Penetrance and expressivity of mitochondrial variants in a large clinically unselected population.

Whole genome sequencing (WGS) from large clinically unselected cohorts provides a unique opportunity to assess the penetrance and expressivity of rare and/or known pathogenic mitochondrial variants in population. Using WGS from 179 862 clinically unselected individuals from the UK Biobank, we performed extensive single and rare variant aggregation association analyses of 15 881 mtDNA variants and 73 known pathogenic variants with 15 mitochondrial disease-relevant phenotypes. We identified 12 homoplasmic and one heteroplasmic variant (m.3243A>G) with genome-wide significant associations in our clinically unselected cohort. Heteroplasmic m.3243A>G (MAF = 0.0002, a known pathogenic variant) was associated with diabetes, deafness and heart failure and 12 homoplasmic variants increased aspartate aminotransferase levels including three low-frequency variants (MAF ~0.002 and beta~0.3 SD). Most pathogenic mitochondrial disease variants (n = 66/74) were rare in the population (<1:9000). Aggregated or single variant analysis of pathogenic variants showed low penetrance in unselected settings for the relevant phenotypes, except m.3243A>G. Multi-system disease risk and penetrance of diabetes, deafness and heart failure greatly increased with m.3243A>G level ≥ 10%. The odds ratio of these traits increased from 5.61, 12.3 and 10.1 to 25.1, 55.0 and 39.5, respectively. Diabetes risk with m.3243A>G was further influenced by type 2 diabetes genetic risk. Our study of mitochondrial variation in a large-unselected population identified novel associations and demonstrated that pathogenic mitochondrial variants have lower penetrance in clinically unselected settings. m.3243A>G was an exception at higher heteroplasmy showing a significant impact on health making it a good candidate for incidental reporting.

Assessing renal tissue temperature changes and perfusion effects during laser activation in an in vivo porcine model.

INTRODUCTION: High fluid temperatures have been seen in both in vitro and in vivo studies with laser lithotripsy, yet the thermal distribution within the renal parenchyma has not been well characterized. Additionally, the heat-sink effect of vascular perfusion remains uncertain. Our objectives were twofold: first, to measure renal tissue temperatures in response to laser activation in a calyx, and second, to assess the effect of vascular perfusion on renal tissue temperatures. METHODS: Ureteroscopy was performed in three porcine subjects with a prototype ureteroscope containing a temperature sensor at its tip. A needle with four thermocouples was introduced percutaneously into a kidney with ultrasound guidance to allow temperature measurement in the renal medulla and cortex. Three trials of laser activation (40W) for 60 s were conducted with an irrigation rate of 8 ml/min at room temperature in each subject. After euthanasia, three trials were repeated without vascular perfusion in each subject. RESULTS: Substantial temperature elevation was observed in the renal medulla with thermal dose in two of nine trials exceeding threshold for tissue injury. The temperature decay time (t½) of the non-perfused trials was longer than in the perfused trials. The ratio of t½ between them was greater in the cortex than the medulla. CONCLUSION: High-power laser settings (40W) can induce potentially injurious temperatures in the in vivo porcine kidney, particularly in the medullary region adjacent to the collecting system. Additionally, the influence of vascular perfusion in mitigating thermal risk in this susceptible area appears to be limited.

The impact of siphoning effect on renal pelvis pressure during ureteroscopy using an in vitro kidney and ureter model.

