Regenerative Medicine in Orthopedic Surgery: Expanding Our Toolbox.

Regenerative medicine leverages the body's inherent regenerative capabilities to repair damaged tissues and address organ dysfunction. In orthopedics, this approach includes a variety of treatments collectively known as orthoregeneration, encompassing modalities such as prolotherapy, extracorporeal shockwave therapy, pulsed electromagnetic field therapy, therapeutic ultrasound, and photobiomodulation therapy, and orthobiologics like platelet-rich plasma and cell-based therapies. These minimally invasive techniques are becoming prominent due to their potential for fewer complications in orthopedic surgery. As regenerative medicine continues to advance, surgeons must stay informed about these developments. This paper highlights the current state of regenerative medicine in orthopedics and advocates for further clinical research to validate and expand these treatments to enhance patient outcomes.

Ultrasmall Enzyodynamic PANoptosis Nano-Inducers for Ultrasound-Amplified Hepatocellular Carcinoma Therapy and Lung Metastasis Inhibition.

Addressing the inefficiency of current therapeutic approaches for hepatocellular carcinoma is an urgent and pressing challenge. PANoptosis, a form of inflammatory programmed cell death, presents a dependable strategy for combating cancer by engaging multiple cell death pathways (apoptosis, pyroptosis, and necroptosis). In this study, an ultrasmall Bi2Sn2O7 nanozyme with ultrasound-magnified multienzyme-mimicking properties is designed and engineered as a PANoptosis inducer through destroying the mitochondrial function of tumor cells and enhancing the intracellular accumulation of toxic reactive oxygen species, finally triggering the activation of PANoptosis process. The role of PANoptosis inducer has been verified by the expression of related proteins, including cleaved Caspase 3, NLRP3, N-GSDMD, cleaved Caspase 1, p-MLKL, and RIPK3. The inclusion of external ultrasonic irradiation significantly augments the enzyodynamic therapeutic efficiency. In vitro and in vivo antineoplastic efficacy, along with inhibition of lung metastasis, validate the benefits of the Bi2Sn2O7-mediated PANoptosis pathway. This study not only elucidates the intricate mechanisms underlying Bi2Sn2O7 as a PANoptosis inducer, but also offers a novel perspective for the treatment of hepatocellular carcinoma.

The Effectiveness of Ultrasound-Guided Infiltrations Combined with Early Rehabilitation in the Management of Low Back Pain: A Retrospective Observational Study.

Background and Aims: Low back pain is a prevalent condition affecting 60-85% of individuals during their lifetime. Despite various proposed mechanisms, the etiology of low back pain remains unclear. This study aims to evaluate the effectiveness of combining ultrasound-guided infiltrations with early rehabilitation in reducing pain and improving functional limitations in patients with chronic nonspecific low back pain. Methods: A retrospective observational study was conducted, reviewing data from January to April 2024 involving 40 patients with chronic nonspecific low back pain. Each patient received two cycles of ultrasound-guided lidocaine and corticosteroid infiltrations at the level of the posterior lower iliac spine, followed by 10 rehabilitation sessions. Patients were assessed at baseline (T0), after the first treatment cycle (T1), and after the second cycle (T2) using the Oswestry Disability Index, Quebec Back Pain Disability Scale, Roland Disability Questionnaire, and Numeric Rating Scale. Results: Significant improvements were observed across all assessment scales. The ODI scores decreased from 33.5 at baseline to 3.5 after treatment (p < 0.001). Similar reductions were noted in the QBPDS (from 61.5 to 10.3), RDQ (from 18 to 3.4), and NRS (from 7.4 to 1.3). The combination of ultrasound-guided infiltrations and early rehabilitation resulted in a significant reduction in pain and disability, with the most notable improvements occurring after the second treatment cycle. Conclusions: The integration of ultrasound-guided infiltrations with early rehabilitation is highly effective in managing chronic nonspecific low back pain, significantly reducing both pain and functional limitations.

