Molecular and clinical presentation of UBA1-mutated myelodysplastic syndromes.

Mutations in UBA1, which are disease-defining for VEXAS syndrome, have been reported in patients diagnosed with myelodysplastic syndromes (MDS). Here, we define the prevalence and clinical associations of UBA1 mutations in a representative cohort of patients with MDS. Digital droplet PCR profiling of a selected cohort of 375 male patients lacking MDS disease-defining mutations or established WHO disease classification identified 28 patients (7%) with UBA1 p.M41T/V/L mutations. Using targeted sequencing of UBA1 in a representative MDS cohort (n=2,027), we identified an additional 27 variants in 26 patients (1%), which we classified as likely/pathogenic (n=12) and unknown significance (n=15). Among the total 40 patients with likely/pathogenic variants (2%), all were male and 63% were classified by WHO2016 as MDS-MLD/SLD. Patients had a median of one additional myeloid gene mutation, often in TET2 (n=12), DNMT3A (n=10), ASXL1 (n=3), or SF3B1 (n=3). Retrospective clinical review where possible showed that 83% (28/34) UBA1-mutant cases had VEXAS-associated diagnoses or inflammatory clinical presentation. The prevalence of UBA1-mutations in MDS patients argues for systematic screening for UBA1 in the management of MDS.

Initial non-invasive in vivo sensing of the lung using time domain diffuse optics.

The in vivo diagnosis and monitoring of pulmonary disorders (caused for example by emphysema, Covid-19, immature lung tissue in infants) could be effectively supported by the non-invasive sensing of the lung through light. With this purpose, we investigated the feasibility of probing the lung by means of time-resolved diffuse optics, leveraging the increased depth (a few centimeters) attained by photons collected after prolonged propagation time (a few nanoseconds). We present an initial study that includes measurements performed on 5 healthy volunteers during a breathing protocol, using a time-resolved broadband diffuse optical spectroscopy system. Those measurements were carried out across the spectral range of 600-1100 nm at a source-detector distance of 3 cm, and at 820 nm over a longer distance (7-9 cm). The preliminary analysis of the in vivo data with a simplified homogeneous model revealed a maximum probing depth of 2.6-3.9 cm, suitable for reaching the lung. Furthermore, we observed variations in signal associated with respiration, particularly evident at long photon propagation times. However, challenges stemming from both intra- and inter-subject variability, along with inconsistencies potentially arising from conflicting scattering and absorption effects on the collected signal, hindered a clear interpretation. Aspects that require further investigation for a more comprehensive understanding are outlined.

Current experimental and early investigational agents for cardiac fibrosis: where are we at?

INTRODUCTION: Myocardial fibrosis (MF) is induced by factors activating pro-fibrotic pathways such as acute and prolonged inflammation, myocardial ischemic events, hypertension, aging process, and genetically-linked cardiomyopathies. Dynamics and characteristics of myocardial fibrosis development are very different. The broad range of myocardial fibrosis presentations suggests the presence of multiple potential targets. AREA COVERED: Heart failure treatment involves medications primarily aimed at counteracting neurohormonal activation. While these drugs have demonstrated efficacy against MF, not all specifically target inflammation or fibrosis progression with some exceptions such as RAAS inhibitors. Consequently, new therapies are being developed to address this issue. This article is aimed to describe anti-fibrotic drugs currently employed in clinical practice and emerging agents that target specific pathways, supported by evidence from both preclinical and clinical studies. EXPERT OPINION: Despite various preclinical findings suggesting the potential utility of new drugs and molecules for treating cardiac fibrosis in animal models, there is a notable scarcity of clinical trials investigating these effects. However, the pathology of damage and repair in the heart muscle involves a complex network of interconnected inflammatory pathways and various types of immune cells. Our comprehension of the positive and negative roles played by specific immune cells and cytokines is an emerging area of research.

Statistics of maximum photon penetration depth in a two-layer diffusive medium.

