Occupational groups and lower urinary tract symptoms: A cross-sectional analysis of women in the Boston Area Community Health Study.

OBJECTIVES: The objective of this study is to inform our hypothesis that the workplace toileting environment may impact lower urinary tract symptoms (LUTS); we examined the prevalence of LUTS across occupational groups in the Boston Area Community Health Survey. METHODS: At baseline, women (n = 3205) reported their occupation and frequency of 15 LUTS. Using the US Department of Labor's Standard Occupational Classification (SOC) system, we categorized women into 11 standard occupational groups. Prevalence ratios (PRs) were calculated by log-link generalized linear models, adjusting for age, race, education, fluid intake, and parity. Women classified in Office and Administrative Support were used as the reference group given their potential for fewer workplace toileting restrictions. RESULTS: Of the 3189 women with complete data, 68% of women reported any LUTS, ranging from 57% to 82% across the SOCs. Relative to women in Office and Administrative Support (n = 576), women in Computing, Engineering, and Science (n = 64) were more likely to report any LUTS (PR = 1.2, 95% confidence interval [95% CI]: 1.0-1.4) and urinating again in <2 h (PR = 1.7, 95% CI: 1.4-2.2), and women in Education, Legal, Community Service, Arts, and Media (n = 477), as well as Healthcare Practitioner and Technical Occupations (n = 162), were less likely to report perceived frequent daytime urination (PR = 0.6, 95% CI: 0.5-0.9 and PR = 0.6, 95% CI: 0.4-0.9, respectively). CONCLUSIONS: Our cross-sectional findings suggest that urination frequency varies across understudied occupational groups with various workplace toileting environments. Future studies should examine this relationship prospectively to inform the influence of workplace toileting environments on urination frequency, as well as the development and/or worsening of LUTS.

Design considerations and analytical framework for reliably identifying a beneficial individualized treatment rule.

An individualized treatment rule (ITR) formalizes personalized medicine by assigning treatment as a function of patients' clinical information, which contrasts with a static treatment rule that assigns everyone the same treatment. ITR identification has become a common aim in randomized clinical trials but sample size considerations for this aim are lacking. One approach is to select a sample size that will reliably identify an ITR with a performance close to the theoretical optimal rule. However, this approach could still lead to identifying ITRs that perform worse than the optimal static rule, particularly in the absence of substantial effect heterogeneity. This limitation motivates sample size considerations aimed at reliable identification of a beneficial ITR, which outperforms the optimal static rule, and analysis methods that identify the estimated optimal static rule when there is substantial uncertainty about whether an ITR will improve outcomes. To address these limitations, we propose a sample size approach based on the probability of identifying a beneficial ITR and introduce an approach for selecting the LASSO penalty parameter such that in the absence of treatment effect heterogeneity the estimated optimal static rule is identified with high probability. We apply these approaches to the PLUTO trial aimed at developing methods to assist with smoking cessation.

Urination Frequency Ranges in Healthy Women.

BACKGROUND: Limited information on the normal range of urination frequencies in women is available to guide bladder health promotion efforts. OBJECTIVES: This study used data from the Boston Area Community Health (BACH) Survey to (a) estimate normative reference ranges in daytime and nighttime urination frequencies in healthy women based on two operational definitions of "healthy" and (b) compare urination frequencies by age, race/ethnicity, and fluid intake. METHODS: A secondary analysis of cross-sectional interview data collected from female participants was performed using less restrictive ("healthy") and strict ("elite healthy") inclusion criteria. All analyses were weighted to account for the BACH sampling design. Normative reference values corresponding to the middle 95% of the distribution of daytime and nighttime urination frequencies were calculated overall and stratified by age, race/ethnicity, and fluid intake. Generalized linear regression with a log-link was used to estimate rate ratios of daytime and nighttime urination frequencies by age, race/ethnicity, and fluid intake. RESULTS: Of the 2,534 women who completed the BACH follow-up interviews, 1,505 women met healthy eligibility criteria, and 300 met elite healthy criteria. Overall, reference ranges for urination frequencies were 2-10 times/day and 0-4 times/night in healthy women and 2-9 times/day and 0-2 times/night in elite healthy women. Women ages 45-64 years, but not 65+ years, reported a greater number of daytime urination than those aged 31-44 years, whereas women 65+ years reported a greater number of nighttime urination. Black women reported fewer daytime urination and more nighttime urinations than White women. Women who consumed less than 49 oz daily reported fewer daytime and nighttime urinations than those who drank 50-74 oz; drinking 75+ oz had only a small effect on urination frequencies. DISCUSSION: Normative reference values for daytime and nighttime urination frequencies were similar in women using strict and relaxed definitions of health. These results indicate a wide range of "normal" urination frequencies, with some differences by age, race/ethnicity, and fluid intake. Future research is needed to examine urination frequencies in minority women and whether fluid intake amount and type influence the development of lower urinary tract symptoms.