Exploring the Role of Ultrasound Therapy in Modern Dentistry: A Comprehensive Overview.

This paper explores the use of ultrasound therapy in dentistry, focusing on its working principle, various applications, advantages, limitations, precautions, contraindications, and future directions. Ultrasound therapy presents a promising non-invasive treatment modality with a wide range of applications within the field of dentistry.

Ultrasound-assisted laser therapy for selective removal of melanoma cells.

The current study explores the potential of ultrasound-assisted laser therapy (USaLT) to selectively destroy melanoma cells. The technology was tested on an ex vivo melanoma model, which was established by growing melanoma cells in chicken breast tissue. Ultrasound-only and laser-only treatments were used as control groups. USaLT was able to effectively destroy melanoma cells and selectively remove 66.41% of melanoma cells in the ex vivo tumor model when an ultrasound peak negative pressure of 2 MPa was concurrently applied with a laser fluence of 28 mJ/cm2 at 532 nm optical wavelength for 5 min. The therapeutic efficiency was further improved with the use of a higher laser fluence, and the treatment depth was improved to 3.5 mm with the use of 1,064 nm laser light at a fluence of 150 mJ/cm2. None of the laser-only and ultrasound-only treatments were able to remove any melanoma cells. The treatment outcome was validated with histological analyses and photoacoustic imaging. This study opens the possibility of USaLT for melanoma that is currently treated by laser therapy, but at a much lower laser fluence level, hence improving the safety potential of laser therapy.

Non-Invasive Ultrasound Therapy for Severe Aortic Stenosis: Early Effects on the Valve, Ventricle, and Cardiac Biomarkers (A Case Series).

Background: Transcatheter aortic valve replacement (TAVR) was developed for inoperable patients with severe aortic stenosis. However, despite TAVR advancements, some patients remain untreated due to complex comorbidities, necessitating less-invasive approaches. Non-invasive ultrasound therapy (NIUT), a new treatment modality, has the potential to address this treatment gap, delivering short ultrasound pulses that create cavitation bubble clouds, aimed at softening embedded calcification in stiffened valve tissue. Methods: In the prospective Valvosoft® Serbian first-in-human study, we assessed the safety and efficacy of NIUT and its impact on aortic valve hemodynamics, on the left ventricle, and on systemic inflammation in patients with severe symptomatic aortic stenosis not eligible for TAVR or surgery. Results: Ten patients were included. Significant improvements were observed in hemodynamic parameters from baseline to one month, including a 39% increase in the aortic valve area (from 0.5 cm2 to 0.7 cm2, p = 0.001) and a 23% decrease in the mean transvalvular gradient (from 54 mmHg to 38 mmHg, p = 0.01). Additionally, left ventricular global longitudinal strain significantly rose, while global wasted work significantly declined at one month. A dose-response relationship was observed between treatment parameters (peak acoustic power, intensity spatial-peak pulse-average, and mean acoustic energy) and hemodynamic outcomes. NIUT was safely applied, with no clinically relevant changes in high-sensitivity troponin T or C-reactive protein and with a numerical, but not statistically significant, reduction in brain natriuretic peptide (from 471 pg/mL at baseline to 251 pg/mL at one month). Conclusions: This first-in-human study demonstrates that NIUT is safe and confers statistically significant hemodynamic benefits both on the valve and ventricle.

Ultrasound therapy for pain reduction in musculoskeletal disorders: a systematic review and meta-analysis.

