Identifying Medical Diagnoses and Treatable Diseases by Image-Based Deep Learning.

The implementation of clinical-decision support algorithms for medical imaging faces challenges with reliability and interpretability. Here, we establish a diagnostic tool based on a deep-learning framework for the screening of patients with common treatable blinding retinal diseases. Our framework utilizes transfer learning, which trains a neural network with a fraction of the data of conventional approaches. Applying this approach to a dataset of optical coherence tomography images, we demonstrate performance comparable to that of human experts in classifying age-related macular degeneration and diabetic macular edema. We also provide a more transparent and interpretable diagnosis by highlighting the regions recognized by the neural network. We further demonstrate the general applicability of our AI system for diagnosis of pediatric pneumonia using chest X-ray images. This tool may ultimately aid in expediting the diagnosis and referral of these treatable conditions, thereby facilitating earlier treatment, resulting in improved clinical outcomes. VIDEO ABSTRACT.

Laser frequency noise characterization using high-finesse plano-concave optical microresonators.

Characterizing laser frequency noise is essential for applications including optical sensing and coherent optical communications. Accurate measurement of ultra-narrow linewidth lasers over a wide frequency range using existing methods is still challenging. Here we present a method for characterizing the frequency noise of lasers using a high-finesse plano-concave optical microresonator (PCMR) acting as a frequency discriminator. To enable noise measurements at a wide range of laser frequencies, an array of PCMRs was produced with slight variations of thickness resulting in a series of discriminators operating at a series of periodical frequencies. This method enables measuring the frequency noise over a wide linewidth range (15 Hz to <100 MHz) over the 1440-1630 nm wavelength range. To assess the performance of the method, four different lasers were characterized, and the results were compared to the estimations of a commercial frequency noise analyzer.

Extending the In Vivo Residence Time of Macrophage Membrane-Coated Nanoparticles through Genetic Modification.

Nanoparticles coated with natural cell membranes have emerged as a promising class of biomimetic nanomedicine with significant clinical potential. Among them, macrophage membrane-coated nanoparticles hold particular appeal due to their versatility in drug delivery and biological neutralization applications. This study employs a genetic engineering approach to enhance their in vivo residence times, aiming to further improve their performance. Specifically, macrophages are engineered to express proline-alanine-serine (PAS) peptide chains, which provide additional protection against opsonization and phagocytosis. The resulting modified nanoparticles demonstrate prolonged residence times when administered intravenously or introduced intratracheally, surpassing those coated with the wild-type membrane. The longer residence times also contribute to enhanced nanoparticle efficacy in inhibiting inflammatory cytokines in mouse models of lipopolysaccharide-induced lung injury and sublethal endotoxemia, respectively. This study underscores the effectiveness of genetic modification in extending the in vivo residence times of macrophage membrane-coated nanoparticles. This approach can be readily extended to modify other cell membrane-coated nanoparticles toward more favorable biomedical applications.

ABCD transfer matrix model of Gaussian beam propagation in plano-concave optical microresonators.

Plano-concave optical microresonators (PCMRs) are optical microcavities formed of one planar and one concave mirror separated by a spacer. PCMRs illuminated by Gaussian laser beams are used as sensors and filters in fields including quantum electrodynamics, temperature sensing, and photoacoustic imaging. To predict characteristics such as the sensitivity of PCMRs, a model of Gaussian beam propagation through PCMRs based on the ABCD matrix method was developed. To validate the model, interferometer transfer functions (ITFs) calculated for a range of PCMRs and beams were compared to experimental measurements. A good agreement was observed, suggesting the model is valid. It could therefore constitute a useful tool for designing and evaluating PCMR systems in various fields. The computer code implementing the model has been made available online.

ABCD transfer matrix model of Gaussian beam propagation in Fabry-Perot etalons.

