1. Health Imaging, Dec 19, 2016, Contrast-enhanced sonography a ‘sound’ alternative in pediatric advanced imaging By Dave Pearson
2. Clinical Hemorheology and Microcirculation, Dec 8, 2016
Percutaneous irreversible electroporation (IRE) of prostate cancer: Contrast-enhanced ultrasound (CEUS) findings during follow up Authors: Beyer LP, et al
Dec 19, 2016
Contrast-enhanced sonography a ‘sound’ alternative in pediatric advanced imaging
By Dave Pearson
Off-label use of contrast-enhanced ultrasound (CEUS) may be the best advanced-imaging choice—safe, accurate and cost-effective as compared to guideline-recommended CT and MRI—for examining children in many instances, according to a British study published online Dec. 13 in the American Journal of Roentgenology.
Gibran Yusuf, MBBS, and colleagues at King’s College Hospital in London concluded as much after reviewing the medical records of all pediatric patients who were imaged with CEUS at their institution between January 2008 and December 2015.
In total, they looked at 305 cases (187 boys, 118 girls; age range, 1 month to 18 years).
Most of the exams were for characterizing liver lesions (48.2 percent) and trauma (37.1 percent); the others were for renal, vascular and intracavitary assessment (14.8 percent).
None of the patients had immediate adverse reactions, the authors report.
Only two (0.7 percent) had delayed adverse reactions (0.7 percent), and both were asymptomatic and transient (hypertension and tachycardia).
The potential cost savings of CEUS were $74 per exam over CT and $180 over MRI, the authors calculate.
In their discussion, Yusuf et al. note that, in adults, CEUS has sensitivity and specificity comparable to that of CT and MRI.
They point out that CEUS can be safer than CT, as CEUS doesn’t involve ionizing radiation, and safer than MRI, as it almost never requires sedation or anesthesia, much less gadolinium-based contrast administration.
CEUS is generally the most cost-effective of the three advanced-imaging modalities—and the authors found the modality saved their institution almost $16,000 versus what the tab would have been had MRI and CT been used where indicated per institutional norms.
The authors caution that, while CEUS is safe, the use of any contrast calls for vigilance during and after administration.
They also acknowledge the imperfect diagnostic accuracy of CEUS.
“Correlating modalities were often performed before the CEUS examination; simultaneous cross-sectional diagnostic imaging was not performed for confirmatory purposes,” they write. “Patients undergoing sonographic examination were referred for further imaging if there was any doubt in the diagnosis, but there remains the possibility of misdiagnosis, as with all methods of imaging.”
Clinical Hemorheology and Microcirculation
vol. Preprint, no. Preprint, pp. 1-6, 2016
PMID: 27935553 DOI: 10.3233/CH-168125
Dec 8, 2016
Percutaneous irreversible electroporation (IRE) of prostate cancer: Contrast-enhanced ultrasound (CEUS) findings during follow up.
Authors: Beyer LP1, Pregler B1, Nießen C1, Michalik K1, Haimerl M1, Stroszczynski C1, Jung EM1, Wiggermann P1.
1Department of Radiology, University Medical Center Regensburg, Germany.
Irreversible electroporation (IRE) is a focal non-thermal ablation technique that can be used to treat prostate cancer (Pca). The objective was to document the evolution of the volume of the prostate gland and the ablation zone after IRE of Pca.
MATERIAL AND METHODS:
A retrospective analysis of the image findings of CEUS 1 day, 6 weeks, 3 months and 6 months after IRE of 25 patients was conducted. The prostate gland volumes and the size of the ablation zones were documented. Changes in volume and size over time were calculated.
There was a significant volume reduction of the prostate gland in the first 3 months after ablation. The mean percentage change after 6 weeks was 34.3% with another decrease of 35.0% after 3 months. Volume did not change between month 3 and 6. Size of ablation zone measured in short- and long-axis significantly diminished until 6 months after ablation.
CEUS showed a significant involution of the prostate gland during the first 3 months and a significant decrease of the ablation zone during the first 6 months after IRE of prostate cancer.
1. Theranostics, Jan 1, 2017, Efficient Enhancement of Blood-Brain Barrier Permeability Using Acoustic Cluster Therapy (ACT)
Authors: Andreas K.O. Åslund, et al
2. Oncotarget, Dec 14, 2016, Biodegradable double-targeted PTX-mPEG-PLGA nanoparticles for ultrasound contrast enhanced imaging and antitumor therapy in vitro Authors: Jing Ma, et al.