Changes in Bladder Health over Time: A Longitudinal Analysis of Adult Women in the Boston Area Community Health Survey.

PURPOSE: Our goal was to describe changes in bladder health, defined as "a complete state of physical, mental, and social well-being related to bladder function that permits daily activities, adapts to short-term stressors, and allows optimal well-being," in women over time. MATERIALS AND METHODS: We used data on 15 lower urinary tract symptoms (LUTS) and interference from urinary experiences assessed at the baseline and 5-year followup interviews of the BACH (Boston Area Community Health) Survey to estimate changes in bladder health over time in women. Associations between baseline and followup bladder health (defined as the maximum frequency of LUTS or interference at each time point) were calculated by ordinal logistic regression and generalized linear models. RESULTS: A total of 2,526 women provided complete information on bladder health at baseline and followup. Over the 5-year followup, 6.5% of women maintained optimal bladder health (no LUTS or interference), 33.6% developed worse bladder health (including 10.4% who transitioned from optimal to less than optimal health), 31.4% maintained their less than optimal bladder health status and 28.7% improved. Despite these changes, women with poorer bladder health at baseline were still more likely to have poorer bladder health 5 years later (eg multivariable-adjusted relative risk=3.27, 95% confidence interval: 2.49-4.29 for severe LUTS/interference at followup among those with severe LUTS/interference at baseline). CONCLUSIONS: Findings from our large secondary analysis of BACH Survey data suggest considerable variability in bladder health over time, and underscore the importance of bladder health promotion to prevent the initial onset and progression of poor bladder health in women.

Toileting Behaviors and Lower Urinary Tract Symptoms: A Cross-sectional Study of Diverse Women in the United States.