A numerical model of Gaussian beam propagation in planar Fabry-Perot (FP) etalons is presented. The model is based on the ABCD transfer matrix method. This method is easy to use and interpret, and readily connects models of lenses, mirrors, fibres and other optics to aid simulating complex multi-component etalon systems. To validate the etalon model, its predictions were verified using a previously validated model based on Fourier optics. To demonstrate its utility, three different etalon systems were simulated. The results suggest the model is valid and versatile and could aid in designing and understanding a range of systems containing planar FP etalons. The method could be extended to model higher order beams, other FP type devices such as plano-concave resonators, and more complex etalon systems such as those involving tilted components.

A systematic review of patient-reported outcome measures in paediatric endocrinology.

CONTEXT: Patient reported outcome measures (PROMs) are useful tools in paediatric endocrinology to gauge health status in children, especially since they are often unable to clearly communicate it themselves. We aimed to systematically search and appraise all available PROMs relevant to paediatric endocrinology and provide a curated resource for health professionals to utilise. EVIDENCE ACQUISITION: We identified PROMs in paediatric endocrinology by systematically searching the Cochrane Library, MEDLINE, World Health Organisation International Clinical Trials Registry Platform, and the Cumulative Index to Nursing and Allied Health Literature on May 20, 2022. Additional studies were located through hand searching and content area expert contributions. We assessed the quality of each PROM using the COSMIN risk of bias checklist. EVIDENCE SYNTHESIS: We identified 5003 papers in the initial search. After applying exclusion criteria we included seven PROMs in the review. Six PROMs were specific to Type I Diabetes and one to Hypothyroidism. We gave all studies an overall COSMIN score of 'inadequate' due to poorly detailed PROM development. CONCLUSION: The scope and quality of PROMs in paediatric endocrinology is limited. Further research and development of PROM tools are required in paediatric endocrinology to allow for improved patient care.

Intraoperative Needle Tip Tracking with an Integrated Fibre-Optic Ultrasound Sensor.

Ultrasound is an essential tool for guidance of many minimally-invasive surgical and interventional procedures, where accurate placement of the interventional device is critical to avoid adverse events. Needle insertion procedures for anaesthesia, fetal medicine and tumour biopsy are commonly ultrasound-guided, and misplacement of the needle may lead to complications such as nerve damage, organ injury or pregnancy loss. Clear visibility of the needle tip is therefore critical, but visibility is often precluded by tissue heterogeneities or specular reflections from the needle shaft. This paper presents the in vitro and ex vivo accuracy of a new, real-time, ultrasound needle tip tracking system for guidance of fetal interventions. A fibre-optic, Fabry-Pérot interferometer hydrophone is integrated into an intraoperative needle and used to localise the needle tip within a handheld ultrasound field. While previous, related work has been based on research ultrasound systems with bespoke transmission sequences, the new system-developed under the ISO 13485 Medical Devices quality standard-operates as an adjunct to a commercial ultrasound imaging system and therefore provides the image quality expected in the clinic, superimposing a cross-hair onto the ultrasound image at the needle tip position. Tracking accuracy was determined by translating the needle tip to 356 known positions in the ultrasound field of view in a tank of water, and by comparison to manual labelling of the the position of the needle in B-mode US images during an insertion into an ex vivo phantom. In water, the mean distance between tracked and true positions was 0.7 ± 0.4 mm with a mean repeatability of 0.3 ± 0.2 mm. In the tissue phantom, the mean distance between tracked and labelled positions was 1.1 ± 0.7 mm. Tracking performance was found to be independent of needle angle. The study demonstrates the performance and clinical compatibility of ultrasound needle tracking, an essential step towards a first-in-human study.

High pulse energy fibre laser as an excitation source for photoacoustic tomography.

