A Data-Driven Approach for Estimating Temperature Variations Based on B-mode Ultrasound Images and Changes in Backscattered Energy.

Thermal treatments that use ultrasound devices as a tool have as a key point the temperature control to be applied in a specific region of the patient's body. This kind of procedure requires caution because the wrong regulation can either limit the treatment or aggravate an existing injury. Therefore, determining the temperature in a region of interest in real-time is a subject of high interest. Although this is still an open problem, in the field of ultrasound analysis, the use of machine learning as a tool for both imaging and automated diagnostics are application trends. In this work, a data-driven approach is proposed to address the problem of estimating the temperature in regions of a B-mode ultrasound image as a supervised learning problem. The proposal consists in presenting a novel data modeling for the problem that includes information retrieved from conventional B-mode ultrasound images and a parametric image built based on changes in backscattered energy (CBE). Then, we compare the performance of classic models in the literature. The computational results presented that, in a simulated scenario, the proposed approach that a Gradient Boosting model would be able to estimate the temperature with a mean absolute error of around 0.5°C, which is acceptable in practical environments both in physiotherapic treatments and high intensity focused ultrasound (HIFU).

Quadratic versus linear models to estimate the mean scattering spacing as a function of temperature in ex-vivo tissue.

Previous works have shown the feasibility of temperature estimation during ultrasonic therapy using pulse-echo diagnostic ultrasound. These methods are based on the measurement of thermally induced changes in backscattered RF echoes due to thermal expansion and changes in ultrasonic velocity. They assume a joint contribution of these two parameters and a linear dependence with temperature. In this work, the contributions of velocity changes and thermal expansion to the evolution of the mean scatterer spacing of ex vivo bovine skeletal muscle tissue samples were decoupled. This was achieved by employing an experimental setup which allows measuring the absolute velocity value, using the through-transmission technique in a direct transmission configuration. The mean-scatterer spacing was estimated from spectral analysis of the backscattered signals obtained in pulse-echo mode. We propose a quadratic model of the thermal expansion coefficient to fit the evolution of the mean-scatterer spacing with temperature. The temperature increase estimated by the linear model, in the range of 29.5-47 °C, presents a percentage error (mean square error) of 11 %, while for the quadratic model the error is 4.8 %.

The AE4 transporter mediates kidney acid-base sensing.

The kidney plays a key role in the correction of systemic acid-base imbalances. Central for this regulation are the intercalated cells in the distal nephron, which secrete acid or base into the urine. How these cells sense acid-base disturbances is a long-standing question. Intercalated cells exclusively express the Na+-dependent Cl-/HCO3- exchanger AE4 (Slc4a9). Here we show that AE4-deficient mice exhibit a major dysregulation of acid-base balance. By combining molecular, imaging, biochemical and integrative approaches, we demonstrate that AE4-deficient mice are unable to sense and appropriately correct metabolic alkalosis and acidosis. Mechanistically, a lack of adaptive base secretion via the Cl-/HCO3- exchanger pendrin (Slc26a4) is the key cellular cause of this derailment. Our findings identify AE4 as an essential part of the renal sensing mechanism for changes in acid-base status.

Relationship between intervention dosage and success of resource connections in a social needs intervention.

OBJECTIVES: Social needs interventions in medical settings aim to mitigate the effects of adverse social circumstances on health outcomes by connecting vulnerable patients with resources. This study examined the relationship between intervention dosage and the success of resource connections using data from a social needs intervention in multiple clinical settings across the US. STUDY DESIGN: The intervention uses a case management approach to connect patients with unmet needs to resources and services in the community. Intervention dosage was conceptualized as the number of contacts between the navigator and the patient, categorized as direct contact (phone vs. in person) and indirect contact (initiated by the navigator vs. patient). Success of the intervention was conceptualized as 'none,' 'partial,' or 'optimal' for each patient, based on the number of social needs the resource connections addressed. METHODS: Administrative data were extracted for 38,404 unique patients who screened positive for unmet resource needs between 2012 and 2017. Owing to the large sample size, statistical corrections were made to reduce type I error. RESULTS: Multinomial logistic regression analyses showed that higher intervention dosage was related to greater success of resource connections, after adjusting for the patient and site characteristics, and the number of needs (odds ratios ranged from 1.62 to 2.89). In-person contact, although received by only 25% of the patients, was associated with the highest probability of optimal success. CONCLUSIONS: This study demonstrates a feasible way to conceptualize an intervention dose for a social needs intervention that uses a case management approach and has implications for how intervention delivery may improve success of resource connections.