We present numerical results for the probability density function f(z) and for the mean value of photon maximum penetration depth zmax> in a two-layer diffusive medium. Both time domain and continuous wave regime are considered with several combinations of the optical properties (absorption coefficient, reduced scattering coefficient) of the two layers, and with different geometrical configurations (source detector distance, thickness of the upper layer). Practical considerations on the design of time domain and continuous wave systems are derived. The methods and the results are of interest for many research fields such as biomedical optics and advanced microscopy.

"I don't think of it as a shelter. I say I'm going home": a qualitative evaluation of a low-threshold shelter for women who use drugs.

BACKGROUND: In 2021-2022, encampments in a downtown Boston neighborhood reached record heights, increasing the visibility of drug use and homelessness in the city. In response, the city planned a "sweep" (i.e., eradication of encampments) and requested support from social services and medical providers to pilot low-threshold shelters. Low-threshold shelters reduce barriers to staying in traditional congregate shelters with more flexible regulations, longer-term bed assignments, and secured storage for contraband (e.g., drugs, weapons) instead of forced disposal. One homeless service provider opened a harm reduction-focused shelter for women who use drugs. This report describes the low-threshold shelter design and program evaluation. METHODS: This program evaluation had two primary aims: (1) to examine guests' beliefs about shelter policies and practices; and (2) to understand the staff's experiences working in a low-threshold model. We conducted semi-structured qualitative interviews with 16 guests and 12 staff members during the summer 2022. Interviews were thematically analyzed. RESULTS: Guests expressed overwhelming approval for the shelter's policies, which they stated supported their autonomy, dignity, and safety. They emphasized the staff's willingness to build relationships, thus demonstrating true commitment to the guests. Guests highlighted the value of daytime access to the shelter, as it granted them autonomy over their time, reduced their substance use, and helped them build relationships with staff and other guests. The co-directors and staff designed the shelter quickly and without US models for reference; they turned to international literature, local harm reduction health care providers, and women living in encampments for guidance on the shelter policies. The staff were passionate and committed to the health and stability of the guests. Most staff found value in the low-threshold model, though some were challenged by it, believing it enabled drug use and did not require the guests to "get better." CONCLUSIONS: This evaluation indicates the value of low-threshold, harm reduction shelters as alternatives to traditional models. While these shelters do not mitigate the need for overarching housing reform, they are important measures to meet the needs of women experiencing unsheltered homelessness who face intersectional oppression.

Fast data fitting scheme for compressive multispectral fluorescence lifetime imaging.

A single-pixel camera combined with compressive sensing techniques is a promising fluorescence microscope scheme for acquiring a multidimensional dataset (space, spectrum, and lifetime) and for reducing the measurement time with respect to conventional microscope schemes. However, upon completing the acquisition, a computational step is necessary for image reconstruction and data analysis, which can be time-consuming, potentially canceling out the beneficial effect of compressive sensing. In this work, we propose and experimentally validate a fast-fit workflow based on global analysis and multiple linear fits, which significantly reduces the computation time from tens of minutes to less than 1 s. Moreover, as the method is interlaced with the measurement flow, it can be applied in parallel with the acquisitions.

Application limits of the scaling relations for Monte Carlo simulations in diffuse optics. Part 1: theory.

Monte Carlo (MC) is a powerful tool to study photon migration in scattering media, yet quite time-consuming to solve inverse problems. To speed up MC-simulations, scaling relations can be applied to an existing initial MC-simulation to generate a new data-set with different optical properties. We named this approach trajectory-based since it uses the knowledge of the detected photon trajectories of the initial MC-simulation, in opposition to the slower photon-based approach, where a novel MC-simulation is rerun with new optical properties. We investigated the convergence and applicability limits of the scaling relations, both related to the likelihood that the sample of trajectories considered is representative also for the new optical properties. For absorption, the scaling relation contains smoothly converging Lambert-Beer factors, whereas for scattering it is the product of two quickly diverging factors, whose ratio, for NIRS cases, can easily reach ten orders of magnitude. We investigated such instability by studying the probability-distribution for the number of scattering events in trajectories of given length. We propose a convergence test of the scattering scaling relation based on the minimum-maximum number of scattering events in recorded trajectories. We also studied the dependence of MC-simulations on optical properties, most critical in inverse problems, finding that scattering derivatives are ascribed to small deviations in the distribution of scattering events from a Poisson distribution. This paper, which can also serve as a tutorial, helps to understand the physics of the scaling relations with the causes of their limitations and devise new strategies to deal with them.