A custom fibre laser designed as an excitation source for biomedical photoacoustic tomography has been developed. It is based on a custom-drawn large core diameter fibre (200 µm) that enables high pulse energies (∼10 mJ) to be achieved. The system can provide variable pulse durations (10 - 500 ns) and pulse repetition frequencies (100 Hz - 1 kHz), as well as arbitrary pulse bursts according to specific user defined sequences. The system is also compact and does not require external water cooling. This, along with the flexibility in the temporal characteristics of its output that it offers, will aid the translation of photoacoustic imaging to practical application in medicine and biology.

Modelling Fabry-Pérot etalons illuminated by focussed beams.

Fabry-Pérot (FP) etalons are used as filters and sensors in a range of optical systems. Often FP etalons are illuminated by collimated laser beams, in which case the transmitted and reflected light fields can be calculated analytically using well established models. However, FP etalons are sometimes illuminated by more complex beams such as focussed Gaussian beams, which may also be aberrated. Modelling the response of FP etalons to these beams requires a more sophisticated model. To address this need, we present a model that can describe the response of an FP etalon that is illuminated by an arbitrary beam. The model uses an electromagnetic wave description of light and can therefore compute the amplitude, phase and polarization of the optical field at any position in the system. It can also account for common light delivery and detection components such as lenses, optical fibres and photo-detectors, allowing practical systems to be simulated. The model was validated against wavelength resolved measurements of transmittance and reflectance obtained using a system consisting of an FP etalon illuminated by a focussed Gaussian beam. Experiments with focal spot sizes ranging from 30 µm to 250 µm and FP etalon mirror reflectivities in the range 97.2 % to 99.2 % yielded excellent visual agreement between simulated and experimental data and an average error below 10% for a range of quantitative comparative metrics. We expect the model to be a useful tool for designing, understanding and optimising systems that use FP etalons.

Miniature all-optical flexible forward-viewing photoacoustic endoscopy probe for surgical guidance.

A miniature flexible photoacoustic endoscopy probe that provides high-resolution 3D images of vascular structures in the forward-viewing configuration is described. A planar Fabry-Perot ultrasound sensor with a -3dB bandwidth of 53 MHz located at the tip of the probe is interrogated via a flexible fiber bundle and a miniature optical relay system to realize an all-optical probe measuring 7.4 mm in outer diameter at the tip. This approach to photoacoustic endoscopy offers advantages over previous piezoelectric based distal-end scanning probes. These include a forward-viewing configuration in widefield photoacoustic tomography mode, finer spatial sampling (87 µm spatial sampling interval), and wider detection bandwidth (53 MHz) than has been achievable with conventional ultrasound detection technology and an all-optical passive imaging head for safe endoscopic use.

DNA methylation markers for diagnosis and prognosis of common cancers.

The ability to identify a specific cancer using minimally invasive biopsy holds great promise for improving the diagnosis, treatment selection, and prediction of prognosis in cancer. Using whole-genome methylation data from The Cancer Genome Atlas (TCGA) and machine learning methods, we evaluated the utility of DNA methylation for differentiating tumor tissue and normal tissue for four common cancers (breast, colon, liver, and lung). We identified cancer markers in a training cohort of 1,619 tumor samples and 173 matched adjacent normal tissue samples. We replicated our findings in a separate TCGA cohort of 791 tumor samples and 93 matched adjacent normal tissue samples, as well as an independent Chinese cohort of 394 tumor samples and 324 matched adjacent normal tissue samples. The DNA methylation analysis could predict cancer versus normal tissue with more than 95% accuracy in these three cohorts, demonstrating accuracy comparable to typical diagnostic methods. This analysis also correctly identified 29 of 30 colorectal cancer metastases to the liver and 32 of 34 colorectal cancer metastases to the lung. We also found that methylation patterns can predict prognosis and survival. We correlated differential methylation of CpG sites predictive of cancer with expression of associated genes known to be important in cancer biology, showing decreased expression with increased methylation, as expected. We verified gene expression profiles in a mouse model of hepatocellular carcinoma. Taken together, these findings demonstrate the utility of methylation biomarkers for the molecular characterization of cancer, with implications for diagnosis and prognosis.