Method for estimating average grey-level's measurement uncertainty from ultrasound images for non-invasive estimation of temperature in different tissue types.

The objective of this work is to assess, on metrological basis, the average grey-levels (AVGL) calculated from B-Mode images for estimating temperature variations non-invasively in different kinds of tissues. Thermal medicine includes several thermal therapies, being hyperthermia the most noted and well known. Recently, efforts have been made to understand the benefits of ultrasound hyperthermia at mild temperature levels, i.e., between 39 °C and 41 °C. Moreover, the best practices on ultrasound bio-effects research have been encouraged by recommending that temperature rise in the region of interest should be measured even when a thermal mechanism is not being tested. In this work, the average grey-levels (AVGL) calculated from B-Mode images were assessed for non-invasive temperature estimation in a porcine tissue sample containing two different tissue types, fat and muscle, with temperature varying from 35 °C to 41 °C. The sample was continuously imaged with an ultrasound scanner, and simultaneously the temperature was measured. The achieved results were assessed under the light of the measurement uncertainty in order to allow comparability among different ultrasound thermometry methods. The highest expanded uncertainty of estimating temperature variation using AVGL was determined as 0.68 °C.

Durability study of a gellan gum-based tissue-mimicking phantom for ultrasonic thermal therapy.

Stability and duration of ultrasonic phantoms are still subjects of research. This work presents a tissue-mimicking material (TMM) to evaluate high-intensity therapeutic ultrasound (HITU) devices, composed of gellan gum (matrix), microparticles (scatterers), and chemicals. The ultrasonic velocity and attenuation coefficient were characterized as a function of temperature (range 20 °C-85 °C). The nonlinear parameter B/A was determined by the finite amplitude insertion substitution (FAIS) method, and the shear modulus was determined by a transient elastography technique. The thermal conductivity and specific heat were determined by the line source method. The attenuation was stable for 60 days, and in an almost linear frequency dependence (0.51f0.96 dB cm-1), at 20 °C (1-10 MHz). All other evaluated physical parameters are also close to typical soft tissue values. Longitudinal ultrasonic velocities were between 1.49 and 1.75 mm µs-1, the B/A parameter was 7.8 at 30 °C, and Young's modulus was 23.4 kPa. The thermal conductivity and specific heat values were 0.7 W(m K)-1 and 4.7 kJ(kg K)-1, respectively. Consistent temperature increases and thermal doses occurred under identical HITU exposures. Low cost, longevity, thermal stability, and thermal repeatability make TMM an excellent material for ultrasonic thermal applications. The TMM developed has the potential to assess the efficacy of hyperthermia devices and could be used to adjust the ultrasonic emission of HITU devices.

The Oxysterol Synthesising Enzyme CH25H Contributes to the Development of Intestinal Fibrosis.

Intestinal fibrosis and stenosis are common complications of Crohn's disease [CD], frequently requiring surgery. Anti-inflammatory strategies can only partially prevent fibrosis; hence, anti-fibrotic therapies remain an unmet clinical need. Oxysterols are oxidised cholesterol derivatives with important roles in various biological processes. The enzyme cholesterol 25-hydroxylase [CH25H] converts cholesterol to 25-hydroxycholesterol [25-HC], which modulates immune responses and oxidative stress. In human intestinal samples from CD patients, we found a strong correlation of CH25H mRNA expression with the expression of fibrosis markers. We demonstrate reduced intestinal fibrosis in mice deficient for the CH25H enzyme, using the sodium dextran sulphate [DSS]-induced chronic colitis model. Additionally, using a heterotopic transplantation model of intestinal fibrosis, we demonstrate reduced collagen deposition and lower concentrations of hydroxyproline in CH25H knockouts. In the heterotopic transplant model, CH25H was expressed in fibroblasts. Taken together, our findings indicate an involvement of oxysterol synthesis in the pathogenesis of intestinal fibrosis.