Two-layer reconstruction of Raman spectra in diffusive media based on an analytical model in the time domain.

We derive and validate an analytical model that describes the migration of Raman scattered photons in two-layer diffusive media, based on the diffusion equation in the time domain. The model is derived under a heuristic approximation that background optical properties are identical on the excitation and Raman emission wavelengths. Methods for the reconstruction of two-layer Raman spectra have been developed, tested in computer simulations and validated on tissue-mimicking phantom measurements data. Effects of different parameters were studied in simulations, showing that the thickness of the top layer and number of detected photon counts have the most significant impact on the reconstruction. The concept of quantitative, mathematically rigorous reconstruction using the proposed model was finally proven on experimental measurements, by successfully separating the spectra of silicone and calcium carbonate (calcite) layers, showing the potential for further development and eventual application in clinical diagnostics.

Time domain diffuse Raman spectroscopy using single pixel detection.

Diffuse Raman spectroscopy (DIRS) extends the high chemical specificity of Raman scattering to in-depth investigation of thick biological tissues. We present here a novel approach for time-domain diffuse Raman spectroscopy (TD-DIRS) based on a single-pixel detector and a digital micromirror device (DMD) within an imaging spectrometer for wavelength encoding. This overcomes the intrinsic complexity and high cost of detection arrays with ps-resolving time capability. Unlike spatially offset Raman spectroscopy (SORS) or frequency offset Raman spectroscopy (FORS), TD-DIRS exploits the time-of-flight distribution of photons to probe the depth of the Raman signal at a single wavelength with a single source-detector separation. We validated the system using a bilayer tissue-bone mimicking phantom composed of a 1 cm thick slab of silicone overlaying a calcium carbonate specimen and demonstrated a high differentiation of the two Raman signals. We reconstructed the Raman spectra of the two layers, offering the potential for improved and quantitative material analysis. Using a bilayer phantom made of porcine muscle and calcium carbonate, we proved that our system can retrieve Raman peaks even in the presence of autofluorescence typical of biomedical tissues. Overall, our novel TD-DIRS setup proposes a cost-effective and high-performance approach for in-depth Raman spectroscopy in diffusive media.

Learning rules of engagement for social exchange within and between groups.

Globalizing economies and long-distance trade rely on individuals from different cultural groups to negotiate agreement on what to give and take. In such settings, individuals often lack insight into what interaction partners deem fair and appropriate, potentially seeding misunderstandings, frustration, and conflict. Here, we examine how individuals decipher distinct rules of engagement and adapt their behavior to reach agreements with partners from other cultural groups. Modeling individuals as Bayesian learners with inequality aversion reveals that individuals, in repeated ultimatum bargaining with responders sampled from different groups, can be more generous than needed. While this allows them to reach agreements, it also gives rise to biased beliefs about what is required to reach agreement with members from distinct groups. Preregistered behavioral (N = 420) and neuroimaging experiments (N = 49) support model predictions: Seeking equitable agreements can lead to overly generous behavior toward partners from different groups alongside incorrect beliefs about prevailing norms of what is appropriate in groups and cultures other than one's own.

Interstitial null-distance time-domain diffuse optical spectroscopy using a superconducting nanowire detector.