Use of a flexible optical fibre bundle to interrogate a Fabry-Perot sensor for photoacoustic imaging.

Photoacoustic imaging systems based on a Fabry Perot (FP) ultrasound sensor that is read-out by scanning a free-space laser beam over its surface can provide high resolution photoacoustic images. However, this type of free-space scanning usually requires a bulky 2-axis galvanometer based scanner that is not conducive to the realization of a lightweight compact imaging head. It is also unsuitable for endoscopic applications that may require complex and flexible access. To address these limitations, the use of a flexible, coherent fibre bundle to interrogate the FP sensor has been investigated. A laboratory set-up comprising an x-y scanner, a commercially available, 1.35 mm diameter, 18,000 core flexible fibre bundle with a custom-designed telecentric optical relay at its distal end was used. Measurements of the optical and acoustic performance of the FP sensor were made and compared to that obtained using a conventional free-space FP based scanner. Spatial variations in acoustic sensitivity were greater and the SNR lower with the fibre bundle implementation but high quality photoacoustic images could still be obtained. 3D images of phantoms and ex vivo tissues with a spatial resolution and fidelity consistent with a free-space scanner were acquired. By demonstrating the feasibility of interrogating the FP sensor with a flexible fibre bundle, this study advances the realization of compact hand-held clinical scanners and flexible endoscopic devices based on the FP sensing concept.

In vivo three-dimensional photoacoustic imaging of the renal vasculature in preclinical rodent models.

Noninvasive imaging of the kidney vasculature in preclinical murine models is important for the assessment of renal development, studying diseases and evaluating new therapies but is challenging to achieve using existing imaging modalities. Photoacoustic imaging is a promising new technique that is particularly well suited to visualizing the vasculature and could provide an alternative to existing preclinical imaging methods for studying renal vascular anatomy and function. To investigate this, an all-optical Fabry-Perot-based photoacoustic scanner was used to image the abdominal region of mice. High-resolution three-dimensional, noninvasive, label-free photoacoustic images of the mouse kidney and renal vasculature were acquired in vivo. The scanner was also used to visualize and quantify differences in the vascular architecture of the kidney in vivo due to polycystic kidney disease. This study suggests that photoacoustic imaging could be utilized as a novel preclinical imaging tool for studying the biology of renal disease.

Circulating tumour DNA methylation markers for diagnosis and prognosis of hepatocellular carcinoma.

An effective blood-based method for the diagnosis and prognosis of hepatocellular carcinoma (HCC) has not yet been developed. Circulating tumour DNA (ctDNA) carrying cancer-specific genetic and epigenetic aberrations may enable a noninvasive 'liquid biopsy' for diagnosis and monitoring of cancer. Here, we identified an HCC-specific methylation marker panel by comparing HCC tissue and normal blood leukocytes and showed that methylation profiles of HCC tumour DNA and matched plasma ctDNA are highly correlated. Using cfDNA samples from a large cohort of 1,098 HCC patients and 835 normal controls, we constructed a diagnostic prediction model that showed high diagnostic specificity and sensitivity (P < 0.001) and was highly correlated with tumour burden, treatment response, and stage. Additionally, we constructed a prognostic prediction model that effectively predicted prognosis and survival (P < 0.001). Together, these findings demonstrate in a large clinical cohort the utility of ctDNA methylation markers in the diagnosis, surveillance, and prognosis of HCC.

Rapid volumetric photoacoustic tomographic imaging with a Fabry-Perot ultrasound sensor depicts peripheral arteries and microvascular vasomotor responses to thermal stimuli.