PURPOSE: To experimentally measure renal pelvis pressure (PRP) in an ureteroscopic model when applying a simple hydrodynamic principle, the siphoning effect. METHODS: A 9.5Fr disposable ureteroscope was inserted into a silicone kidney-ureter model with its tip positioned at the renal pelvis. Irrigation was delivered through the ureteroscope at 100 cm above the renal pelvis. A Y-shaped adapter was fitted onto the model's renal pelvis port, accommodating a pressure sensor and a 4 Fr ureteral access catheter (UAC) through each limb. The drainage flowrate through the UAC tip was measured for 60 s each run. The distal tip of the UAC was placed at various heights below or above the center of the renal pelvis to create a siphoning effect. All trials were performed in triplicate for two lengths of 4Fr UACs: 100 cm and 70 cm (modified from 100 cm). RESULTS: PRP was linearly dependent on the height difference from the center of the renal pelvis to the UAC tip for both tested UAC lengths. In our experimental setting, PRP can be reduced by 10 cmH20 simply by lowering the distal tip of a 4 Fr 70 cm UAC positioned alongside the ureteroscope by 19.7 cm. When using a 4 Fr 100 cm UAC, PRP can drop 10 cmH20 by lowering the distal tip of the UAC 23.3 cm below the level of the renal pelvis. CONCLUSION: Implementing the siphoning effect for managing PRP during ureteroscopy could potentially enhance safety and effectiveness.

Ultrasound-Derived Fat Fraction for Hepatic Steatosis Assessment: Prospective Study of Agreement With MRI PDFF and Sources of Variability in a Heterogeneous Population.

BACKGROUND. Metabolic dysfunction-associated steatotic liver disease is a growing global public health concern. Quantitative ultrasound measurements, such as ultrasound-derived fat fraction (UDFF), could provide noninvasive, cost-effective, and portable steatosis evaluation. OBJECTIVE. The purpose of this article was to evaluate utility of UDFF for steatosis assessment using proton density fat fraction (PDFF) as reference in patients undergoing liver MRI for heterogeneous indications and to assess UDFF variability. METHODS. This prospective study included a primary analysis of 187 patients (mean age, 53.8 years; 112 men, 75 women) who underwent 3-T liver MRI for any clinical indication from December 2020 to July 2021. Patients underwent investigational PDFF measurement, including determination of PDFFwhole-liver (mean PDFF of entire liver), and PDFFvoxel (PDFF in single voxel within right lobe, measured by MR spectroscopy), as well as investigational ultrasound with UDFF calculation (mean of five inter-costal measurements) within 1 hour after MRI. In a subanalysis, 21 of these patients underwent additional UDFF measurements 1, 3, and 5 hours after meal consumption. The study also included repeatability and reproducibility analysis of 30 patients (mean age, 26.3 years; 10 men, 20 women) who underwent clinical abdominal ultrasound between November 2022 and January 2023; in these patients, three operators sequentially performed UDFF measurements. RESULTS. In primary analysis, UDFF and PDFFwhole-liver measurements showed intra-class correlation coefficient (ICC) of 0.79. In Bland-Altman analysis, UDFF and PDFFvoxel measurements showed mean difference of 1.5% (95% CI, 0.6-2.4%), with 95% limits of agreement from -11.0% to 14.0%. UDFF measurements exhibited AUC for detecting PDFFvoxel at historic thresholds of 6.5% and greater, 17.4% and greater, and 22.1% and greater of 0.90, 0.95, and 0.95, respectively. In subanalysis, mean UDFF was not significantly different across time points with respect to meal consumption (p = .21). In repeatability and reproducibility analysis, ICC for intraoperator repeatability ranged from 0.98 to 0.99 and for interoperator reproducibility from 0.90 to 0.96. Visual assessment of patient-level data plots indicated increasing variability of mean UDFF measurements across operators and of intercostal measurements within individual patients with increasing steatosis. CONCLUSION. UDFF showed robust agreement with PDFF, diagnostic performance for steatosis grades, and intraoperator repeatability and interoperator reproducibility. Nonetheless, UDFF exhibited bias toward slightly larger values versus PDFF; intraoperator and interoperator variation increased with increasing steatosis. CLINICAL IMPACT. UDFF shows promise for steatosis assessment across diverse populations, although continued optimization remains warranted.

Insights from in vivo preclinical cancer studies with histotripsy.