Background: Ultrasound therapy is a non-invasive technique used to address a variety of health issues. Objectives: This systematic review and meta-analysis aim to assess the effectiveness of ultrasound therapy in alleviating pain associated with musculoskeletal diseases. Design: This study was conducted following PRISMA guidelines, with relevant articles identified through comprehensive searches in electronic databases. Data sources and methods: We conducted searches across multiple databases, including Scopus, PubMed, MEDLINE, ProQuest, Science Direct, CINAHL, AIM, and ELDIS. Two independent reviewers screened the titles and abstracts of the retrieved articles. We included randomized controlled trials (RCTs) and observational cohort studies published between 2010 and 2023 that evaluated ultrasound therapy for knee and shoulder skeletal disorders. The selected data were analyzed qualitatively and synthesized, with the risk of bias assessed using the RoB2 tool. Results: Initially, 117 articles were reviewed using the search strategy, and 10 trials that met the inclusion criteria were identified. In seven of these studies, the primary musculoskeletal disorder was osteoarthritis, while three studies focused on shoulder pain and impingement. Most studies indicated that ultrasound therapy significantly reduced pain. The meta-analysis showed that ultrasound therapy was significantly more effective than other interventions for knee disorders (I 2 = 51%, Z = 2.65, p = 0.008). However, for shoulder disorders, both ultrasound and other intervention methods were found to be ineffective (I 2 = 93%, Z = 0.73, p = 0.46). Conclusion: The current evidence supports the effectiveness of ultrasound therapy in reducing pain and aiding rehabilitation for knee conditions. However, there are mixed results regarding its efficacy for shoulder conditions, highlighting the need for further research in this area.

Clinical recommendations for non-invasive ultrasound neuromodulation.

Non-invasive ultrasound neuromodulation has experienced exponential growth in the neuroscientific literature, recently also including clinical studies and applications. However, clinical recommendations for the secure and effective application of ultrasound neuromodulation in pathological brains are currently lacking. Here, clinical experts with neuroscientific expertise in clinical brain stimulation and ultrasound neuromodulation present initial clinical recommendations for ultrasound neuromodulation with relevance for all ultrasound neuromodulation techniques. The recommendations start with methodological safety issues focusing on technical issues to avoid harm to the brain. This is followed by clinical safety issues focusing on important factors concerning pathological situations.

Effectiveness of extracorporeal shock wave therapy on functional ability in grade IV knee osteoarthritis - a randomized controlled trial.

Extracorporeal shockwave therapy (ESWT) is a non-invasive physical therapy intervention that has emerged in the recent past to address the upswing of osteoarthritis (OA). However, insufficient evidence is present to prove the efficacy of ESWT on grade IV knee osteoarthritis (KOA). The present study aimed to examine the effects of ESWT on functional ability in patients suffering from grade IV KOA. Thirty volunteers aged 45-60 years with grade IV primary KOA diagnosed by an orthopaedic surgeon based on the Kellgren-Lawrence score participated in the study. The participants were equally and randomly divided into two groups (i.e. experimental and control), with 15 participants in each group. The participants in the control group performed conventional physiotherapy (CPT) that included ultrasound therapy, isometric quadriceps, SLR and isometric hip adductor strengthening exercises. The participants in the experimental group received ESWT in addition to CPT. Lower extremity functional scale (LEFS) score was measured before and after the four weeks of intervention. In both groups, a statistically significant (p = 0.001) improvement in LEFS was observed. In the experimental groups, it improved by 81.92% and in the control groups by 48.15%. A statistically significant (p < 0.001) difference was observed in LEFS post-intervention values between both groups. As demonstrated by our trial results, the addition of ESWT to the CPT program will yield beneficial results in ameliorating the functional disability in patients with primary KOA (grade IV). Further studies are needed to confirm and apply these findings to a larger cohort.

Sustained acoustic medicine treatment of discogenic chronic low back pain: A randomized, multisite, double-blind, placebo-controlled trial.