Background: Toileting behaviors are increasingly recognized as factors potentially contributing to development of lower urinary tract symptoms (LUTS). Objectives: To examine adult women's toileting behaviors and LUTS across age and race/ethnicity groups and relationships between toileting behaviors and LUTS. Design: Planned secondary analysis of questionnaire data collected in a focus group study on bladder health. Settings: Questionnaires were completed at the conclusion of focus groups conducted in community settings affiliated with seven research centers across the United States. Participants: Community-living women regardless of LUTS status. Methods: Forty-four focus groups were conducted with 360 adolescent and adult cisgender women. After each focus group, participants completed questionnaires to assess toileting behaviors (Toileting Behaviors-Women's Elimination Behaviors Scale (TB-WEB)) and their experience of LUTS (Lower Urinary Tract Symptom Tool), This analysis includes quantitative data from the subgroup of 316 participants who completed the questionnaires. Results: Participants ranged in age from 18-93 years (Mean=50.2 years). A significant effect for age was found for delayed voiding behavior, reported by 76.5% of women ages 18-25 years and 21.9% of those 75+ years (p<0.001). Conversely, reports of premature voiding were lowest in the youngest and higher in the oldest three age groups (p=0.022). Racial/ethnic differences were found for three domains of toileting behavior. Black and Hispanic women expressed a stronger preference for voiding at home rather than away from home (98.9%, 93.5%, respectively) compared to White women (90.4%, p=0.041), were more likely to void prematurely (37.6%, 33.3% vs. 21.2%, p=0.048) and to crouch, squat, or stand rather than sit to void when away from home (69.9%, 58.3% vs. 41.3%, p<0.001). Four toileting behavior domains were significantly associated with LUTS. Premature voiding was associated with any bothersome LUTS (OR=2.5; 95% confidence interval [CI]=1.3-4.8) and any bothersome storage LUTS (OR=2.9; CI=1.5-5.5). Delayed voiding was associated with bothersome emptying symptoms (OR=2.8; CI=1.1-6.6). Straining to void was associated with bothersome storage symptoms (OR=2.0; CI=1.0-3.7), bothersome emptying symptoms (OR=3.7; CI=1.9-7.3), and any bothersome LUTS (OR=2.3; CI=1.2-4.3). Preference for non-sitting positions to void when away from home was associated with bothersome emptying symptoms (OR=2.5; CI=1.3-4.8) and any bothersome LUTS (OR=1.8; CI=1.0-3.2). Conclusions: These findings highlight the need for research to understand underpinnings of age and racial/ethnic differences in toileting behaviors and identify mechanisms by which toileting behaviors might influence development of LUTS over time. Understanding causal pathways is important in the development of public health interventions to encourage toileting behaviors that support bladder health.

Revisiting the Spectrum of Bladder Health: Relationships Between Lower Urinary Tract Symptoms and Multiple Measures of Well-Being.

Background: Little research to date has investigated the spectrum of bladder health in women, including both bladder function and well-being. Therefore, we expanded our previous baseline analysis of bladder health in the Boston Area Community Health (BACH) Survey to incorporate several additional measures of bladder-related well-being collected at the 5-year follow-up interview, including one developed specifically for women. Methods: At follow-up, participants reported their frequency of 15 lower urinary tract symptoms (LUTS), degree of life impact from and thought related to urinary symptoms or pelvic/bladder pain/discomfort, and perception of their bladder condition. Prevalence ratios were calculated by generalized linear models with robust variance estimation, adjusting for LUTS risk factors and individual LUTS. The BACH Survey was approved by the New England Research Institutes Institutional Review Board and all participants provided written informed consent. Results: Generally similar findings were observed in the 5-year cross-sectional analysis as at baseline, irrespective of how we categorized LUTS or measured bladder-related well-being. Approximately one in five women (16.2%-18.0% of 2527 eligible women) reported no LUTS and no diminished bladder-related well-being, the majority (55.8%-65.7%) reported some LUTS and/or diminished well-being, and a further one in five (16.9%-26.6%) reported the maximum frequency, number, or degree of LUTS and/or diminished well-being. Measures of storage function (urinating again after <2 hours, perceived frequency, nocturia, incontinence, and urgency) and pain were independently associated with bladder-related well-being. Conclusions: Our similar distribution of bladder health and consistent associations between LUTS and bladder-related well-being across multiple measures of well-being, including a female-specific measure, lend confidence to the concept of a bladder health spectrum and reinforce the bothersome nature of storage dysfunction and pain.

The Spectrum of Bladder Health: The Relationship Between Lower Urinary Tract Symptoms and Interference with Activities.