Histotripsy is the first noninvasive, non-ionizing, and non-thermal ablation technique that mechanically fractionates target tissue into acellular homogenate via controlled acoustic cavitation. Histotripsy has been evaluated for various preclinical applications requiring noninvasive tissue removal including cancer, brain surgery, blood clot and hematoma liquefaction, and correction of neonatal congenital heart defects. Promising preclinical results including local tumor suppression, improved survival outcomes, local and systemic anti-tumor immune responses, and histotripsy-induced abscopal effects have been reported in various animal tumor models. Histotripsy is also being investigated in veterinary patients with spontaneously arising tumors. Research is underway to combine histotripsy with immunotherapy and chemotherapy to improve therapeutic outcomes. In addition to preclinical cancer research, human clinical trials are ongoing for the treatment of liver tumors and renal tumors. Histotripsy has been recently approved by the FDA for noninvasive treatment of liver tumors. This review highlights key learnings from in vivo shock-scattering histotripsy, intrinsic threshold histotripsy, and boiling histotripsy cancer studies treating cancers of different anatomic locations and discusses the major considerations in planning in vivo histotripsy studies regarding instrumentation, tumor model, study design, treatment dose, and post-treatment tumor monitoring.

Equilibrium Mechanical Properties of the Nonhuman Primate Cervix.

Cervical remodeling is critical for a healthy pregnancy. Premature tissue changes can lead to preterm birth (PTB), and the absence of remodeling can lead to post-term birth, causing significant morbidity. Comprehensive characterization of cervical material properties is necessary to uncover the mechanisms behind abnormal cervical softening. Quantifying cervical material properties during gestation is challenging in humans. Thus, a nonhuman primate (NHP) model is employed for this study. In this study, cervical tissue samples were collected from Rhesus macaques before pregnancy and at three gestational time points. Indentation and tension mechanical tests were conducted, coupled with digital image correlation (DIC), constitutive material modeling, and inverse finite element analysis (IFEA) to characterize the equilibrium material response of the macaque cervix during pregnancy. Results show, as gestation progresses: (1) the cervical fiber network becomes more extensible (nonpregnant versus pregnant locking stretch: 2.03 ± 1.09 versus 2.99 ± 1.39) and less stiff (nonpregnant versus pregnant initial stiffness: 272 ± 252 kPa versus 43 ± 43 kPa); (2) the ground substance compressibility does not change much (nonpregnant versus pregnant bulk modulus: 1.37 ± 0.82 kPa versus 2.81 ± 2.81 kPa); (3) fiber network dispersion increases, moving from aligned to randomly oriented (nonpregnant versus pregnant concentration coefficient: 1.03 ± 0.46 versus 0.50 ± 0.20); and (4) the largest change in fiber stiffness and dispersion happen during the second trimester. These results, for the first time, reveal the remodeling process of a nonhuman primate cervix and its distinct regimes throughout the entire pregnancy.

Simulation of ultrasonic scattering from scatterer size distributions using Field II.

Quantitative analysis of radio frequency (RF) signals obtained from ultrasound scanners can yield objective parameters that are gaining clinical relevance as imaging biomarkers. These include the backscatter coefficient (BSC) and the effective scatterer diameter (ESD). Biomarker validation is typically performed in phantoms which do not provide the flexibility of systematic variation of scattering properties. Computer simulations, such as those from the ultrasound simulator Field II, can allow more flexibility. However, Field II does not allow simulation of RF data from a distribution of scatterers with finite size. In this work, a simulation method is presented which builds upon previous work by including Faran theory models representative of distributions of scatterer size. These are systematically applied to RF data simulated in Field II. The method is validated by measuring the root mean square error of the estimated BSC and percent bias of the ESD and comparing to experimental results. The results indicate the method accurately simulates distributions of scatterer sizes and provides scattering similar to that seen in data from clinical scanners. Because Field II is widely used by the ultrasound community, this method can be adopted to aid in validation of quantitative ultrasound imaging biomarkers.

Change in renal blood flow in response to intrarenal pressure alterations induced by ureteroscopy in an in-vivo porcine model.