PURPOSE: To determine if a new photoacoustic imaging (PAI) system successfully depicts (1) peripheral arteries and (2) microvascular circulatory changes in response to thermal stimuli. METHODS: Following ethical permission, 8 consenting subjects underwent PAI of the dorsalis pedis (DP) artery, and 13 completed PAI of the index fingertip. Finger images were obtained after immersion in warm (30-35 °C) or cold (10-15 °C) water to promote vasodilation or vasoconstriction. The PAI instrument used a Fabry-Perot interferometeric ultrasound sensor and a 30-Hz 750-nm pulsed excitation laser. Volumetric images were acquired through a 14 × 14 × 14-mm volume over 90 s. Images were evaluated subjectively and quantitatively to determine if PAI could depict cold-induced vasoconstriction. The full width at half maximum (FWHM) of resolvable vessels was measured. RESULTS: Fingertip vessels were visible in all participants, with mean FWHM of 125 µm. Two radiologists used PAI to correctly identify vasoconstricted fingertip capillary beds with 100% accuracy (95% CI 77.2-100.0%, p < 0.001). The number of voxels exhibiting vascular signal was significantly smaller after cold water immersion (cold: 5263 voxels; warm: 363,470 voxels, p < 0.001). The DP artery was visible in 7/8 participants (87.5%). CONCLUSION: PAI achieves rapid, volumetric, high-resolution imaging of peripheral limb vessels and the microvasculature and is responsive to vasomotor changes induced by thermal stimuli. KEY POINTS: • Fabry-Perot interferometer-based photoacoustic imaging (PAI) generates volumetric, high-resolution images of the peripheral vasculature. • The system reliably detects thermally induced peripheral vasoconstriction (100% correct identification rate, p < 0.001). • Vessels measuring less than 100 µm in diameter can be depicted in vivo.

Characterization and modeling of Fabry-Perot ultrasound sensors with hard dielectric mirrors for photoacoustic imaging.

A Fabry-Perot ultrasound sensor with nonhygroscopic dielectric mirrors made out of Ta2O5 and SiO2 for use in photoacoustic tomography is described. The sensor offers flat frequency response up to 36 MHz, low noise-equivalent pressure (70 Pa), and near-omnidirectional response up to 20 MHz as well as optical transparency for near-infrared illumination. A numerical model was developed to predict its frequency response, and the results were validated experimentally. An image of the human palm was acquired to demonstrate in vivo imaging capabilities.

Pre-operative high resolution computed tomography scans for cholesteatoma: has anything changed?

OBJECTIVE: CT temporal bone scans are often performed to aid in surgical planning and management of cholesteatomas. With improvements in the resolution of CT scans today, it is now possible to obtain more information from these scans than before. The aim of this study is to compare findings on high resolution CT (HRCT) temporal bone scans to intra-operative findings, so as to determine how well various middle ear structures are assessed by HRCT scanning. STUDY DESIGN: Retrospective study. SETTING: Otology clinic of a tertiary otolaryngology centre. SUBJECTS AND METHODS: 32 mastoidectomies performed by a single otologist for clinically confirmed cholesteatoma were included. Correlation of CT and intra-operative findings on the status of structures including the ossicles, semicircular canals, facial canal and tegmen was analysed using kappa and AC1 statistics. RESULTS: In all patients, a soft tissue mass with bony erosion in keeping with a cholesteatoma was seen on CT. Radiosurgical agreement was excellent for the presence of semicircular canal erosion (k=0.89, AC1=0.96), facial canal dehiscence (k=0.74, AC1=0.76), tegmen erosion (k=0.76, AC1=0.92) and malleus erosion (k=0.76, AC1=0.85). It was good for incus erosion (k=0.71, AC1=0.92) and stapes erosion (k=0.63, AC1=0.73). CONCLUSION: There was good to excellent radiosurgical agreement in the assessment of the status of various middle ear structures. Improvement in radiosurgical agreement from existing studies in the literature was noted. This was especially true for features such as facial canal dehiscence. With technological advancements, CT temporal bone scans appear even more valuable for evaluation of patients prior to cholesteatoma surgery.

Dual-modality rigid endoscope for photoacoustic imaging and white light videoscopy.