Background: Little research to date has focused on lower urinary tract symptom (LUTS) prevention and bladder health promotion in women. To address this gap, the Prevention of LUTS Research Consortium developed the following working bladder health definition: "A complete state of physical, mental, and social well-being related to bladder function [that] permits daily activities [and] allows optimal well-being." To begin to inform and quantify this definition, we used data from the Boston Area Community Health Survey, drawing upon its rare collection of information on LUTS and LUTS-specific interference with activities. Methods: At baseline, participants reported their frequency of 15 LUTS and interference with 7 activities. Prevalence ratios (PRs) were calculated by generalized linear models with robust variance estimation, adjusting for LUTS risk factors and individual LUTS. Results: Of the 3169 eligible participants, 17.5% reported no LUTS or interference, whereas the remaining 82.5% reported some frequency of LUTS/interference: 15.1% rarely; 21.7% a few times; 22.6% fairly often/usually; and 22.9% almost always. LUTS independently associated with interference were urgency incontinence, any incontinence, urgency, nocturia, perceived frequency, and urinating again after <2 hours (PRs = 1.2-1.5, all p < 0.05). Conclusions: Our findings suggest that bladder health exists on a continuum, with approximately one in five women considered to have optimal bladder health (no LUTS/interference), the majority to have intermediate health (LUTS/interference rarely to usually), and a further one in five to have worse or poor health (LUTS/interference almost always). These findings underscore the need for LUTS prevention and bladder health promotion.

Enhanced Shock Scattering Histotripsy With Pseudomonopolar Ultrasound Pulses.

Shock scattering histotripsy involves a complex interaction between positive and negative phases of an acoustic burst to initiate a robust cavitation bubble cloud. To more precisely study these effects and optimize shock scattering histotripsy therapy, we constructed a frequency compounding transducer to generate pseudomonopolar ultrasound pulses. The transducer consisted of 113 individual piezoelectric elements with various resonant frequencies (250 kHz, 500 kHz, 750 kHz, 1 MHz, 1.5 MHz, 2 MHz, and 3 MHz). For each resonant frequency, an extremely short pulse could be generated. Pseudomonopolar peak positive pulses were generated by aligning the principal peak positive pressures of individual frequency components temporally, so that they added constructively, and destructive interference occurred outside the peak-positive-overlapped temporal window. After inverting the polarity of the excitation signals, pseudomonopolar peak negative pulses were generated similarly by aligning principal peak negative pressures. Decoupling the positive and negative acoustic phases could have significant advantages for therapeutic applications enhancing precision and avoiding cavitation at tissue interfaces by using mostly positive pressure pulses. For example, we show that 16 shock scattering bubble clouds can be generated using only peak positive pulses following a single peak negative pulse that initiates a pressure release "seed cloud" from which the first shock front is "scattered." Subsequent positive only pulses result in a precise elongated lesion within red blood cell phantoms.

In vivo histotripsy brain treatment.

OBJECTIVE: Histotripsy is an ultrasound-based treatment modality relying on the generation of targeted cavitation bubble clouds, which mechanically fractionate tissue. The purpose of the current study was to investigate the in vivo feasibility, including dosage requirements and safety, of generating well-confined destructive lesions within the porcine brain utilizing histotripsy technology. METHODS: Following a craniectomy to open an acoustic window to the brain, histotripsy pulses were delivered to generate lesions in the porcine cortex. Large lesions with a major dimension of up to 1 cm were generated to demonstrate the efficacy of histotripsy lesioning in the brain. Gyrus-confined lesions were generated at different applied dosages and under ultrasound imaging guidance to ensure that they were accurately targeted and contained within individual gyri. Clinical evaluation as well as MRI and histological outcomes were assessed in the acute (≤ 6 hours) and subacute (≤ 72 hours) phases of recovery. RESULTS: Histotripsy was able to generate lesions with a major dimension of up to 1 cm in the cortex. Histotripsy lesions were seen to be well demarcated with sharp boundaries between treated and untreated tissues, with histological evidence of injuries extending ≤ 200 µm from their boundaries in all cases. In animals with lesions confined to the gyrus, no major hemorrhage or other complications resulting from treatment were observed. At 72 hours, MRI revealed minimal to no edema and no radiographic evidence of inflammatory changes in the perilesional area. Histological evaluation revealed the histotripsy lesions to be similar to subacute infarcts. CONCLUSIONS: Histotripsy can be used to generate sharply defined lesions of arbitrary shapes and sizes in the swine cortex. Lesions confined to within the gyri did not lead to significant hemorrhage or edema responses at the treatment site in the acute or subacute time intervals.

