pH inactivation of SARS-CoV-2 and SARS-CoV in virus spiked protein A eluates from a mAb purification process.

Biopharmaceutical manufacturing processes may include a low pH treatment step as a means of inactivating enveloped viruses. Small scale virus clearance studies are routinely performed using model enveloped viruses such as murine leukemia virus to assess inactivation at the pH range used in the downstream manufacturing process. Further, as a means of bioburden reduction, chromatography resins may be cleaned and stored using sodium hydroxide and this can also inactivate viruses. The susceptibility of SARS-CoV-2 and SARS-CoV to low pH conditions using protein A eluate derived material from a monoclonal antibody production process as well as high pH cleaning conditions was addressed. SARS-CoV-2 was effectively inactivated at pH 3.0, moderately inactivated at pH 3.4, but not inactivated at pH 3.8. Low pH was less effective at inactivating SARS-CoV. Both viruses were inactivated at a high pH of ca.13.4. These studies provide important information regarding the effectiveness of viral clearance and inactivation steps of novel coronaviruses when compared to other enveloped viruses.

Investigation of the molecular switching process between spin crossover states of triazole complexes as basis for optical sensing applications.

With the advent of the first laser sources and suitable detectors, optical sensor applications immediately also came into focus. During the last decades, a huge variety of optical sensor concepts were developed, yet the forecast for the future application potential appears even larger. In this context, the development of new sensor probes at different scales down to the atomic or molecular level open new avenues for research and development. We investigated an iron based triazole molecular spin-crossover complex changing its absorption characteristics significantly by varying environmental parameters such as humidity, temperature, magnetic or electric field, respectively, with respect to its suitability for a new class of versatile molecular sensor probes. Hereby, besides the investigation of synthesized pure bulk material using different analyzing methods, we also studied amorphous micro particles which were applied in or onto optical waveguide structures. We found that significant changes of the reflection spectra can also be obtained after combining the particles with different types of optical waveguides.The obtained results demonstrate the suitability of the material complex for a broad field of future sensor applications.

Non-invasive 3D imaging of human melanocytic lesions by combined ultrasound and photoacoustic tomography: a pilot study.

The accurate determination of the size and depth of infiltration is critical to the treatment and excision of melanoma and other skin cancers. However, current techniques, such as skin biopsy and histological examination, pose invasiveness, time-consumption, and have limitations in measuring at the deepest level. Non-invasive imaging techniques like dermoscopy and confocal microscopy also present limitations in accurately capturing contrast and depth information for various skin types and lesion locations. Thus, there is a pressing need for non-invasive devices capable of obtaining high-resolution 3D images of skin lesions. In this study, we introduce a novel device that combines 18 MHz ultrasound and photoacoustic tomography into a single unit, enabling the acquisition of colocalized 3D images of skin lesions. We performed in vivo measurements on 25 suspicious human skin nevi that were promptly excised following measurements. The combined ultrasound/photoacoustic tomography imaging technique exhibited a strong correlation with histological Breslow thickness between 0.2 and 3 mm, achieving a coefficient of determination (R[Formula: see text]) of 0.93, which is superior to the coefficients from the individual modalities. The results procured in our study underscore the potential of combined ultrasound and photoacoustic tomography as a promising non-invasive 3D imaging approach for evaluating human nevi and other skin lesions. Furthermore, the system allows for integration of other optical modalities such as optical coherence tomography, microscopy, or Raman spectroscopy in future applications.

The potential of patient-based nurse staffing - a queuing theory application in the neonatal intensive care setting.

Faced by a severe shortage of nurses and increasing demand for care, hospitals need to optimally determine their staffing levels. Ideally, nurses should be staffed to those shifts where they generate the highest positive value for the quality of healthcare. This paper develops an approach that identifies the incremental benefit of staffing an additional nurse depending on the patient mix. Based on the reasoning that timely fulfillment of care demand is essential for the healthcare process and its quality in the critical care setting, we propose to measure the incremental benefit of staffing an additional nurse through reductions in time until care arrives (TUCA). We determine TUCA by relying on queuing theory and parametrize the model with real data collected through an observational study. The study indicates that using the TUCA concept and applying queuing theory at the care event level has the potential to improve quality of care for a given nurse capacity by efficiently trading situations of high versus low workload.

Improved polarimetric analysis of human skin through stitching: advantages, limitations, and applications in dermatology.