BACKGROUND: Sustained acoustic medicine (SAM) is a noninvasive long-term treatment that provides essential mechanical and thermal stimulus to accelerate soft tissue healing, alleviate pain, and improve physical activity. SAM increases localized deep tissue temperature, blood flow, cellular proliferation, migration, and nutrition exchange, resulting in reduced inflammation and an increased rate of tissue regeneration. OBJECTIVE: To assess the efficacy of SAM treatment of discogenic back pain in the lower spinal column to reduce pain, improve quality of life, and lower pharmacotherapy use. METHODS: Sixty-five subjects with chronic low back pain were randomly assigned to SAM (N= 33) or placebo (N= 32) groups. Subjects self-applied SAM device bilaterality on the lower lumbar region for 4 hours daily for 8 weeks and completed daily pain diaries before, during, and after treatment. Subjects recorded pain reduction using a numeric rating scale (NRS), medication use, and physical activity using the Global Rating of Change (GROC) and Oswestry Disability Index (ODI). RESULTS: SAM treatment significantly reduced chronic lower back pain from baseline relative to placebo treatment (p< 0.0001). SAM treated subjects reported significantly lower back pain at 4 weeks, with the highest pain reduction (-2.58 points NRS, p< 0.0001) reported at 8 weeks. Similar trends were observed in improved physical activity (3.48 GROC, p< 0.0001, 69-88% ODI, p< 0.0001) and 22.5% (15.2 morphine milligram equivalent) reduction in the use of opioid medication from baseline to 8 weeks. CONCLUSION: Daily, home-use SAM treatment significantly improves the clinical symptoms of chronic lower back pain, improves physical mobility, and reduces daily medication use. SAM treatment is well-tolerated by patients and may be considered a safe, non-invasive treatment option for chronic discogenic, lower back pain.

Effectiveness of Ultrasound Therapy, TheraBite Device, Masticatory Muscle Exercises, and Stabilization Splint for the Treatment of Masticatory Myofascial Pain: A Randomized Controlled Trial.

BACKGROUND: Myofascial pain syndrome (MPS) is a particular type of temporomandibular joint disorder. Research findings comparing various treatment approaches are scarce and controversial. Therefore, this study aimed to compare the effectiveness of ultrasound therapy, stabilization splint, TheraBite device, and masticatory muscle exercises in reducing pain intensity and improving mandibular mobility in patients with MPS. METHODS: It was a single-blind, randomized, parallel-group, active-controlled trial that took place between April 2023 and October 2023 at the Department of Fixed Prosthodontics, Damascus University. Patients older than 18 years old with myofascial pain accompanied by limited jaw opening and pain lasting for at least 6 months were included. Eighty patients were randomly assigned into four groups using online randomization software: ultrasound therapy, stabilization splint, TheraBite device, and masticatory muscle exercises. Only outcome assessors were masked to treatment allocation. The exercise regimen was the exercise program for patients with TMD. The following primary outcome measures were considered at the baseline (t0), at the first (t1), second (t2), and fourth (t3) week of treatment, and at the second (t4) and fifth (t5) month of follow-up: pain intensity using the visual analogue scale, maximum interincisal opening, right lateral movement, and left lateral movement measured in millimeters. RESULTS: The pain level changed from severe to mild at t3 in ultrasound therapy, stabilization splint, and TheraBite device groups. In the masticatory muscle exercises group, it changed to moderate, with a significant difference between ultrasound therapy (p = 0.012) and stabilization splint (p = 0.013) groups. In addition, the mandibular mobility continued to improve at the subsequent follow-up periods (t4 and t5). CONCLUSIONS: All therapies are equally effective after 5-month follow-up. However, ultrasound therapy and stabilization splints have the benefit of achieving rapid improvement. TRIAL REGISTRATION: ISRCTN20833186.

The impact of pulse repetition frequency on microbubble activity and drug delivery during focused ultrasound-mediated blood-brain barrier opening.