An overview of MCT1 and MCT4 in GBM: small molecule transporters with large implications.

Monocarboxylate transporters (MCTs) represent a diverse group of transmembrane proteins encoded by the SLC16 gene family found ubiquitously across mammalian species. Two members of this family, MCT1 and MCT4, have been linked to key roles in the metabolic activity of tissues through the proton-coupled transport of monocarboxylates, most notably L-lactate, ketone bodies, and pyruvate. This review aims to provide an overview of MCT1 and MCT4, followed by the implications of their expression in a multitude of cancers and in glioblastoma (GBM) specifically. Further, the possible mechanisms underlying these effects will be discussed. Given the relationships between MCT1 and MCT4 and cancer, they offer a unique opportunity for novel treatment strategies. We aim to explore current therapies focused on MCT1 and MCT4 and propose future studies to better understand their role in GBM to optimize future treatment regimens.

Coalescence of residual histotripsy cavitation nuclei using low-gain regions of the therapy beam during electronic focal steering.

Following collapse of a histotripsy cloud, residual microbubbles may persist for seconds, distributed throughout the focus. Their presence can attenuate and scatter subsequent pulses, hindering treatment speed and homogeneity. Previous studies have demonstrated use of separate low-amplitude (~1 MPa) pulses interleaved with histotripsy pulses to drive bubble coalescence (BC), significantly improving treatment speed without sacrificing homogeneity. We propose that by using electronic focal steering (EFS) to direct the therapy focus throughout specially-designed EFS sequences, it is possible to use low-gain regions of the therapy beam to accomplish BC during EFS without any additional acoustic sequence. First, to establish proof of principle for an isolated focus, a 50-foci EFS sequence was constructed with the first position isolated near the geometric focus and remaining positions distributed post-focally. EFS sequences were evaluated in tissue-mimicking phantoms with gas concentrations of 20% and 100% with respect to saturation. Results using an isolated focus demonstrated that at 20% gas concentration, 49 EFS pulses were sufficient to achieve BC in all samples for pulse repetition frequency (PRF) ⩽ 800 Hz and 84.1% ± 3.0% of samples at 5 kHz PRF. For phantoms prepared with 100% gas concentration, BC was achieved by 49 EFS pulses in 39.2% ± 4.7% of samples at 50 Hz PRF and 63.4% ± 15.3% of samples at 5 kHz. To show feasibility of using the EFS-BC method to ablate a large volume quickly, a 1000-foci EFS sequence covering a volume of approximately 27 ml was tested. Results indicate that the BC effect was similarly present. A treatment rate of 27 ± 6 ml min-1 was achieved, which is signficantly faster than standard histotripsy and ultrasound thermal ablation. This study demonstrates that histotripsy with EFS can achieve BC without employing a separate acoustic sequence which has the potential to accelerate large-volume ablation while minimizing energy deposition.

Soft-Tissue Aberration Correction for Histotripsy.

Acoustic aberrations caused by natural heterogeneities of biological soft tissue are a substantial problem for histotripsy, a therapeutic ultrasound technique that uses acoustic cavitation to mechanically fractionate and destroy unwanted target tissue without damaging surrounding tissue. These aberrations, primarily caused by sound speed variations, result in severe defocusing of histotripsy pulses, thereby decreasing treatment efficacy. The gold standard for aberration correction (AC) is to place a hydrophone at the desired focal location to directly measure phase aberrations, which is a method that is infeasible in vivo. We hypothesized that the acoustic cavitation emission (ACE) shockwaves from the initial expansion of inertially cavitating microbubbles generated by histotripsy can be used as a point source for AC. In this study, a 500-kHz, 112-element histotripsy phased array capable of transmitting and receiving ultrasound on all channels was used to acquire ACE shockwaves. These shockwaves were first characterized optically and acoustically. It was found that the shockwave pressure increases significantly as the source changes from a single bubble to a dense cavitation cloud. The first arrival of the shockwave received by the histotripsy array was from the outer-most cavitation bubbles located closest to the histotripsy array. Hydrophone and ACE AC methods were then tested on ex vivo porcine abdominal tissue samples. Without AC, the focal pressure is reduced by 49.7% through the abdominal tissue. The hydrophone AC approach recovered 55.5% of the lost pressure. Using the ACE AC method, over 20% of the lost pressure was recovered, and the array power required to induce cavitation was reduced by approximately 31.5% compared to without AC. These results supported our hypothesis that the ACE shockwaves coupled with a histotripsy array with transmit and receive capability can be used for AC for histotripsy through soft tissue.