Significance: Interstitial fiber-based spectroscopy is gaining interest for real-time in vivo optical biopsies, endoscopic interventions, and local monitoring of therapy. Different from other photonics approaches, time-domain diffuse optical spectroscopy (TD-DOS) can probe the tissue at a few cm distance from the fiber tip and disentangle absorption from the scattering properties. Nevertheless, the signal detected at a short distance from the source is strongly dominated by the photons arriving early at the detector, thus hampering the possibility of resolving late photons, which are rich in information about depth and absorption. Aim: To fully benefit from the null-distance approach, a detector with an extremely high dynamic range is required to effectively collect the late photons; the goal of our paper is to test its feasibility to perform TD-DOS measurements at null source-detector separations (NSDS). Approach: In particular, we demonstrate the use of a superconducting nanowire single photon detector (SNSPD) to perform TD-DOS at almost NSDS ( ≈ 150 µ m ) by exploiting the high dynamic range and temporal resolution of the SNSPD to extract late arriving, deep-traveling photons from the burst of early photons. Results: This approach was demonstrated both on Monte Carlo simulations and on phantom measurements, achieving an accuracy in the retrieval of the water spectrum of better than 15%, spanning almost two decades of absorption change in the 700- to 1100-nm range. Additionally, we show that, for interstitial measurements at null source-detector distance, the scattering coefficient has a negligible effect on late photons, easing the retrieval of the absorption coefficient. Conclusions: Utilizing the SNSPD, broadband TD-DOS measurements were performed to successfully retrieve the absorption spectra of the liquid phantoms. Although the SNSPD has certain drawbacks for use in a clinical system, it is an emerging field with research progressing rapidly, and this makes the SNSPD a viable option and a good solution for future research in needle guided time-domain interstitial fiber spectroscopy.

Acute, Prolonged, and Extensive Myocardial Ischemia in a Patient With Colorectal Cancer.

This case report describes a patient in their 60s with spontaneously subsiding and reoccurring severe acute chest pain that lasted for about 30 minutes as well as a recent diagnosis of colorectal cancer.

Estimation of porcine pancreas optical properties in the 600-1100 nm wavelength range for light-based therapies.

This work reports the optical properties of porcine pancreatic tissue in the broad wavelength range of 600-1100 nm. Absorption and reduced scattering coefficients (µa and µs') of the ex vivo pancreas were obtained by means of Time-domain Diffuse Optical Spectroscopy. We have investigated different experimental conditions-including compression, repositioning, spatial sampling, temporal stability-the effect of the freezing procedure (fresh vs frozen-thawed pancreas), and finally inter-sample variability. Good repeatability under different experimental conditions was obtained (median coefficient of variation less than 8% and ~ 16% for µa and µs', respectively). Freezing-thawing the samples caused an irreversible threefold reduction of µs' and no effect on µa. The absorption and reduced scattering spectra averaged over different samples were in the range of 0.12-0.74 cm-1 and 12-21 cm-1 with an inter-sample variation of ~ 10% and ~ 40% for µa and µs', respectively. The calculated effective transport coefficient (µeff) for fresh pancreatic tissue shows that regions between 800-900 nm and 1050-1100 nm are similar and offer the lowest tissue attenuation in the considered range (i.e., µeff ranging from 2.4 to 2.7 cm-1). These data, describing specific light-pancreas interactions in the therapeutic optical window for the first time, provide pivotal information for planning of light-based thermotherapies (e.g., laser ablation) and instruction of light transport models for biophotonic applications involving this organ.

Enlarged Field of View in Spatially Modulated Selective Volume Illumination Microscopy.

Three-dimensional fluorescence microscopy is a key technology for inspecting biological samples, ranging from single cells to entire organisms. We recently proposed a novel approach called spatially modulated Selective Volume Illumination Microscopy (smSVIM) to suppress illumination artifacts and to reduce the required number of measurements using an LED source. Here, we discuss a new strategy based on smSVIM for imaging large transparent specimens or voluminous chemically cleared tissues. The strategy permits steady mounting of the sample, achieving uniform resolution over a large field of view thanks to the synchronized motion of the illumination lens and the camera rolling shutter. Aided by a tailored deconvolution method for image reconstruction, we demonstrate significant improvement of the resolution at different magnification using samples of varying sizes and spatial features.