3. PR.com, Dec 14, 2016, IQ4I Research & Consultancy Published a New Report on “Ultrasound medical devices Global Market – Forecast To 2023”
Author: Monika Donimirska
4. Phys.org, Dec 12, 2016, Nanomedical treatment concept combines NO gas therapy with starvation of tumor cells
Theranostics 2017; 7(1):23-30. doi:10.7150/thno.16577
Jan 1, 2017
Efficient Enhancement of Blood-Brain Barrier Permeability Using Acoustic Cluster Therapy (ACT)
Authors: Andreas K.O. Åslund1 Corresponding address, Sofie Snipstad1, Andrew Healey2, Svein Kvåle2, Sverre H. Torp3,4, Per C. Sontum2, Catharina de Lange Davies1, Annemieke van Wamel1
1. Department of Physics, Norwegian University of Science and Technology (NTNU), Trondheim, Norway;
2. Phoenix Solutions AS, Oslo, Norway;
3. Department of Pathology and Medical Genetics, St. Olavs University Hospital, Trondheim, Norway;
4. Department of Laboratory Medicine, Children's and Women's Health, NTNU, Trondheim, Norway.
The blood-brain barrier (BBB) is a major obstacle in drug delivery for diseases of the brain, and today there is no standardized route to surpass it. One technique to locally and transiently disrupt the BBB, is focused ultrasound in combination with gas-filled microbubbles. However, the microbubbles used are typically developed for ultrasound imaging, not BBB disruption. Here we describe efficient opening of the BBB using the promising novel Acoustic Cluster Therapy (ACT), that recently has been used in combination with Abraxane® to successfully treat subcutaneous tumors of human prostate adenocarcinoma in mice. ACT is based on the conjugation of microbubbles to liquid oil microdroplets through electrostatic interactions. Upon activation in an ultrasound field, the microdroplet phase transfers to form a larger bubble that transiently lodges in the microvasculature. Further insonation induces volume oscillations of the activated bubble, which in turn induce biomechanical effects that increase the permeability of the BBB. ACT was able to safely and temporarily permeabilize the BBB, using an acoustic power 5-10 times lower than applied for conventional microbubbles, and successfully deliver small and large molecules into the brain.
Dec 14, 2016
Biodegradable double-targeted PTX-mPEG-PLGA nanoparticles for ultrasound contrast enhanced imaging and antitumor therapy in vitro
Authors: Jing Ma1,2,3,*, Ming Shen4,*, Chang Song Xu5,*, Ying Sun4, You Rong Duan4, Lian Fang Du2
1Department of Ultrasound, Songjiang Hospital Affiliated to The First People’s Hospital of Shanghai Jiao tong University, Shanghai 201600, China
2Department of Ultrasound, Shanghai First People’s Hospital Affiliated to Shanghai Jiao tong University School of Medicine, Shanghai 200080, China
3Department of Ultrasound, Shanghai East Hospital Affiliated to Tong ji University, Shanghai 200120, China
4State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200032, P. R. China
5Huai’an First People’s Hospital, Nanjing Medical University, Jiangsu 223001, China
*These authors have contributed equally to this work
A porous-structure nano-scale ultrasound contrast agent (UCA) was made of monomethoxypoly (ethylene glycol)-poly (lactic-co-glycolic acid) (mPEG-PLGA), and modified by double-targeted antibody: anti-carcinoembryonic antigen (CEA) and anti-carbohydrate antigen 19-9 (CA19-9), as a double-targeted nanoparticles (NPs). Anti-tumor drug paclitaxel (PTX) was encapsulated in the double-targeted nanoparticles (NPs). The morphor and release curve were characterized. We verified a certain anticancer effect of PTX-NPs through cytotoxicity experiments. The cell uptake result showed much more NPs may be facilitated to ingress the cells or tissues with ultrasound (US) or ultrasound targeted microbubble destruction (UTMD) transient sonoporation in vitro. Ultrasound contrast-enhanced images in vitro and in vivo were investigated. Compared with SonoVue, the NPs prolonged imaging time in rabbit kidneys and tumor of nude mice, which make it possible to further enhance anti-tumor effects by extending retention time in the tumor region. The novel double-targeted NPs with the function of ultrasound contrast enhanced imaging and anti-tumor therapy can be a promising way in clinic.