Polarimetry is a powerful tool for the analysis of the optical properties of materials and systems, such as human skin. However, in many polarimetric setups, the field of view is limited to a few square centimeters. In these cases, it is possible to resort to stitching techniques, which involve combining multiple Mueller matrix measurements obtained from different overlapping regions of the sample. In this paper, we propose a stitching technique for polarimetric data and discuss its advantages and limitations. We also describe the potential of image stitching for improving the accuracy and robustness ofin vivopolarimetry in the presence of random patient movement. We conducted our research using a diverse set of samples which included porcine skin, human skin from arms and fingers, cold cuts of chicken and gelatine, alongside synthetically created sample data. Our results demonstrate the effectiveness of this technique for the application in dermatology. Each additionalin vivomeasurement enhances the field of view by approximately one third, thereby considerably augmenting the total observation area. We show that stitching enables for the polarimetric assessment of large skin patches which is useful for the diagnosis of inflammatory skin diseases.

Combined ultrasound and photoacoustic C-mode imaging system for skin lesion assessment.

Accurate assessment of the size and depth of infiltration is critical for effectively treating and removing skin cancer, especially melanoma. However, existing methods such as skin biopsy and histologic examination are invasive, time-consuming, and may not provide accurate depth results. We present a novel system for simultaneous and co-localized ultrasound and photoacoustic imaging, with the application for non-invasive skin lesion size and depth measurement. The developed system integrates an acoustical mirror that is placed on an ultrasound transducer, which can be translated within a flexible water tank. This allows for 3D (C-mode) imaging, which is useful for mapping the skin structure and determine the invasion size and depth of lesions including skin cancer. For efficient reconstruction of photoacoustic images, we applied the open-source MUST library. The acquisition time per 2D image is <1 s and the pulse energies are below the legal Maximum Permissible Exposure (MPE) on human skin. We present the depth and resolution capabilities of the setup on several self-designed agar phantoms and demonstrate in vivo imaging on human skin. The setup also features an unobstructed optical window from the top, allowing for simple integration with other optical modalities. The perspective towards clinical application is demonstrated.

Universal Newborn Hearing Screening Program: 10-Year Outcome and Follow-Up from a Screening Center in Germany.

Regular reporting of quality control is important in newborn hearing screening, ensuring early diagnosis and intervention. This study reports on a population-based newborn hearing screening program in North-Rhine, Germany and a hospital-based screening at a University Hospital for 2007-2016. The two-staged 'screening' and 'follow-up' program involving TEOAE and AABR recruited newborns through participating birth facilities. Results were sent to the regional tracking center, and the data were analyzed based on recommended benchmarks. The percentage of newborns from the participating birth facilities in the region increased from 1.4% in 2007 to 57.5% in 2016. The 10-year coverage rate for these newborns was 98.7%, the referral rate after a failed two-step screening was 3.4%, and the lost-to-follow-up rate was 1%. At the hospital, >95% of the screened newborns completed screening within 30 days, the 10-year referral rate was 5%, and 64% were referred within 3 months of age. The median time for screening completion was 6 days after birth, for referral it was 74 days after birth, and for diagnosis it was 55 days after birth. Regional-centralized tracking centers with uniform structure are necessary for proper quality control. Obligatory participation of birthing facilities and quality reports may improve performance, but the recommended quality criteria need considerable financial and infrastructural expenditure.

Analysis of SARS-CoV-2 spike RBD binding to ACE2 and its inhibition by fungal cohaerin C using surface enhanced Raman spectroscopy.

The structure of the SARS-CoV-2 spike RBD and human ACE2 as well as changes in the structure due to binding activities were analysed using surface enhanced Raman spectroscopy. The inhibitor cohaerin C was applied to inhibit the binding between spike RBD and ACE2. Differences and changes in the Raman spectra were determined using deconvolution of the amide bands and principal component analysis. We thus demonstrate a fast and label-free analysis of the protein structures and the differentiation between bound and unbound states. The approach is suitable for sensing and screening and might be relevant to investigate other protein systems as well.

Detection of melanin influence on skin samples based on Raman spectroscopy and optical coherence tomography dual-modal approach.