Ex vivo determined experimental correction factor for the ultrasonic source term in the bioheat equation.

The objective of this work is to propose an effective absorption coefficient (αeffec) as an empirical correction factor in the source term of the bioheat equation. The temperature rise in biological tissue due to ultrasound insonification is produced by energy absorption. Usually, the ultrasonic absorption coefficient (αA) is used as a source term in the bioheat equation to quantify the temperature rise, and the effect of scattering is disregarded. The coefficient αeffec includes the scattering contribution as an additional absorption term and should allow us to make a better estimation of the thermal dose (TD), which is important for clinical applications. We simulated the bioheat equation with the source term considering αA or αeffec, and with heating provided by therapeutic ultrasound (1MHz, 2.0Wcm-2) for about 5.5min (temperature range 36-46°C). Experimental data were obtained in similar heating conditions for a bovine muscle tissue (ex vivo) and temperature curves were measured for depths 7, 30, 35, 40 and 45mm. The TD values from the experimental temperature curves at each depth were compared with the numerical solution of the bioheat equation with the classical and corrected source terms. The highest percentual difference between simulated and experimental TD was 42.5% when assuming the classical αA, and 8.7% for the corrected αeffec. The results show that the effective absorption coefficient is a feasible parameter to improve the classical bioheat transfer model, especially for depths larger than the mean free propagation path.

Assessing heating distribution by therapeutic ultrasound on bone phantoms and in vitro human samples using infrared thermography.

BACKGROUND: Bioheat models have been proposed to predict heat distribution in multilayered biological tissues after therapeutic ultrasound (TUS) stimulation. However, evidence on its therapeutic benefit is still controversial for many clinical conditions. The aim of this study was to evaluate and to compare the TUS heating distribution on commercially available bone phantoms and in vitro femur and tibia human samples, at 1 MHz and several ultrasonic pulse regimens, by means of a thermographic image processing technique. METHODS: An infrared camera was used to capture an image after each 5-min 1-MHz TUS stimulation on bone phantoms, as well as in vitro femur and tibia samples (N = 10). An intensity-based processing algorithm was applied to estimate temperature distribution. Sections of five femurs in the coronal plane were also used for the evaluation of heat distribution inside the medullar canal. RESULTS: Temperature increased up to 8.2 and 9.8 °C for the femur and tibia, respectively. Moreover, the temperature increased up to 10.8 °C inside the medullar canal. Although temperature distributions inside the region of interest (ROI) were significantly different (p < 0.001), the average and standard deviation values for bone phantoms were more similar to the femur than to the tibia samples. Pulsed regimens caused lower increments in temperature than continuous sonication, as expected. CONCLUSIONS: Commercially available bone phantoms could be used in research focusing on thermal effects of ultrasound. Small differences in mean and standard deviation temperatures were observed between bone samples and phantoms. Temperature can reach more than 10 °C inside the medullar canal on a fixed probe position which may lead to severe cellular damage.

Thermochromic Phantom and Measurement Protocol for Qualitative Analysis of Ultrasound Physiotherapy Systems.

Thermochromic test bodies are promising tools for qualitatively evaluating the acoustic output of ultrasound physiotherapy systems. Here, a novel phantom, made of silicone mixed with thermochromic powder material, was developed. Additionally, a procedure was developed to evaluate the stability and homogeneity of the phantom in a metrologic and statistical base. Twelve phantoms were divided into three groups. Each group was insonated by a different transducer. An effective intensity of 1.0 W/cm(2) was applied to each phantom; two operators performed the procedure three times in all phantoms. The heated area was measured after image processing. No statistical difference was observed in the heated areas for different samples or in the results for different operators. The heated areas obtained using each transducer were statistically different, indicating that the thermochromic phantom samples had sufficient sensitivity to represent the heated areas of different ultrasonic transducers. Combined with the evaluation procedure, the phantom provides an approach not previously described in the literature. The proposed approach can be used to quickly assess changes in ultrasonic beam cross-sectional shape during the lifetime of ultrasound physiotherapy systems.

