quality-adjusted life years gained. The deep vein thrombosis and pulmonary embolism indications were analysed separately. The analyses were conducted from the Portuguese societal perspective and over a 5-year time horizon. Costs and outcomes were discounted at a 5% annual rate. Several scenario analyses were undertaken to explore the impact on results of varying key modeling assumptions. Results: Rivaroxaban treatment was associated with cost-savings for the treatment of deep vein thrombosis and was both cost-saving and more effective for the treatment of pulmonary embolism, compared with enoxaparin/warfarin. Discussion: The results of the sensitivity and scenario analyses further supported that rivaroxaban is a cost-effective alternative to standard of care treatment. The use of an expert panel to derive some input values and the lack of Portuguese specific utilities were the main limitations. Conclusion: Rivaroxaban represents an efficient alternative to using enoxaparin/warfarin in Portugal, as it’s associated with lower costs (for both indications) and greater quality adjusted life years (for the pulmonary embolism indication). Keywords: Venous Thrombosis; Pulmonary Embolism; Rivaroxaban; Venous Thromboembolism.