Significance: There has been significant interest in the development of miniature photoacoustic imaging probes for a variety of clinical uses, including the in situ assessment of tumors and minimally invasive surgical guidance. Most of the previously implemented probes are either side viewing or operate in the optical-resolution microscopy mode in which the imaging depth is limited to ∼1 mm. We describe a forward-viewing photoacoustic probe that operates in tomography mode and simultaneously provides white light video images. Aim: We aim to develop a dual-modality endoscope capable of performing high-resolution PAT imaging and traditional white light videoscopy simultaneously in the forward-viewing configuration. Approach: We used a Fabry-Pérot ultrasound sensor that operates in the 1500 to 1600 nm wavelength range and is transparent in the visible and near infrared region (580 to 1250 nm). The FP sensor was optically scanned using a miniature MEMs mirror located at the proximal end of the endoscope, resulting in a system that is sufficiently compact (10 mm outer diameter) and lightweight for practical endoscopic use. Results: The imaging performance of the endoscope is evaluated, and dual-mode imaging capability is demonstrated using phantoms and abdominal organs of an ex vivo mouse including spleen, liver, and kidney. Conclusions: The proposed endoscope design offers several advantages including the high acoustic sensitivity and wide detection bandwidth of the FP sensor, dual-mode imaging capability, compact footprint, and an all-optical distal end for improved safety. The dual-mode imaging capability also offers the advantage of correlating the tissue surface morphology with the underlying vascular anatomy. Potential applications include the guidance of laparoscopic surgery and other interventional procedures.

Biohybrid microrobots regulate colonic cytokines and the epithelium barrier in inflammatory bowel disease.

Cytokines have been identified as key contributors to the development of inflammatory bowel disease (IBD), yet conventional treatments often prove inadequate and carry substantial side effects. Here, we present an innovative biohybrid robotic system, termed "algae-MΦNP-robot," for addressing IBD by actively neutralizing colonic cytokine levels. Our approach combines moving green microalgae with macrophage membrane-coated nanoparticles (MΦNPs) to efficiently capture proinflammatory cytokines "on the fly." The dynamic algae-MΦNP-robots outperformed static counterparts by enhancing cytokine removal through continuous movement, better distribution, and extended retention in the colon. This system is encapsulated in an oral capsule, which shields it from gastric acidity and ensures functionality upon reaching the targeted disease site. The resulting algae-MΦNP-robot capsule effectively regulated cytokine levels, facilitating the healing of damaged epithelial barriers. It showed markedly improved prevention and treatment efficacy in a mouse model of IBD and demonstrated an excellent biosafety profile. Overall, our biohybrid algae-MΦNP-robot system offers a promising and efficient solution for IBD, addressing cytokine-related inflammation effectively.

Capsulated Cellular Nanosponges for the Treatment of Experimental Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD) is a chronic gastrointestinal tract disorder characterized by uncontrolled inflammatory responses to the disrupted intestinal epithelial barrier and gut microbiome dysbiosis. Currently available small-molecule immunosuppressive agents and anticytokine biologics show limited potency, mainly due to the complexity of the inflammatory network involved in IBD. Here, we develop an oral formulation of macrophage membrane-coated nanoparticles capsulated in enteric polymer-coated gelatin capsules (denoted "cp-MΦ-NPs") for IBD treatment. The capsules protect the nanoparticles from gastric degradation and allow for targeted delivery to the colon. At the inflamed colon, cp-MΦ-NPs act as macrophage decoys that bind and neutralize pro-inflammatory cytokines. The in vivo treatment efficacy of cp-MΦ-NPs is tested in a mouse model of dextran sulfate sodium-induced colitis. In both prophylactic and delayed treatment regimens, the oral delivery of cp-MΦ-NPs significantly alleviates IBD severity, reflected by reduced intestinal inflammation and intestinal barrier restoration. Overall, cp-MΦ-NPs provide a biomimetic nanomedicine strategy for the treatment of IBD.