Influence of ultrasonic scattering in the calculation of thermal dose in ex-vivo bovine muscular tissues.

This study explores the effect of ultrasound scattering on the temperature increase in phantoms and in samples of ex-vivo biological tissue through the calculation of the thermal dose (TD). Phantoms with different weight percentages of graphite powder (0-1%w/w, different scattering mean free paths, ℓS) and ex-vivo bovine muscle tissue were isonified by therapeutic ultrasound (1 MHz). The TD values were calculated from the first 4 min of experimental temperature curves obtained at several depths and were compared with those acquired from the numerical solution of the bio-heat transfer equation (simulated with 1 MHz and 0.5-2.0 W cm(-2)). The temperature curves suggested that scattering had an important role because the temperature increments were found to be higher for higher percentages of graphite powder (lower ℓS). For example, at a 30-mm depth and a 4-min therapeutic ultrasound application (0.5 W cm(-2)), the TDs (in equivalent minutes at 43 °C) were 7.2, 17.8, and 58.3 for the phantom with ℓS of 4.35, 3.85, and 3.03 mm, respectively. In tissue, the inclusion of only absorption or full attenuation in the bio-heat transfer equation (BHTE) heat source term of the simulation leads to under- or overestimation of the TD, respectively, as compared to the TD calculated from experimental data. The experiments with phantoms (with different scatterer concentrations) and ex-vivo samples show that the high values of TD were caused by the increase of energy absorption due to the lengthening of the propagation path caused by the changing in the propagation regime.

Evaluating geodesic active contours in microcalcifications segmentation on mammograms.

Breast cancer is the most commonly occurring type of cancer among women, and it is the major cause of female cancer-related deaths worldwide. Its incidence is increasing in developed as well as developing countries. Efficient strategies to reduce the high death rates due to breast cancer include early detection and tumor removal in the initial stages of the disease. Clinical and mammographic examinations are considered the best methods for detecting the early signs of breast cancer; however, these techniques are highly dependent on breast characteristics, equipment quality, and physician experience. Computer-aided diagnosis (CADx) systems have been developed to improve the accuracy of mammographic diagnosis; usually such systems may involve three steps: (i) segmentation; (ii) parameter extraction and selection of the segmented lesions and (iii) lesions classification. Literature considers the first step as the most important of them, as it has a direct impact on the lesions characteristics that will be used in the further steps. In this study, the original contribution is a microcalcification segmentation method based on the geodesic active contours (GAC) technique associated with anisotropic texture filtering as well as the radiologists' knowledge. Radiologists actively participate on the final step of the method, selecting the final segmentation that allows elaborating an adequate diagnosis hypothesis with the segmented microcalcifications presented in a region of interest (ROI). The proposed method was assessed by employing 1000 ROIs extracted from images of the Digital Database for Screening Mammography (DDSM). For the selected ROIs, the rate of adequately segmented microcalcifications to establish a diagnosis hypothesis was at least 86.9%, according to the radiologists. The quantitative test, based on the area overlap measure (AOM), yielded a mean of 0.52±0.20 for the segmented images, when all 2136 segmented microcalcifications were considered. Moreover, a statistical difference was observed between the AOM values for large and small microcalcifications. The proposed method had better or similar performance as compared to literature for microcalcifications with maximum diameters larger than 460µm. For smaller microcalcifications the performance was limited.

Renal handling of phosphate and sulfate.

In the kidney, both anions, phosphate and sulfate, are almost freely filtered and afterwards reclaimed (reabsorbed) to a large extent from tubular fluid along the proximal tubules. Under normal dietary conditions, fractional excretion of these anions is approximately 10%. Reabsorption of both anions occurs along the proximal tubules by active, saturable, and regulated transepithelial processes. Most of the transporters involved in renal handling of phosphate and sulfate have been identified and their transport functions as well as their cellular localizations have been described in detail. The role of these transporters in the renal handling of phosphate and sulfate has been investigated by the use of several mice knock out models and also by analysis of several inherited human diseases. Numerous hormonal and nonhormonal factors, have been described that alter renal excretion of phosphate or sulfate by mechanisms that alter the abundance of known phosphate/sulfate transporters and consequently renal excretion. These mechanisms contribute to the homeostasis of the extracellular concentrations of phosphate and sulfate.