INTRODUCTION: High irrigation rates are commonly used during ureteroscopy and can increase intrarenal pressure (IRP) substantially. Concerns have been raised that elevated IRP may diminish renal blood flow (RBF) and perfusion of the kidney. Our objective was to investigate the real-time changes in RBF while increasing IRP during Ureteroscopy (URS) in an in-vivo porcine model. METHODS: Four renal units in two porcine subjects were used in this study, three experimental units and one control. For the experimental units, RBF was measured by placing an ultrasonic flow cuff around the renal artery, while performing ureteroscopy in the same kidney using a prototype ureteroscope with a pressure sensor at its tip. Irrigation was cycled between two rates to achieve targeted IRPs of 30 mmHg and 100 mmHg. A control data set was obtained by placing the ultrasonic flow cuff on the contralateral renal artery while performing ipsilateral URS. RESULTS: At high IRP, RBF was reduced in all three experimental trials by 10-20% but not in the control trial. The percentage change in RBF due to alteration in IRP was internally consistent in each porcine renal unit and independent of slower systemic variation in RBF encountered in both the experimental and control units. CONCLUSION: RBF decreased 10-20% when IRP was increased from 30 to 100 mmHg during ureteroscopy in an in-vivo porcine model. While this reduction in RBF is unlikely to have an appreciable effect on tissue oxygenation, it may impact heat-sink capacity in vulnerable regions of the kidney.

Quantification of outflow resistance for ureteral drainage devices used during ureteroscopy.

PURPOSE: Since renal pelvis pressure is directly related to irrigation flowrate and outflow resistance, knowledge of outflow resistance associated with commonly used drainage devices could help guide the selection of the type and size of ureteral access sheath or catheter for individual ureteroscopic cases. This study aims to quantitatively measure outflow resistance for different drainage devices utilized during ureteroscopy. METHODS: With measured irrigation flowrate and renal pelvis pressure, outflow resistance was calculated using a hydrodynamic formula. After placement of a drainage device into a silicone kidney-ureter model, a disposable ureteroscope with a 9.5-Fr outer diameter was inserted with its tip positioned at the renal pelvis. Irrigation was delivered through the ureteroscope from varying heights above the renal pelvis. Renal pelvis pressure was measured directly from the port of the kidney model using a pressure sensor (Opsens, Canada). Outflow resistance was determined by plotting flowrate versus renal pelvis pressure. All trials were performed in triplicate for each drainage device inserted. RESULTS: Flowrate was linearly dependent on renal pelvis pressure for all drainage devices tested. Outflow resistance values were 0.2, 1.1, 1.4, 3.9, and 6.5 cmH2O/[ml/min] for UAS 13/15 Fr, UAS 11/13 Fr, UAC 6 Fr, UAC 4.8 Fr, and UAC 4.0 Fr, respectively, across the range of commonly used irrigation flowrates. CONCLUSIONS: In this study, outflow resistance of different ureteral drainage devices was quantitatively measured. This knowledge can be useful when selecting which type and size of drainage device to insert to maintain safe renal pelvis pressure during ureteroscopy.

Frightened of giants: fear responses to elephants approach that of predators.

Animals are faced with a variety of dangers or threats, which are increasing in frequency with ongoing environmental change. While our understanding of fearfulness of such dangers is growing in the context of predation and parasitism risk, the extent to which non-trophic, interspecific dangers elicit fear in animals remains less appreciated. We provide an experimental test for fear responses of savannah ungulates to a dominant and aggressive megaherbivore, the African bush elephant (Loxodonta africana), and contrast responses to an apex predator known to elicit fear in this system. Using an automated behavioural response system, we contrast vigilance and run responses of ungulates to elephant, leopard (Panthera pardus), and control (red-chested cuckoo Cuculus solitarius) vocalizations. Overall, we find that ungulates responded to elephant calls, both in terms of an increase in run and vigilance responses relative to controls. The magnitude of most behavioural responses (four of six considered) to elephant vocalizations were not significantly different than responses to leopards. These results suggest that megaherbivores can elicit strong non-trophic fear responses by ungulates and call to broaden frameworks on fear to consider dominant species, such as megaherbivores, as key modifiers of fear-induced interactions.