Objective.Pulsed focused ultrasound (FUS) can deliver therapeutics to the brain by using intravenous microbubbles (MBs) to open the blood-brain barrier (BBB). MB emissions indicate treatment outcomes, like BBB opening (harmonics) and damage (broadband). Typically, a pulse repetition frequency (PRF) of 1 Hz is used, but the effect of PRF on MBs is not fully understood. We investigated the effect of PRF on MB activity and tracer delivery.Approach.The effect of PRF (0.125, 0.25, 0.5, 1, and 2 Hz) on MB activity was monitored through harmonic and wideband emissions during FUS sonications of the rat brain at 274.3 kHz. BBB opening was quantified through fluorescence imaging to estimate the concentration of Trypan Blue (TB) dye following a 75-pulse FUS exposure for PRFs of 1 and 0.25 Hz.Main results.At a fixed acoustic pressure, the percentage change in maximum harmonic amplitude compared to the control (PRF = 1 Hz) decreased with increasing PRF, with a median change of 73.8% at 0.125 Hz and -38.3% at 2 Hz. There was no difference in the pressure threshold for broadband emissions between PRFs of 0.25 and 1 Hz. PRF = 0.25 Hz, led to a 68.2% increase in the mean concentration of TB measured after FUS, with a 53.9% increase in the mean harmonic sum, compared with PRF = 1 Hz. Harmonic emissions-based control at PRF = 0.25 Hz yielded similar TB delivery, with less damage at histology, compared with 1 Hz.Significance.For a fixed number of FUS pulses, reducing the PRF was shown to increase the magnitude of harmonic emissions and TB delivery, but not the threshold for broadband emissions. While further research is necessary to understand the mechanisms involved, these results may be useful to improve clinical safety margins and sensitivity to detecting small harmonic signals from cavitating MBs.

Efficacy of ultrasound therapy with neck retraction exercises vs. ultrasound therapy with deep cervical flexor training for excessive screen time users: a pilot randomized controlled study.

[Purpose] To compare the effectiveness of ultrasound therapy in combination with neck retraction exercises and deep cervical flexor training on pain, forward head posture, and deep cervical flexor muscle strength in excessive screen time users. [Participants and Methods] This 4-week intervention study included 36 participants with forward head posture, categorized into three groups: 1) ultrasound therapy with neck retraction exercises 2) ultrasound therapy with deep cervical flexor training, and 3) a control group. The outcomes were pain, forward head posture, and strength of the deep cervical flexor muscles. [Results] The strength of the deep cervical flexor muscles exhibited a notable increase, indicating a relatively higher mean value in the first intervention group. Upon follow-up, significant changes in all outcomes were observed between the first intervention group and the control group. Also, significant differences were revealed in the deep cervical flexor muscles between the second intervention group and the control group. [Conclusion] Ultrasound therapy with neck retraction exercises could have a more positive effect on pain, forward head posture, and strength of the deep cervical flexor muscles in comparison to ultrasound therapy with deep cervical flexor training for excessive screen time users.

A pilot study exploring the use of hyaluronic acid in treating insertional achilles tendinopathy.

PURPOSE: This study explores the use of ultrasound-guided Hyaluronic Acid (HA) injections for Insertional Achilles Tendinopathy (IAT). METHODS: A cohort of 15 ankles diagnosed with IAT received three weekly ultrasound-guided HA injections. The Victorian Institute of Sport Assessment - Achilles (VISA-A) questionnaire scored the severity of symptoms and functional impairment before treatment, and at one and six months post-treatment. RESULTS: Significant improvement was observed in VISA-A scores post-treatment, rising from an average baseline of 34.8 ± 15.2 (11-63) to 53.6 ± 20.9 (15-77) after one month, and then to 50.7 ± 18.6 (20-75) after six months. No adverse reactions were noted, underscoring the safety of the intervention. CONCLUSION: The pilot study presents HA injections as a potentially effective treatment for IAT, while interpretation of these findings must take into account the variability in results, indicating a range of patient responses. It encourages further research to confirm these findings and to explore HA's full potential in managing IAT, despite the limitations of a small sample size and lack of control group.