Oral and topical boswellic acid attenuates mouse osteoarthritis.

OBJECTIVE: Boswellic acid is a plant-derived molecule with putative anti-inflammatory effects. This study was performed to determine whether oral or topical administration of boswellic acid can attenuate joint damage in a mouse model of osteoarthritis (OA). METHODS: Levels of boswellic acid were measured in the blood and synovium of mice treated with oral or topical boswellic acid. OA was generated by surgical destabilization of the medial meniscus (DMM). Therapy with oral or topical boswellic acid was initiated one day after surgery and continued for 12 weeks, when knees were harvested and scored histologically for degree of cartilage loss, osteophyte formation, and synovitis. Microdissected OA synovium was stimulated with IL-1ß or lipopolysaccharide (LPS) in the presence or absence of boswellic acid and cytokine production by quantitative polymerase chain reaction (PCR) or multiplex enzyme linked immunoabsorbant assay (ELISA). RESULTS: Topical treatment resulted in synovial concentrations of boswellic acid 2-6-fold higher than that measured in plasma. Cartilage loss was significantly reduced in mice treated with oral or topical boswellic acid compared with vehicle control (P < 0.01 for both oral and topical therapies). Likewise, treatment with either oral boswellic acid or boswellic acid ointment reduced of synovitis (P = 0.006 and 0.025, respectively) and osteophyte formation (P = 0.009 and 0.030, respectively). In vitro, boswellic acid was able to inhibit IL-1ß and TLR4 mediated induction of several inflammatory mediators from OA synovial explant tissue. CONCLUSIONS: Significant synovial concentration and therapeutic efficacy can be achieved with topical boswellic acid treatment. These findings suggest that boswellic acid has potential as a disease-modifying agent in OA.

Homozygous and compound heterozygous mutations in the ATP6V1B1 gene in patients with renal tubular acidosis and sensorineural hearing loss.

Distal renal tubular acidosis (dRTA) is characterized by the inability to excrete acid in the renal collecting ducts resulting in inappropriately alkaline urine and hyperchloremic (normal anion gap) metabolic acidosis in the context of a normal (or near-normal) glomerular filtration rate. Inborn dRTA can be due to autosomal dominant or recessive gene defects. Clinical symptoms vary from mild acidosis, incidental detection of kidney stones or renal tract calcification to severe findings such as failure to thrive, severe metabolic acidosis, and nephrocalcinosis. The majority of patients with recessive dRTA present with sensorineural hearing loss (SNHL). Few cases with abnormal widening of the vestibular aqueduct have been described with dRTA. Mutations in three different genes have been identified, namely SLC4A1, ATP6V1B1, and ATP6V0A4. Patients with mutations in the ATP6V1B1 proton pump subunit develop dRTA and in most of the cases sensorineural hearing loss early in childhood. We present two patients from two different and non-consanguineous families with dRTA and SNHL. Direct sequencing of the ATP6V1B1 gene revealed that one patient harbors two homozygous mutations and the other one is a compound heterozygous. To our knowledge, this is the first case in the literature describing homozygosity in the same dRTA gene on both alleles.

Assessing the combined performance of texture and morphological parameters in distinguishing breast tumors in ultrasound images.

PURPOSE: This work aims to investigate the combination of morphological and texture parameters in distinguishing between malignant and benign breast tumors in ultrasound images. METHODS: Linear discriminant analysis was applied to sets of up to five parameters, and then the performances were assessed using the area A(z) (± standard error) under the receiver operator characteristic curve, accuracy (Ac), sensitivity (Se), specificity (Sp), positive predictive value, and negative predictive value. RESULTS: The most relevant individual parameter was the normalized residual value (nrv), calculated from the convex polygon technique. The best performance among all studied combinations was achieved by two morphological and three texture parameters (nrv, con, std, R, and asm(i)), which correctly distinguished nearly 85% of the breast tumors. CONCLUSIONS: This result indicates that the combination of morphological and texture parameters may be useful to assist physicians in the diagnostic process, especially if it is associated with an automatic classification tool.