Dec 14, 2016
IQ4I Research & Consultancy Published a New Report on “Ultrasound medical devices Global Market – Forecast To 2023”
Author: Monika Donimirska
Ultrasound is a kind of imaging technique/procedure that makes use of high-frequency sound waves for scanning and creating an image of body part. Due to its less cost, best imaging quality, workflow efficiency, reliability, no requirement of same computing power, fast frame rates or specialized transducers now-a-days ultrasound scans are most popularly used diagnostic imaging technique.
Boston, MA, December 14, 2016 –(PR.com)– Ultrasound is one of the renowned technologies in the medical field. This safe, non-invasive and non-use of ionizing radiation procedure involves sound waves of higher frequencies waves, (greater than 20,000 Hz) for producing various structural echo patterns of internal body parts. An ultrasound machine during diagnosis, works by bouncing off sound waves when in contact with solid parts of the body. In addition with the diagnosis, ultrasounds are being used to treat medical conditions too and thereby ultrasounds have role to play in therapeutic application. As estimated by IQ4I Research, Ultrasound medical devices global market is expected to grow at a double digit CAGR to reach $10,106 million by 2023.
Rising population of chronic and lifestyle disorder, availability of public-private investments, increasing demand for point of care testing and rising adoption of ultrasound technology in the various fields especially in cardiology, oncology and emergency medicine are the factors driving the market growth. However, some of the factors like lack of skilled professionals, high cost ultrasound devices, stringent regulations and unfavorable reimbursement cuts may hinder the growth of global ultrasound device market.
Advancements and newer technologies like contrast enhanced ultrasound and ultrasound elastography are revolutionizing ultrasound market. Contrast enhanced ultrasound technology which involves microbubble contrast agents and specialized techniques for imaging the blood flow and perfusion within the human body are becoming most popular medical imaging method. In September 7th, 2016 Toshiba America Medical Systems, Inc. announced its launch of Aplio 500 Platinum contrast enhanced ultrasound system after the recent approval from FDA for the use of microbubbles. Lumason and SonoVue from Bracco Diagnostics, Inc. (U.S.), Optison from GE Healthcare (U.S) are few FDA approved contrast enhanced ultrasound agents. Siemens Healthcare provides Cadence Contrast Pulse Sequencing (CPS) Technology on its ACUSON Sequoia Ultrasound platform providing detailed images of micro and macro vascularity enhancing lesion characterization. Philips HD11 XE has the versatility to expand into a complete digital imaging technology incorporating contrast imaging to enhance cardiovascular imaging capabilities. Similarly Ultrasound elastography is one of the emerging technologies where stress is applied on the organs to assess the mechanical properties (elasticity) and stiffness of fibrotic and cancerous lesions. Hitachi Medical Corporation has developed Real-Time Tissue Elastography (RTTE) application on its Hi Vision Avius ultrasound platform which differentiates the healthy and malignant tissues of breast, thyroid, prostrate, liver and pancreas. In addition the major players such as Toshiba Medical systems introduced elastography technique in its Aplio MX platform, Philips Healthcare on its iU22 platform and Siemens Healthcare in its ACUSON S2000 ultrasound platform.
The ultrasound medical devices global market is segmented based on their technology, display, portability, application, end users and geography. The market by technology is divided into diagnostic and therapeutic, based on display the market is segmented into black & white and color and based on portability market is divided into trolley/cart based and portable ultrasound medical devices. The ultrasound medical devices application is further sub-segmented into radiology/general imaging, women’s health, cardiology, point of care, urology, orthopedic, cancer, neurology and others. The radiology/general imaging occupied highest market in ultrasound medical devices application market.
Geographically, European regions held the largest market share where Germany accounted for the largest share, this growth is driven due to its high acceptance of advanced technologies and sophisticated universal treatment facilities. Among North American regions U.S. dominates, the market with the share of 77.9% and is expected to show a strong growth due to the high advanced healthcare facilities, increased growing awareness about the technological advancements, availability of Medicare and third party insurance facilities, easy availability of skilled personnel are driving the market growth. In Asia- Pacific region, Japan has held the largest market share due to its increase in healthcare spending and advancements in healthcare facilities, the easy access to advanced healthcare technology. In RoW regions, Brazil has the largest market share and is expected to grow at the strong rate due to increasing trends of medical tourism, large patient pool, Medicare facilities and increase in technological advancements.