Melanoma is responsible for more than half of the deaths related to skin cancer in the last few decades. A dual-modality optical biopsy system with Raman spectroscopy and optical coherence tomography approach was built with the goal of achieving noninvasive skin measurement. To mimic melanoma and evaluate the effect of melanin on skin, models have been created by dissolving synthetic melanin in dimethyl sulfoxide and adding it to fresh skin samples. Compared to the untreated samples, morphological images showed that the imaging depth on melanin-treated skin has been increased from 250 µm to 350 µm due to the optical clearing effect of the DMSO solvent, and Raman analysis revealed that relative spectral intensities of melanin-treated samples were lower in the amide-I and CH2 -deformation bands, and higher in the CH2 -twist and C-C stretch bands. Using machine learning for skin type classification, an accuracy of 89% is achieved.

Referral rate and false-positive rates in a hearing screening program among high-risk newborns.

AIM: More studies exploring referral rates and false-positive rates are needed to make hearing screening programs in newborns better and cost-effective. Our aim was to study the referral and false-positivity rates among high-risk newborns in our hearing screening program and to analyze the factors potentially associated with false-positive hearing screening test results. METHODS: A retrospective cohort study was done among the newborns hospitalized at a university hospital from January 2009 to December 2014 that underwent hearing screening with a two-staged AABR screening protocol. Referral rates and false-positivity rates were calculated and possible risk factors for false-positivity were analyzed. RESULTS: 4512 newborns were screened for hearing loss in the neonatology department. The referral rate for the two-staged AABR-only screening was 3.8% with false-positivity being 2.9%. Our study showed that the higher the birthweight or gestational age of the newborn, the lower the odds of the hearing screening results being false-positive, and the higher the chronological age of the infant at the time of screening, the higher the odds of the results being false-positive. Our study did not show a clear association between the mode of delivery or gender and false-positivity. CONCLUSION: Among high-risk infants, prematurity and low-birthweight increased the rate of false-positivity in the hearing screening, and the chronological age at the time of the test seems to be significantly associated with false-positivity.

Validation of the ABPMpro ambulatory blood pressure monitor in the general population according to AAMI/ESH/ISO Universal Standard (ISO 81060-2:2018).

OBJECTIVE: The objective of this study is to evaluate the accuracy of the oscillometric upper-arm device ABPMpro (SOMNOmedics) for ambulatory blood pressure measurement in the general population according to the Association for the Advancement of Medical Instrumentation/European Society of Hypertension/International Organization for Standardization (AAMI/ESH/ISO) Universal Standard (ISO 81060-2:2018) at rest and during dynamic exercise. METHODS: Subjects were recruited to fulfill the age, sex, blood pressure (BP) and cuff distribution criteria of the AAMI/ESH/ISO standard using the same arm sequential BP measurement method. Three appropriate cuff sizes (18-24, 24-34 and 34-46 cm) of the tested device were used for the arm-varying circumferences. The inflation and deflation measurement modes of the ABPMpro were investigated. RESULTS: For the general validation study, 100 subjects were recruited and 90 were analyzed. For validation criterion (1), the mean ± SD of the differences between ABPMpro and reference BP was 0.7 ± 7.3/-0.7 ± 5.8 mmHg (systolic/diastolic) for inflation and 1.4 ± 7.7/-0.6 ± 6.1 mmHg for deflation measurements. For criterion (2), the SD of the averaged BP differences per subject was 5.98/5.10 mmHg for inflation and 6.46/5.36 mmHg for deflation measurements, thereby passing the threshold. In the ambulatory validation study ( N = 36), the mean difference was -1.2 ± 7.9/ 2.4 ± 6.6 mmHg for inflation and -0.7 ± 7.6/3.1 ± 7.0 mmHg for deflation measurements. CONCLUSION: The ABPMpro device fulfilled the ISO 81060-2:2018 requirements in the general population and in the ambulatory setting and can therefore be recommended for clinical use.

Mueller Matrix Microscopy for In Vivo Scar Tissue Diagnostics and Treatment Evaluation.