US Quantification of Liver Fat: Past, Present, and Future.

Fatty liver disease has a high and increasing prevalence worldwide, is associated with adverse cardiovascular events and higher long-term medical costs, and may lead to liver-related morbidity and mortality. There is an urgent need for accurate, reproducible, accessible, and noninvasive techniques appropriate for detecting and quantifying liver fat in the general population and for monitoring treatment response in at-risk patients. CT may play a potential role in opportunistic screening, and MRI proton-density fat fraction provides high accuracy for liver fat quantification; however, these imaging modalities may not be suited for widespread screening and surveillance, given the high global prevalence. US, a safe and widely available modality, is well positioned as a screening and surveillance tool. Although well-established qualitative signs of liver fat perform well in moderate and severe steatosis, these signs are less reliable for grading mild steatosis and are likely unreliable for detecting subtle changes over time. New and emerging quantitative biomarkers of liver fat, such as those based on standardized measurements of attenuation, backscatter, and speed of sound, hold promise. Evolving techniques such as multiparametric modeling, radiofrequency envelope analysis, and artificial intelligence-based tools are also on the horizon. The authors discuss the societal impact of fatty liver disease, summarize the current state of liver fat quantification with CT and MRI, and describe past, currently available, and potential future US-based techniques for evaluating liver fat. For each US-based technique, they describe the concept, measurement method, advantages, and limitations. © RSNA, 2023 Online supplemental material is available for this article. Quiz questions for this article are available through the Online Learning Center.

Aberration correction in abdominal histotripsy.

In transabdominal histotripsy, ultrasound pulses are focused on the body to noninvasively destroy soft tissues via cavitation. However, the ability to focus is limited by phase aberration, or decorrelation of the ultrasound pulses due to spatial variation in the speed of sound throughout heterogeneous tissue. Phase aberration shifts, broadens, and weakens the focus, thereby reducing the safety and efficacy of histotripsy therapy. This paper reviews and discusses aberration effects in histotripsy and in related therapeutic ultrasound techniques (e.g., high intensity focused ultrasound), with an emphasis on aberration by soft tissues. Methods for aberration correction are reviewed and can be classified into two groups: model-based methods, which use segmented images of the tissue as input to an acoustic propagation model to predict and compensate phase differences, and signal-based methods, which use a receive-capable therapy array to detect phase differences by sensing acoustic signals backpropagating from the focus. The relative advantages and disadvantages of both groups of methods are discussed. Importantly, model-based methods can correct focal shift, while signal-based methods can restore substantial focal pressure, suggesting that both methods should be combined in a 2-step approach. Aberration correction will be critical to improving histotripsy treatments and expanding the histotripsy treatment envelope to enable non-invasive, non-thermal histotripsy therapy for more patients.

Comparison of four commercial immunomagnetic separation kits for the detection of Cryptosporidium.

Cryptosporidium spp. are protozoan parasites of significant health importance found in environmental waters globally. Four commercially available Cryptosporidium-specific immunomagnetic separation (IMS) kits used in various water sample matrices were analysed and compared. Beads were characterised by flow cytometry and tested for the recovery efficiencies for oocysts spiked into different matrices: river water sediment, clay sample, and filter backwash sample. Results showed that Dynabeads™ Cryptosporidium and Waterborne Crypto-Grab™ kits contained immunoglobulin IgM antibody-coated beads. In contrast, the BioPoint CryptoBead and the TCS Isolate kits contained immunoglobulin IgG antibody-coated beads. BioPoint CryptoBead was significantly coated with more antibodies and were able to capture oocysts more rapidly compared to the other beads. Recovery efficiencies of Dynabeads™, TCS Isolate® beads, and BioPoint CryptoBead ranged from 55 to 93% when tested against different sample matrices, with BioPoint CryptoBead resulting in the highest at 93% in reagent-grade water and Dynabeads™ at 55%, the lowest against clay samples. The Waterborne beads did not perform well on any samples, with recovery efficiencies ranging from 0 to 8%. Fluorescence microscopy analyses showed that both the IMS method and the sample matrix processed affect the quality of the membranes, with the cleanest samples for microscopy examination observed from BioPoint CryptoBead.