Some of the prominent players in ultrasound medical device market include Analogic Corporation (U.S), Esaote (Italy), Fujifilm Holdings Corporation (Japan), GE Healthcare (U.S.), Hitachi Ltd (Japan), Koninklijke Philips N.V. (Netherlands), Mindray Medical International Limited (China), Samsung Electronics Co. Ltd (South Korea), Siemens AG (Germany) and Toshiba Medical Systems Corporation (Japan).
Dec 12, 2016
Nanomedical treatment concept combines NO gas therapy with starvation of tumor cells
Read more at: http://phys.org/news/2016-12-nanomedical-treatment-concept-combines-gas.html#jCp
Biocompatible nanocapsules, loaded with an amino acid and equipped with an enzyme now combine two anti-tumor strategies into a synergistic treatment concept. Researchers hope this increases effectiveness and decreases side effects. In the journal Angewandte Chemie, the scientists explain the concept: tumor cells are deprived of their nutrient glucose as this is converted to toxic nitrogen monoxide (NO) and hydrogen peroxide (H2O2).
NO is a toxic gas that causes smog. However, in low concentrations in the body it is an important messenger molecule that regulates such things as circulation and libido. It is also an important physiological defense weapon against fungi and bacteria. In higher concentrations, NO is capable of killing tumor cells and increasing the effectiveness of photodynamic and radiological treatments. For clinical use, NO needs to be released in the target area from a biocompatible precursor.
The natural amino acid L-arginine (L-Arg) may be useful in such a system, because the native enzyme inducible NO synthase (iNOS) makes NO from L-Arg. NO is also formed when L-Arg is oxidized by H2O2. This is interesting because the microenvironment around tumors is rich in H2O2. This approach to NO gas therapy is being pursued by researchers at Shenzhen University (China), the National Institutes of Health (Bethesda, USA), and the University of Maryland (College Park, USA). Their special twist is to combine this gas therapy with a method for starving cancer cells in a synergistic treatment.
Instead of starving a tumor by blocking the blood vessels that feed it, the researchers intend to remove the glucose that the tumor needs for nutrition by consuming it in a metabolic reaction: the enzyme glucose oxidase (GOx) converts the glucose into gluconic acid and H2O2. The increased H2O2 concentration is a useful side effect, because H2O2 is both cytotoxic and accelerates the release of NO from L-Arg. Another useful side effect is that H2O2 and NO react to form highly toxic peroxynitrites that damage the tumor cells.
The research team led by Peng Huang, Tianfu Wang, and Xiaoyuan Chen has now reached an important milestone in the development of this concept. They have developed biocompatible, biodegradable, porous nanocapsules made of organosilicates that transport GOx and L-Arg into tumor cells simultaneously. GOx is bound to the surface; L-Arg is stored inside the capsule. While the GOx is active immediately after injection of the nanocapsules into the tumor, L-Arg is released little by little, first through the capsule pores, then as the capsule disintegrates. Their large cavity also allows the capsules to serve as an ultrasound contrast material for better localization of the tumor.
Experiments with both cell cultures and mice have demonstrated the significant synergistic effect of this combination therapy, which successfully inhibits cell growth, initiates cell death, and shrinks the tumors in mice.
- MedicalXpress, Nov 30, 2016, Faster, non-invasive method to determine the severity of a heart failure (Eindhoven University of Technology)
- DOTmed.com, Healthcare Business, Nov 29, 2016, Physicians at RSNA make case for contrast-enhanced ultrasound by John W. Mitchell
- Breast Cancer News, Nov 9, 2016, Mammogram Alternative Would Be Radiation-Free, Less Uncomfortable By Ines Martins, PhD
Nov 30, 2016
Faster, non-invasive method to determine the severity of a heart failure
Provided by: Eindhoven University of Technology
Methods currently employed to determine the severity of a heart failure are very limited. Researchers at TU/e and the Catharina Hospital in Eindhoven have therefore developed a method that is very quick, non-invasive, cost-effective and can be performed at the hospital bedside. Moreover, this method appears to have a predictive value for whether or not a double pacemaker will be successful. Researchers Ingeborg Herold and Salvatore Saporito received their doctorates earlier this month for their study.