Scars usually do not show strong contrast under standard skin examination relying on dermoscopes. They usually develop after skin injury when the body repairs the damaged tissue. In general, scars cause multiple types of distress such as movement restrictions, pain, itchiness and the psychological impact of the associated cosmetic disfigurement with no universally successful treatment option available at the moment. Scar treatment has significant economic impact as well. Mueller matrix polarimetry with integrated autofocus and automatic data registration can potentially improve scar assessment by the dermatologist and help to make the evaluation of the treatment outcome objective. Polarimetry can provide new physical parameters for an objective treatment evaluation. We show that Mueller matrix polarimetry can enable strong contrast for in vivo scar imaging. Additionally, our results indicate that the polarization stain images obtained form there could be a useful tool for dermatology. Furthermore, we demonstrate that polarimetry can be used to monitor wound healing, which may help prevent scarring altogether.

Focus stacking in non-contact dermoscopy.

Dermoscopy is the main tool for early detection of skin cancer. Non-contact dermoscopes often suffer from a small depth of field leading to images of skin topographies with regions that are not in focus. We aim to provide an easy-to-implement focus stacking-based approach to ensure all-in-focus images from a non-contact dermoscope. Further, we aim to extract additional information about the skin topography from the image stacks. The focus stacking procedure itself is implemented in a non-contact dermoscope with an electrically adjustable focus realized by using a tunable liquid lens. We show that all-in-focus imaging is possible for non-contact dermoscopy and deliver a method to extract topographical information for dermatologists from the acquired image stacks. Our finding indicate that the approach can be valuable for non-contact dermoscopic examination as well as for the early detection of skin diseases such as cancer as it possible to derive hyperfocus images and information on the skin topography. With this, we were able to develop a software for the acquisition of the raw image data and its processing into a high resolution hyperresolution dermoscopic image. In the next steps, we plan to apply the approach in the clinical environment for skin cancer diagnostics or imaging of inflammatory skin diseases.

Registration of polarimetric images for in vivo skin diagnostics.

SIGNIFICANCE: Mueller matrix (MM) polarimetry is a promising tool for the detection of skin cancer. Polarimetric in vivo measurements often suffer from misalignment of the polarimetric images due to motion, which can lead to false results. AIM: We aim to provide an easy-to-implement polarimetric image data registration method to ensure proper image alignment. APPROACH: A feature-based image registration is implemented for an MM polarimeter for phantom and in vivo human skin measurements. RESULTS: We show that the keypoint-based registration of polarimetric images is necessary for in vivo skin polarimetry to ensure reliable results. Further, we deliver an efficient semiautomated method for the registration of polarimetric images. CONCLUSIONS: Image registration for in vivo polarimetry of human skin is required for improved diagnostics and can be efficiently enhanced with a keypoint-based approach.

Multimodal system for optical biopsy of melanoma with integrated ultrasound, optical coherence tomography and Raman spectroscopy.

We introduce a new single-head multimodal optical system that integrates optical coherence tomography (OCT), 18 MHz ultrasound (US) tomography and Raman spectroscopy (RS), allowing for fast (<2 min) and noninvasive skin cancer diagnostics and lesion depth measurement. The OCT can deliver structural and depth information of smaller skin lesions (<1 mm), while the US allows to measure the penetration depth of thicker lesions (≥4 mm), and the RS analyzes the chemical composition from a small chosen spot (≤300 µm) that can be used to distinguish between benign and malignant melanoma. The RS and OCT utilize the same scanning and optical setup, allowing for co-localized measurements. The US on the other side is integrated with an acoustical reflector, which enables B-mode measurements on the same position as OCT and RS. The US B-mode scans can be translated across the sample by laterally moving the US transducer, which is made possible by the developed adapter with a flexible membrane. We present the results on custom-made liquid and agar phantoms that show the resolution and depth capabilities of the setup, as well as preliminary ex vivo measurements on mouse models with ∼4.3 mm thick melanoma.

Self-made transparent optoacoustic detector for measurement of skin lesion thicknessin vivo.

In skin cancer diagnosis and treatment, one of the key factors is tumor depth, which is connected to the severity and the required excision depth. Optoacoustical (OA) imaging is a relatively popular technique that provides information based on the optical absorption of the sample. Although often demonstrated withex vivomeasurements orin vivoimaging on parts of small animals,in vivomeasurements on humans are more challenging. This is presumably because it is too time consuming and the required excitation pulse energies and their number exceed the allowed maximum permissible exposure (MPE). Here, we demonstrate thickness measurements with a transparent optoacoustical detector of different suspicious skin lesionsin vivoon patients. We develop the signal processing technique to automatically convert the raw signal into thickness via deconvolution with the impulse response function. The transparency of the detector allows optical excitation with the pulsed laser to be performed perpendicularly on the lesion, in contrast to the conventional illumination from the side. For validation, the measured results were compared to the histological thickness determined after excision. We show that this simple transparent detector allows to determine the thickness of a lesion and thus, aid the dermatologist to estimate the excision depth in the future.