A Geometric Model of Ultrasound Backscatter to Describe Microstructural Anisotropy of Tissue.

Methods to assess ultrasound backscatter anisotropy from clinical array transducers have recently been developed. However, they do not provide information about the anisotropy of microstructural features of the specimens. This work develops a simple geometric model, referred to as the secant model, of backscatter coefficient anisotropy. Specifically, we evaluate anisotropy of the frequency dependence of the backscatter coefficient parameterized in terms of effective scatterer size. We assess the model in phantoms with known scattering sources and in a skeletal muscle, a well-known anisotropic tissue. We demonstrate that the secant model can determine the orientation of the anisotropic scatterers, as well as accurately determining effective scatterer sizes, and it may classify isotropic versus anisotropic scatterers. The secant model may find utility in monitoring disease progression as well as characterizing normal tissue architectures.

Potential Effects of Dobbs v. Jackson Women's Health on Civil Commitment Law.

Since the publication of the U.S. Supreme Court's decision in Dobbs v Jackson Women's Health in June of 2022, much attention has been paid to the direct effects of that decision on reproductive health care for pregnant or potentially pregnant individuals; and to the potential effects of the Court's approach in Dobbs to other established precedent related to privacy and autonomy, such as rights to contraception and marriage equality. This Article will explore another potential negative consequence of Dobbs; its potential effect on the constitutional parameters of the law of civil commitment and involuntary medication of the mentally ill.The foundational Supreme Court case establishing the parameters of the State's right to involuntarily commit an individual to a mental institution was decided only two years after Roe v. Wade. In 1975, the Supreme Court in O'Connor v Donaldson held that an individual has a liberty interest in "prefer[ring] one's home to the comforts of an institution," and that a State could not, "without more," confine a non-dangerous individual. The two-prong test of requiring a showing of both mental illness and dangerousness to one's self or to others has remained the cornerstone of civil commitment law ever since.The language and analysis of O'Connor is similar to that of Roe, the abortion rights case overturned by Dobbs. In particular, the grounding of the right to avoid civil commitment in the individual liberty and privacy interests are common themes in the two cases. The current Court, in its decision in Dobbs, has cast substantial doubt on the continued vitality of that analysis; and one can easily imagine a reconceptualization of O'Connor along the lines of Dobbs that substantially alters the requirements for civil commitment. In particular, the reliance in Dobbs and other recent Supreme Court opinions on historical precedent as a linchpin of originalist analysis could lead the Court to search for justifications in colonial or 19th-century mental health practices, time periods which predate modern psychiatric science.This Article will explore the parallels in approach between Roe and O'Connor, and will suggest ways in which the post-Dobbs Supreme Court majority might disrupt the civil commitment status quo, including potential expansion of civil commitment or other detention of pregnant individuals for the protection of the fetus; and possible relaxation of the dangerousness requirement for civil commitment articulated in O'Connor.

Pulse-Echo Quantitative US Biomarkers for Liver Steatosis: Toward Technical Standardization.

Excessive liver fat (steatosis) is now the most common cause of chronic liver disease worldwide and is an independent risk factor for cirrhosis and associated complications. Accurate and clinically useful diagnosis, risk stratification, prognostication, and therapy monitoring require accurate and reliable biomarker measurement at acceptable cost. This article describes a joint effort by the American Institute of Ultrasound in Medicine (AIUM) and the RSNA Quantitative Imaging Biomarkers Alliance (QIBA) to develop standards for clinical and technical validation of quantitative biomarkers for liver steatosis. The AIUM Liver Fat Quantification Task Force provides clinical guidance, while the RSNA QIBA Pulse-Echo Quantitative Ultrasound Biomarker Committee develops methods to measure biomarkers and reduce biomarker variability. In this article, the authors present the clinical need for quantitative imaging biomarkers of liver steatosis, review the current state of various imaging modalities, and describe the technical state of the art for three key liver steatosis pulse-echo quantitative US biomarkers: attenuation coefficient, backscatter coefficient, and speed of sound. Lastly, a perspective on current challenges and recommendations for clinical translation for each biomarker is offered.