Heart failure – when the heart is no longer able to pump enough blood through the body – is a very common problem. To get the right treatment, it is important to measure how well the heart is still able to do its job. There are currently various methods for doing this, but all have their limitations. Sensors often need to be placed in the large arteries, via the shoulder or neck, and that is quite an invasive procedure. MRI is a possibility, but not for patients that are seriously ill. Patients that are short of breath nearly always undergo blood analysis, a method that examines the concentration of a particular protein in the blood and provides a very good, patient-friendly indicator, but it takes several hours before the outcome is known.
The Eindhoven researchers have developed a patient-friendly method that uses an echo scanner, which is known mainly for echoes performed during pregnancy, to determine the severity of heart failure. To do this, they measure the time it takes for the blood to travel from the heart's right ventricle through the lungs to the left ventricle, which is responsible for pumping oxygenated blood through the body. In order to measure this pulmonary transit time (PTT), they inject harmless microbubbles that can be seen clearly by the echo scanner. They then look at the heart and see how long it takes for the bubbles to get from the right to the left ventricle.
It may seem simple enough but there was a significant scientific challenge in calculating an unequivocal PTT for the observed microbubbles that get dispersed in the blood flow. But once that had been solved, they compared the transit time with a number of existing indicators, developing a similar method on the basis of MRI. Comparisons revealed that the PTT measured with the echo scanner provides an excellent indicator for the severity of a heart failure. A healthy heart pumps the blood quickly through the lungs. The longer the PTT, the less well the heart performs. They examined subjects whose heart muscle no longer contracted well, which is the most common type of heart failure. Before the method can be used, there is still work to be done. For example, if it is to be both practical and fast, the analysis will have to be automated.
Another aspect being studied is the extent to which the PTT is able to predict the success of a double pacemaker, whose primary objective is to restore the synchronicity of the two ventricles of the heart. Herold indeed found that there was a fairly firm relationship between the transit time and the success rate. The breaking point is 12.5 seconds; above that, the chance of the pacemaker enabling the heart to perform better reduces. But any application of this indicator requires more research, says Herold. Because the method does not appear to be completely accurate in the prediction, she expects it to be useful in combination with other indicators.
The method is founded on the work of TU/e researcher Massimo Mischi, who has spent a decade working on the development of 'contrast enhanced ultrasound (CEUS)' for analyzing the blood flow using microbubbles as a contrast medium. He has already done this successfully to detect prostate cancer.
Ingeborg Herold gained her doctorate on Thursday 17 November for her thesis 'Assessment of cardiopulmonary function by contrast enhanced echocardiography' while Salvatore Saporito received his PhD the same day for his thesis 'Cardiovascular MRI quantifications in heart failure'.
Nov 29, 2016
Physicians at RSNA make case for contrast-enhanced ultrasound
by John W. Mitchell
Physicians from the U.K., Canada and Italy presented case studies from their use of contrast enhanced ultrasound (CEUS) at the RSNA meeting in Chicago.
The procedure, which was OK’d by the FDA this year for liver screening, but is currently not approved in the U.S. for cardiac disease, shows particular value in imaging children who may otherwise have to
Dr. Paul Sidhu, a radiologist and professor at King’s College in London, made the case that adopting CEUS is as much a philosophical choice as clinical.
“One of the main reasons to adopt CEUS is to reduce radiation burns that we seem to inflict upon our patients,” he told a large Monday morning audience at a Samsung-sponsored event.
He noted the use of CT scans in the U.S. has risen from about three million in 1980 to roughly 80 million in 2015. This is troubling, he noted, as it’s estimated that between 1.5 and 2 percent of cancers, including leukemia, in the U.S. may be attributed to organ dose radiation from CT exams. CEUS offers a radiation-free alternative to CT scanning in diagnosing liver ailments and injuries.
Based on his experience, he said that CEUS has several advantages over CT, as well as MR. CEUS can be performed immediately, with no lab testing. It is also portable and can and it can be conducted at multiple locations, such as the bedside, operating room or in the CT suite. It also operates and provides results in real time, allowing rapid changes to be recorded. He also reported lower adverse rates than for CT or MR.