Multi-laboratory performance assessment of diffuse optics instruments: the BitMap exercise.

SIGNIFICANCE: Multi-laboratory initiatives are essential in performance assessment and standardization-crucial for bringing biophotonics to mature clinical use-to establish protocols and develop reference tissue phantoms that all will allow universal instrument comparison. AIM: The largest multi-laboratory comparison of performance assessment in near-infrared diffuse optics is presented, involving 28 instruments and 12 institutions on a total of eight experiments based on three consolidated protocols (BIP, MEDPHOT, and NEUROPT) as implemented on three kits of tissue phantoms. A total of 20 synthetic indicators were extracted from the dataset, some of them defined here anew. APPROACH: The exercise stems from the Innovative Training Network BitMap funded by the European Commission and expanded to include other European laboratories. A large variety of diffuse optics instruments were considered, based on different approaches (time domain/frequency domain/continuous wave), at various stages of maturity and designed for different applications (e.g., oximetry, spectroscopy, and imaging). RESULTS: This study highlights a substantial difference in hardware performances (e.g., nine decades in responsivity, four decades in dark count rate, and one decade in temporal resolution). Agreement in the estimates of homogeneous optical properties was within 12% of the median value for half of the systems, with a temporal stability of <5 % over 1 h, and day-to-day reproducibility of <3 % . Other tests encompassed linearity, crosstalk, uncertainty, and detection of optical inhomogeneities. CONCLUSIONS: This extensive multi-laboratory exercise provides a detailed assessment of near-infrared Diffuse optical instruments and can be used for reference grading. The dataset-available soon in an open data repository-can be evaluated in multiple ways, for instance, to compare different analysis tools or study the impact of hardware implementations.

Evaluation of a pipeline for simulation, reconstruction, and classification in ultrasound-aided diffuse optical tomography of breast tumors.

SIGNIFICANCE: Diffuse optical tomography is an ill-posed problem. Combination with ultrasound can improve the results of diffuse optical tomography applied to the diagnosis of breast cancer and allow for classification of lesions. AIM: To provide a simulation pipeline for the assessment of reconstruction and classification methods for diffuse optical tomography with concurrent ultrasound information. APPROACH: A set of breast digital phantoms with benign and malignant lesions was simulated building on the software VICTRE. Acoustic and optical properties were assigned to the phantoms for the generation of B-mode images and optical data. A reconstruction algorithm based on a two-region nonlinear fitting and incorporating the ultrasound information was tested. Machine learning classification methods were applied to the reconstructed values to discriminate lesions into benign and malignant after reconstruction. RESULTS: The approach allowed us to generate realistic US and optical data and to test a two-region reconstruction method for a large number of realistic simulations. When information is extracted from ultrasound images, at least 75% of lesions are correctly classified. With ideal two-region separation, the accuracy is higher than 80%. CONCLUSIONS: A pipeline for the generation of realistic ultrasound and diffuse optics data was implemented. Machine learning methods applied to a optical reconstruction with a nonlinear optical model and morphological information permit to discriminate malignant lesions from benign ones.

Compressed sensing in fluorescence microscopy.

Compressed sensing (CS) is a signal processing approach that solves ill-posed inverse problems, from under-sampled data with respect to the Nyquist criterium. CS exploits sparsity constraints based on the knowledge of prior information, relative to the structure of the object in the spatial or other domains. It is commonly used in image and video compression as well as in scientific and medical applications, including computed tomography and magnetic resonance imaging. In the field of fluorescence microscopy, it has been demonstrated to be valuable for fast and high-resolution imaging, from single-molecule localization, super-resolution to light-sheet microscopy. Furthermore, CS has found remarkable applications in the field of mesoscopic imaging, facilitating the study of small animals' organs and entire organisms. This review article illustrates the working principles of CS, its implementations in optical imaging and discusses several relevant uses of CS in the field of fluorescence imaging from super-resolution microscopy to mesoscopy.