Bubble-Induced Color Doppler Feedback Correlates with Histotripsy-Induced Destruction of Structural Components in Liver Tissue.

Bubble-induced color Doppler (BCD) is a histotripsy-therapy monitoring technique that uses Doppler ultrasound to track the motion of residual cavitation nuclei that persist after the collapse of the histotripsy bubble cloud. In this study, BCD is used to monitor tissue fractionation during histotripsy tissue therapy, and the BCD signal is correlated with the destruction of structural and non-structural components identified histologically to further understand how BCD monitors the extent of treatment. A 500-kHz, 112-element phased histotripsy array is used to generate approximately 6- × 6- × 7-mm lesions within ex vivo bovine liver tissue by scanning more than 219 locations with 30-1000 pulses per location. A 128-element L7-4 imaging probe is used to acquire BCD signals during all treatments. The BCD signal is then quantitatively analyzed using the time-to-peak rebound velocity (tprv) metric. Using the Pearson correlation coefficient, the tprv is compared with histologic analytics of lesions generated by various numbers of pulses using a significance level of 0.001. Histologic analytics in this study include viable cell count, reticulin-stained type III collagen area and trichrome-stained type I collagen area. It is found that the tprv metric has a statistically significant correlation with the change in reticulin-stained type III collagen area with a Pearson correlation coefficient of -0.94 (p <0.001), indicating that changes in BCD are more likely because of destruction of the structural components of tissue.

Non-invasive, Rapid Ablation of Tissue Volume Using Histotripsy.

Histotripsy is a non-invasive, non-thermal ablation technique that uses high-amplitude, focused ultrasound pulses to fractionate tissue via acoustic cavitation. The goal of this study was to illustrate the potential of histotripsy with electronic focal steering to achieve rapid ablation of a tissue volume at a rate matching or exceeding those of current clinical techniques (∼1-2 mL/min). Treatment parameters were established in tissue-mimicking phantoms and applied to ex vivo tissue. Six-microsecond pulses were delivered by a 250-kHz array. The focus was electrically steered to 1000 locations at a pulse repetition frequency of 200 Hz (0.12% duty cycle). Magnetic resonance imaging and histology of the treated tissue revealed a distinct region of necrosis in all samples. Mean lesion volume was 35.6 ± 4.3 mL, generated at 0.9-3.3 mL/min, a speed faster than that of any current ablation method for a large volume. These results suggest that histotripsy has the potential to achieve non-invasive, rapid, homogeneous ablation of a tissue volume.

Catheter Hydrophone Aberration Correction for Transcranial Histotripsy Treatment of Intracerebral Hemorrhage: Proof-of-Concept.

Histotripsy is a minimally invasive ultrasound therapy that has shown rapid liquefaction of blood clots through human skullcaps in an in vitro intracerebral hemorrhage model. However, the efficiency of these treatments can be compromised if the skull-induced aberrations are uncorrected. We have developed a catheter hydrophone which can perform aberration correction (AC) and drain the liquefied clot following histotripsy treatment. Histotripsy pulses were delivered through an excised human skullcap using a 256-element, 500-kHz hemisphere array transducer with a 15-cm focal distance. A custom hydrophone was fabricated using a mm PZT-5h crystal interfaced to a coaxial cable and integrated into a drainage catheter. An AC algorithm was developed to correct the aberrations introduced between histotripsy pulses from each array element. An increase in focal pressure of up to 60% was achieved at the geometric focus and 27%-62% across a range of electronic steering locations. The sagittal and axial -6-dB beam widths decreased from 4.6 to 2.2 mm in the sagittal direction and 8 to 4.4 mm in the axial direction, compared to 1.5 and 3 mm in the absence of aberration. After performing AC, lesions with diameters ranging from 0.24 to 1.35 mm were generated using electronic steering over a mm grid in a tissue-mimicking phantom. An average volume of 4.07 ± 0.91 mL was liquefied and drained after using electronic steering to treat a 4.2-mL spherical volume in in vitro bovine clots through the skullcap.