Comparison of the clinical effectiveness of Class IV Laser therapy and therapeutic ultrasound in patients with chronic neck pain: a randomized controlled trial / Comparação da eficácia clínica da terapia a laser Classe IV e do ultrassom terapêutico em pacientes com dor cervical crônica: um estudo controlado e randomizado

INTRODUCTION: Chronic neck pain (CNP) is a common musculoskeletal problem that affects a large proportion of the population and lasts longer than three months. It has a high cost in terms of life, disability, and healthcare. Several modalities have effectively provided immediate and long-term relief for CNP; however, the comparative clinical effectiveness of these modalities is limited. OBJECTIVES: The study aimed to determine the clinical effectiveness of Class IV Laser therapy and Therapeutic Ultrasound (TUS) in patients with CNP. METHODS AND MATERIALS: Forty-four patients with CNP of both genders were recruited from an age range of 20­45 years from the Department of Musculoskeletal Physiotherapy of Maharishi Markandeshwar Institute of Physiotherapy, MM(DU), Ambala, India. They were divided into two groups at random: the LASER group A (n = 22) and the TUS group B (n = 22). The intervention duration was 2 weeks with 6 treatment sessions. Pre- and post-treatment outcome measures were assessed with the Visual Analog Scale (VAS), Algometer, Goniometer, and Neck Disability Index (NDI) questionnaires at baseline and after 2 weeks of intervention. The LASER group received a target dose of 10 joules per cm2 at a power of 10 watts, with a continuous dosage frequency. The TUS group underwent a continuous mode ultrasound (3 MHz, 1 W/cm2) for 6 minutes. The Shapiro-Wilk test was used to assess the normality of the data. For parametric and non-parametric data analysis within the group, the paired t-test and Wilcoxon signed rank were used. The independente t-test and Mann-U Whitney test were used for the group comparison of parametric and non-parametric data, respectively. RESULTS: In both groups, there was a significant improvement in all the outcome measures (p<0.001). There was a statistically significant difference between the two interventions in VAS, Pain Pressure Threshold (PPT), and NDI (p<0.05). CONCLUSION: Class IV Laser therapy is clinically more effective than therapeutic ultrasound in treating patients with chronic neck pain.

INTRODUÇÃO: A dor cervical crônica (DCC) é um problema musculoesquelético comum que afeta uma grande proporção da população e dura mais de três meses. Ela tem um alto custo em termos de vida, incapacidade e assistência médica. Várias modalidades têm proporcionado alívio imediato e de longo prazo para a dor cervical crônica; entretanto, a eficácia clínica comparativa dessas modalidades é limitada. OBJETIVOS: O objetivo do estudo foi determinar a eficácia clínica da terapia a laser de classe IV e do ultrassom terapêutico (UST) em pacientes com DCC. MÉTODOS E MATERIAIS: Quarenta e quatro pacientes com DCC de ambos os sexos, em uma faixa etária de 20 a 45 anos, foram recrutados do Departamento de fisioterapia musculoesquelética do Instituto de Fisioterapia Maharishi Markandeshwar, MM (DU), Ambala, Índia. Eles foram divididos em dois grupos de forma aleatória: o grupo LASER A (n = 22) e o grupo UST B (n = 22). A duração da intervenção foi de 2 semanas com 6 sessões de tratamento. As medidas de resultado pré e pós-tratamento foram avaliadas com os questionários Escala Visual Analógica (EVA), Algometer, Goniometer e Índice de Incapacidade do Pescoço (IIP) na linha de base e após 2 semanas de intervenção. O grupo LASER recebeu dose alvo de 10 joules por cm2 na potência de 10 watts, com frequência de dosagem contínua. O grupo UST foi submetido a ultrassom em modo contínuo (3 MHz, 1 W/cm2) por 6 minutos. O teste de Shapiro-Wilk foi utilizado para avaliar a normalidade dos dados. Para análise dos dados paramétricos e não paramétricos dentro do grupo, foram utilizados o teste t pareado e o posto sinalizado de Wilcoxon. O teste t independente e o teste Mann-U Whitney foram utilizados para comparação de grupos para dados paramétricos e não paramétricos, respectivamente. RESULTADOS: Em ambos os grupos, houve uma melhora significativa em todas as medidas de resultado (p<0,001). Houve uma diferença estatisticamente significativa entre as duas intervenções na EVA, Limiar de pressão de dor (PPT) e IIP (p<0,05). CONCLUSÕES: A terapia a laser de classe IV é clinicamente mais eficaz do que o ultrassom terapêutico no tratamento de pacientes com dor cervical crônica.