Development of an automated laser drilling algorithm to compare stone ablation patterns from different laser pulse modes.

PURPOSE: To develop a novel automated three-dimensional (3D) laser drilling algorithm to further investigate laser-stone interaction with different laser pulse modes. Comparison of post-ablative lattice architecture combined with mass of stone ablated can provide a more complete understanding of differences between pulse mode. METHODS: A 3D positioner (securing laser fiber) was programmed to create a 5 × 5 grid of drill holes spaced 1 mm apart on 15:5 cylindrical BegoStones. Beginning 0.5 mm above the stone surface, the laser fiber was activated and advanced 2 mm toward and into the stone for all 25 points. Four trials for each pulse mode [short pulse (SP), long pulse (LP), Moses Contact (MC), Moses Distance (MD)] were completed. Outcome measures were assessment of lattice preservation and mass of ablated stone. RESULTS: MC exhibited the greatest lattice preservation and least stone mass ablated (50.5 ± 2.2 mg). SP (69.4 ± 4.3 mg) and MD (70.0 ± 2.6 mg) had the greatest lattice destruction and stone mass ablated. The differences in stone ablated between MC and MD (p = 0.00003), MC and SP (p = 0.0002), and LP and MD (p = 0.004) were statistically significant. CONCLUSIONS: Consistent quantitative and qualitative differences between pulse modes were observed with a novel automated 3D laser drilling algorithm applied to BegoStone. The laser drilling algorithm developed here can be used to further enhance mechanistic understanding of laser-stone interactions and facilitate selection of appropriate laser pulse modes to balance precision and efficiency across the range of laser lithotripsy techniques.

Laser operator duty cycle effect on temperature and thermal dose: in-vitro study.

PURPOSE: High-power laser lithotripsy can elevate temperature within the urinary collecting system and increase risk of thermal injury. Temperature elevation is dependent on power settings and operator duty cycle (ODC)-the percentage of time the laser pedal is depressed. The objective of this study was to quantify temperature and thermal dose resulting from laser activation at different ODC in an in-vitro model. METHODS: Holmium laser energy (1800 J) was delivered at 30 W (0.5 J × 60 Hz) to a fluid filled glass bulb. Room temperature irrigation was applied at 8 ml/min. ODC was evaluated in 10% increments from 50-100%. Bulb fluid temperature was recorded and thermal dose calculated. Time to reach threshold of thermal injury and maximal allowable energy were also determined at each ODC. RESULTS: Upon laser activation, there was an immediate rise in fluid temperature with a "saw-tooth" oscillation superimposed on the curves for 50-90% ODC corresponding to periodic activation of the laser. Higher ODC resulted in greater maximum temperature and thermal dose, with ODC ≥ 70% exceeding threshold. Use of 50% compared to 60% ODC resulted in a tenfold increase in time required to reach threshold of thermal injury and an eightfold increase in maximal allowable energy. CONCLUSIONS: Laser activation at higher ODC produced greater fluid temperature and thermal dose. Time to threshold of thermal injury and maximal allowable energy were dramatically higher for 50% compared to 60% ODC at high-power settings. Proper management of laser ODC can enhance patient safety and optimize stone treatment.

First-in-man histotripsy of hepatic tumors: the THERESA trial, a feasibility study.