The response of MRI contrast parameters in in vitro tissues and tissue mimicking phantoms to fractionation by histotripsy.

Histotripsy is a non-invasive, focused ultrasound lesioning technique that can ablate precise volumes of soft tissue using a novel mechanical fractionation mechanism. Previous research suggests that magnetic resonance imaging (MRI) may be a sensitive image-based feedback mechanism for histotripsy. However, there are insufficient data to form some unified understanding of the response of the MR contrast mechanisms in tissues to histotripsy. In this paper, we investigate the response of the MR contrast parameters R1, R2, and the apparent diffusion coefficient (ADC) to various treatment levels of histotripsy in in vitro porcine liver, kidney, muscle, and blood clot as well in formulations of bovine red blood cells suspended in agar gel. We also make a histological analysis of histotripsy lesions in porcine liver. We find that R2 and the ADC are both sensitive to ablation in all materials tested here, and the degree of response varies with tissue type. Correspondingly, under histologic analysis, the porcine liver exhibited various levels of mechanical disruption and necrotic debris that are characteristic of histotripsy. While the area of intact red blood cells and nuclei found within these lesions both decreased with increasing amounts of treatment, the area of red blood cells decreased much more rapidly than the area of intact nuclei. Additionally, the decrease in area of intact red blood cells saturated at the same treatment levels at which the response of the R2 saturated while the area of intact nuclei appeared to vary linearly with the response of the ADC.

Effect of Frequency and Focal Spacing on Transcranial Histotripsy Clot Liquefaction, Using Electronic Focal Steering.

This in vitro study investigated the effects of ultrasound frequency and focal spacing on blood clot liquefaction via transcranial histotripsy. Histotripsy pulses were delivered using two 256-element hemispherical transducers of different frequency (250 and 500 kHz) with 30-cm aperture diameters. A 4-cm diameter spherical volume of in vitro blood clot was treated through 3 excised human skullcaps by electronically steering the focus with frequency proportional focal spacing: λ/2, 2 λ/3 and λ with 50 pulses per location. The pulse repetition frequency across the volume was 200 Hz, corresponding to a duty cycle of 0.08% (250 kHz) and 0.04% (500 kHz) for each focal location. Skull heating during treatment was monitored. Liquefied clot was drained via catheter and syringe in the range of 6-59 mL in 0.9-42.4 min. The fastest rate was 16.6 mL/min. The best parameter combination was λ spacing at 500 kHz, which produced large liquefaction through 3 skullcaps (23.1 ± 4.0, 37.1 ± 16.9 and 25.4 ± 16.9 mL) with the fast rates (3.2 ± 0.6, 5.1 ± 2.3 and 3.5 ± 0.4 mL/min). The temperature rise through the 3 skullcaps remained below 4°C.

Non-Invasive Thrombolysis Using Microtripsy in a Porcine Deep Vein Thrombosis Model.