Real-time stimulated Raman spectroscopy with a non-collinear optical parametric oscillator.

Ultrafast detection of microplastic particles is becoming a vital problem, as these particles are found in water sources worldwide. Ideally, a live analysis in flow is desirable to directly monitor the water quality for contaminations. Therefore, coherent Raman spectroscopy techniques require fast and broadband tunable lasers to address all relevant spectral regions of the investigated samples. In our work, we combine a high power non-collinear optical parametric oscillator with a real-time stimulated Raman scattering spectroscopy setup. The light source is continously tunable from 700 nm to 1030 nm in less than 10 ms, delivering an average output power of more than 500 mW with sub-ps pulses. We show the immediate observation of mixing processes and the detection of microplastic particles in water solution with a spectral window of more than 2000 cm-1.

UV-LED projection photolithography for high-resolution functional photonic components.

The advancement of micro- and nanostructuring techniques in optics is driven by the demand for continuous miniaturization and the high geometrical accuracy of photonic devices and integrated systems. Here, UV-LED projection photolithography is demonstrated as a simple and low-cost approach for rapid generation of two-dimensional optical micro- and nanostructures with high resolution and accuracy using standard optics only. The developed system enables the projection of structure patterns onto a substrate with 1000-fold demagnification. Photonic devices, e.g., waveguides and microring resonators, on rigid or flexible substrates with varied geometrical complexity and overall structure dimensions from the nanometer to centimeter scale were successfully prepared. In particular, high-resolution gratings with feature sizes down to 150 nm and periods as small as 400 nm were realized for the first time by this approach. Waveguides made of doped laser active materials were fabricated, and their spontaneous emission was detected. The demonstrated superior performance of the developed approach may find wide applications in photonics, plasmonics, and optical materials science, among others.

Experimental Investigation of the Rapid Fabrication of Micron and Submicron Structures on Polymers Utilizing Ultrasonic Assisted Embossing.

Small-scale optical components with micron or submicron features have grown in popularity in recent years. High-quality, high-efficient, and cost-effective processing approaches for polymer optics mass production are an urgent need. In this study, ultrasonic vibration will be introduced in embossing. The major advantage is that the required energy can be provided for process times ranging from a few hundred milliseconds to a few seconds, and that the process energy is provided at exactly the required location so that the structures in the surrounding area are not affected. Due to the strong correlation between electrical impedance and the temperature of the material, a novel impedance-based control strategy has been utilized for precisely controlling ultrasonic vibration during the embossing process. The investigation used two types of stamps with grating line widths of 4 µm and 500 nm, respectively. As a result, an embossing time of less than a few seconds was accomplished and a uniform embossed surface with an average fill rate of more than 75% could be achieved.

Fiber Optic Sensors Embedded in Textile-Reinforced Concrete for Smart Structural Health Monitoring: A Review.

The last decade has seen rapid developments in the areas of carbon fiber technology, additive manufacturing technology, sensor engineering, i.e., wearables, and new structural reinforcement techniques. These developments, although from different areas, have collectively paved way for concrete structures with non-corrosive reinforcement and in-built sensors. Therefore, the purpose of this effort is to bridge the gap between civil engineering and sensor engineering communities through an overview on the up-to-date technological advances in both sectors, with a special focus on textile reinforced concrete embedded with fiber optic sensors. The introduction section highlights the importance of reducing the carbon footprint resulting from the building industry and how this could be effectively achieved by the use of state-of-the-art reinforcement techniques. Added to these benefits would be the implementations on infrastructure monitoring for the safe operation of structures through their entire lifespan by utilizing sensors, specifically, fiber optic sensors. The paper presents an extensive description on fiber optic sensor engineering that enables the incorporation of sensors into the reinforcement mechanism of a structure at its manufacturing stage, enabling effective monitoring and a wider range of capabilities when compared to conventional means of structural health monitoring. In future, these developments, when combined with artificial intelligence concepts, will lead to distributed sensor networks for smart monitoring applications, particularly enabling such distributed networks to be implemented/embedded at their manufacturing stage.