Rationale Current hepatic locoregional therapies are limited in terms of effectiveness and toxicities. Given promising pre-clinical results, a first in-human trial was designed to assess the technical effectiveness and safety profile of histotripsy, a noninvasive, non-thermal, non-ionizing focused ultrasound therapy that creates precise, predictable tissue destruction, in patients with primary and secondary liver tumors.Methods A multicenter phase I trial (Theresa Study) was performed in a single country with 8 weeks of planned follow-up. Eight of fourteen recruited patients were deemed eligible and enrolled in the study. Hepatic histotripsy, was performed with a prototype system (HistoSonics, Inc., Ann Arbor, MI). Eleven tumors were targeted in the 8 patients who all had unresectable end-stage multifocal liver tumors: colorectal liver metastases (CRLM) in 5 patients (7 tumors), breast cancer metastases in 1 (1 tumor), cholangiocarcinoma metastases in 1 (2 tumors), and hepatocellular carcinoma (HCC) in 1 (1 tumor). The primary endpoint was acute technical success, defined as creating a zone of tissue destruction per planned volume assessed by MRI 1-day post-procedure. Safety (device-related adverse events) through 2 months was a secondary endpoint.Results The 8 patients had a median age of 60.4 years with an average targeted tumor diameter of 1.4 cm. The primary endpoint was achieved in all procedures. The secondary safety profile endpoint identified no device-related adverse events. Two patients experienced a continuous decline in tumor markers during the eight weeks following the procedure.Conclusions This first-in-human trial demonstrates that hepatic histotripsy effectively destroys liver tissue in a predictable manner, correlating very well with the planned histotripsy volume, and has a high safety profile without any device-related adverse events. Based on these results, the need for more definitive clinical trials is warranted. Trial Registration: Study to Evaluate VORTX Rx (Theresa). NCT03741088. https://clinicaltrials.gov/ct2/show/NCT03741088 KEY POINTSHistotripsy, a new noninvasive, non-thermal, non-ionizing focused ultrasound therapy, safely created a zone of tissue destruction in the liver that correlated very well with the pre-defined planned tissue destruction volume.In this first human trial histotripsy was well tolerated with no histotripsy device-related adverse events and its primary endpoint of acute technical success was achieved in all 8 enrolled patients with primary or secondary liver tumors.This new locoregional therapy for patients with liver tumors is safe and effective, warranting further trials.

Pulse modulation with Moses technology improves popcorn laser lithotripsy.

PURPOSE: Moses™ technology has been developed to improve holmium laser fragmentation at 1-2 mm distance from the stone. Because popcorn lithotripsy is a non-contact technique, we compared short pulse (SP) and Moses distance (MD) modes in an in vitro model. METHODS: BegoStones were fragmented using a 120 W Ho:YAG laser (P120 Moses) and a 230 µm core fiber introduced through a ureteroscope. 20 W (1 J × 20 Hz; 0.5 J × 40 Hz) and 40 W (1 J × 40 Hz; 0.5 J × 80 Hz) settings (total energy 4.8 kJ) were tested using SP and MD modes. We assessed fragment size distribution and mass lost in fluid (initial mass-final dry mass of all sievable fragments). High-speed video analysis of fragmentation strike rate and vapor bubble characteristics was conducted for 1 J × 20 Hz and 0.5 J × 80 Hz. Laser strike rate (number of strikes divided by frequency) was categorized as: (1) direct-a visual plume of dust ejected from stone while in contact with fiber tip; (2) indirect-a visual plume of dust ejected with distance between stone and fiber tip. RESULTS: For 1 J × 20 Hz (20 W), MD resulted in more mass lost in fluid and a lower distribution of fragments ≥ 2 mm compared to SP (p < 0.05). 0.5 J × 80 Hz (40 W) produced no fragments ≥ 2 mm, and there were no significant differences in fragment distribution between MD and SP (p = 0.34). When using MD at 1 J × 20 Hz, 96% of strikes were indirect vs 61% for SP (p = 0.059). In contrast to the single bubble of SP, with MD, there was forward movement of the collapsing second bubble, away from the fiber-tip. CONCLUSIONS: For lower frequency and power popcorn settings, pulse modulation results in more fragmentation through true non-contact laser lithotripsy.