Histotripsy is a non-invasive therapeutic technique that uses ultrasound generated from outside the body to create controlled cavitation in targeted tissue, and fractionates it into acellular debris. We have developed a new histotripsy approach, termed microtripsy, to improve targeting accuracy and to avoid collateral tissue damage. This in vivo study evaluates the safety and efficacy of microtripsy for non-invasive thrombolysis in a porcine deep vein thrombosis model. Acute thrombi were formed in left femoral veins of pigs (∼35 kg) by occluding the vessel using two balloon catheters and infusing with thrombin. Guided by real-time ultrasound imaging, microtripsy thrombolysis treatment was conducted in 14 pigs; 10 pigs were euthanized on the same day (acute) and 4 at 2 wk (subacute). To evaluate vessel damage, 30-min free-flow treatment in the right femoral vein (no thrombus) was also conducted in 8 acute pigs. Blood flow was successfully restored or significantly increased after treatment in 13 of the 14 pigs. The flow channels re-opened by microtripsy had a diameter up to 64% of the vessel diameter (∼6 mm). The average treatment time was 16 min per centimeter-long thrombus. Only mild intravascular hemolysis was induced during microtripsy thrombolysis. No damage was observed on vessel walls after 2 wk of recovery, venous valves were preserved, and there was no sign of pulmonary embolism. The results of this study indicate that microtripsy has the potential to be a safe and effective treatment for deep vein thrombosis in a porcine model.

Enhanced High-Rate Shockwave Lithotripsy Stone Comminution in an In Vivo Porcine Model Using Acoustic Bubble Coalescence.

Cavitation plays a significant role in the efficacy of stone comminution during shockwave lithotripsy (SWL). Although cavitation on the surface of urinary stones helps to improve fragmentation, cavitation bubbles along the propagation path may shield or block subsequent shockwaves (SWs) and potentially induce collateral tissue damage. Previous in vitro work has shown that applying low-amplitude acoustic waves after each SW can force bubbles to consolidate and enhance SWL efficacy. In this study, the feasibility of applying acoustic bubble coalescence (ABC) in vivo was tested. Model stones were percutaneously implanted and treated with 2500 lithotripsy SWs at 120 SW/minute with or without ABC. Comparing the results of stone comminution, a significant improvement was observed in the stone fragmentation process when ABC was used. Without ABC, only 25% of the mass of the stone was fragmented to particles <2 mm in size. With ABC, 75% of the mass was fragmented to particles <2 mm in size. These results suggest that ABC can reduce the shielding effect of residual bubble nuclei, resulting in a more efficient SWL treatment.

Visualizing the Histotripsy Process: Bubble Cloud-Cancer Cell Interactions in a Tissue-Mimicking Environment.

Histotripsy is a non-invasive ultrasonic ablation method that uses cavitation to mechanically fractionate tissue into acellular debris. With a sufficient number of pulses, histotripsy can completely fractionate tissue into a liquid-appearing homogenate with no cellular structures. The location, shape and size of lesion formation closely match those of the cavitation cloud. Previous work has led to the hypothesis that the rapid expansion and collapse of histotripsy bubbles fractionate tissue by inducing large stress and strain on the tissue structures immediately adjacent to the bubbles. In the work described here, the histotripsy bulk tissue fractionation process is visualized at the cellular level for the first time using a custom-built 2-MHz transducer incorporated into a microscope stage. A layer of breast cancer cells were cultured within an optically transparent fibrin-based gel phantom to mimic cells inside a 3-D extracellular matrix. To test the hypothesis, the cellular response to single and multiple histotripsy pulses was investigated using high-speed optical imaging. Bubbles were always generated in the extracellular space, and significant cell displacement/deformation was observed for cells directly adjacent to the bubble during both bubble expansion and collapse. The largest displacements were observed during collapse for cells immediately adjacent to the bubble, with cells moving more than 150-300 µm in less than 100 µs. Cells often underwent multiple large deformations (>150% strain) over multiple pulses, resulting in the bisection of cells multiple times before complete removal. To provide theoretical support to the experimental observations, a numerical simulation was conducted using a single-bubble model, which indicated that histotripsy exerts the largest strains and cell displacements in the regions immediately adjacent to the bubble. The experimental and simulation results support our hypothesis, which helps to explain the formation of the sharp lesions formed in histotripsy therapy localized to the regions directly exposed to the bubbles.