The addition of a contrast line into a venous line does require two operators and the use of the contrast adds almost five minutes to the procedure, but according to Sidhu, the image study results are worth the trade-off. He cited a journal article that concluded: “CEUS and MR are of equal value for the differentiation and specification of newly discovered tumors in clinical practice.”
Another speaker at the event, Dr. Stephanie Wilson, professor of radiology at the University of Calgary, Canada, spoke about her one-week conducting these procedures using the Samsung RS80A with Prestige. She reported very competent diagnostic capabilities for cirrhosis patients and said that using color Doppler was especially helpful in liver diagnosis of obese patients.
“While none of these findings have yet been confirmed (due to the short amount of time she had the machine before the conference) ... I think the findings will be confirmed,” Wilson told the audience, adding that she would present these results and other findings on CEUS diagnostics at next year's RSNA meeting.
The final presenter, Dr. Vito Cantisani, an Italian cardiologist, presented findings on his success using CEUS in diagnosing different types of heart plaques (an application that is not currently approved in the U.S.). He noted that cardiovascular disease contributes up to 10 percent of deaths worldwide, and diagnosing plaques is critical in reducing heart attack and strokes.
Breast Cancer News
Nov 9, 2016
Mammogram Alternative Would Be Radiation-Free, Less Uncomfortable
By Ines Martins, PhD
Researchers are working to develop a new breast-friendly, radiation-free method that may replace the unpleasant mammogram currently used to detect breast cancer.
The new method, described in the study “Towards Dynamic Contrast Specific Ultrasound Tomography,” and published in Scientific Reports, uses ultrasounds to provide 3-D images of the breast, and is meant to reduce not only a woman’s discomfort during the procedure, but also the number of false-positive results seen frequently with current mammogram methods.
Currently, women are screened for breast cancer through a mammogram, where the breast is squeezed tight between two plates to generate 2D X-ray images. The method is not only physically unpleasant and one of the reasons women choose to skip screening, it also comes with the risk that the radiation used in the mammograms can contribute to the development of cancer.
In addition, mammograms generate large numbers of false-positive results. In more than two-thirds of cases where doctors find an abnormal tissue that is recommended for biopsy, it turns out that the abnormal regions are not cancer. In the meantime, women are subjected to high levels of unnecessary worrisome stress.
Researchers have been trying to develop alternatives to this method that provide more accurate results and that reduce women’s discomfort. Recently, a team at Eindhoven University of Technology has been working on a possible alternative for mammograms.
According to a press release, the new technology requires patients to lie on a table with their breast hanging freely in a bowl. Using ultrasounds, a 3-D image of the breast is generated and scanned for tumors. The researchers believe this method will generate far fewer false negative results.
The technology builds up on a patient-friendly prostate cancer detection method also developed at the Eindhoven University of Technology. The approach takes advantage of the distinct vessel architecture found in tumors and healthy tissues. Tiny micro-bubbles that can be precisely monitored with an
echoscanner are injected in the prostate blood vessels, allowing doctors to precisely identify the presence and location of the tumor.
Although this method is now being tested for prostate cancer in hospitals worldwide, breast motion and size have largely limited its application in breast cancer screening.
But researchers may have developed a new variant of the echography method that is suitable to be used in breast cancer. Libertario Demi, Ruud van Sloun and Massimo Mischi developed the Dynamic Contrast Specific Ultrasound Tomography, which uses the same micro-bubbles, but under a different principle. They use the fact that bubbles vibrate in the blood at the same frequency as the sound produced by the echoscanner, and at twice that frequency — the second harmonic.
When the scanner captures that vibration, it knows where the bubbles are located. Similar to the micro-bubbles, the body tissue also generated harmonics, which limited the researchers’ observations. But the researchers found that, contrary to the body tissues, the gas bubbles delayed the second harmonic. And the more bubbles the sound-waves encountered, the bigger the delay.
This, however, can be detected only if the sound is captured on the other side, which makes the technology ideal for the breast tissue.
The researchers are now starting a collaborative effort to conduct preclinical studies with the new tool, and hope it will be included in clinical practice within 10 years, possibly in combination with other methods that will generate high-quality images that allow for highly accurate diagnoses.