Effects of transcutaneous radiofrequency diathermy versus ultrasound on latent myofascial trigger points in the upper trapezius: A randomized crossover trial.

BACKGROUND: Currently, the use of radiofrequency diathermy for the treatment of neck pain is booming. OBJECTIVE: This study aimed to evaluate the clinical efficacy of Digital Capacitive Diathermy (DCD®) on stiffness, pain, cervical range of motion, and cervical disability and to compare it with ultrasound (US) in patients with latent myofascial trigger point (MTrP) in the upper trapezius. METHODS: Nineteen participants with latent MTrPs in the upper trapezius were included in the assessor-masked, randomized, clinical crossover trial. Subjects were exposed to both interventions: US and DCD® and treatment effectiveness was measured by myotonometric variables, pressure pain threshold (PPT), visual analog scale (VAS), cervical side-bending flexion ranges, and the neck disability index scale (NDI). RESULTS: There were no significant differences between US and DCD® interventions regarding changes in outcome measures. The US group achieved a statistically significant difference of 2.16 to 1.13 points (p= 0.005; r= 0.646) for the VAS. The DCD® intervention showed a statistically significant improvement of 1.11 points for the NDI at 1-week following intervention (95% CI 0.14-2.07; p= 0.27; d= 0.217). CONCLUSION: Our findings suggest that DCD® and US can both be considered effective modalities for the treatment of latent MTrPs, having a longer duration of action with DCD® therapy.

Focal high-intensity focused ultrasound therapy for localized prostate cancer: An interim analysis of the multinational FASST study.

BACKGROUND: High-intensity focused ultrasound (HIFU) emerged as a novel approach for the treatment of localized prostate cancer (PCa). However, prospective studies on HIFU-related outcomes and predictors of treatment failure (TF) remain scarce. MATERIALS AND METHODS: We conducted a multinational prospective cohort study among patients undergoing HIFU therapy for localized, low- to intermediate-risk PCa. Follow-up data on serial prostate specific antigen (PSA), multi-parametric magnetic resonance imaging (mpMRI), targeted/systematic biopsies, adverse events and functional outcomes were collected. The primary endpoint was TF, defined as histologically confirmed PCa requiring whole-gland salvage treatment. Uni- and multi-variable adjusted hazard ratios (HRs) were calculated using Cox proportional hazard regression models. RESULTS: At baseline, mean (standard deviation) age was 64.14 (7.19) years, with the majority of patients showing T-stage 1 (73.9%) and International Society of Urological Pathology grading system Grade 2 (58.8%). PSA nadir (median, 1.70 ng/mL) was reached after 6 months. Of all patients recruited, 16% had clinically significant PCa, as confirmed by biopsy, of which 13.4% had TF. Notably, T-stage and number of positive cores at initial biopsy were independent predictors of TF during follow-up (HR [95% CI] 1.27 [1.02-1.59] and 5.02 [1.80-14.03], respectively). Adverse events were minimal (17% and 8% early and late adverse events, respectively), with stable or improved functional outcomes in the majority of patients. CONCLUSIONS: This interim analysis of a multinational study on HIFU therapy for the management of low-to-intermediate-risk PCa reveals good functional outcomes, minimal adverse events and low incidence of TF over the short-term. Data on long-term outcomes, specifically as it relates to oncological outcomes, are awaited eagerly.

Optimization of 3D Passive Acoustic Mapping Image Metrics: Impact of Sensor Geometry and Beamforming Approach.

Three-dimensional passive acoustic mapping (PAM) with matrix arrays typically suffers from high demands on the receiving electronics and high computational load. In our study, we investigated, both numerically and experimentally, the influence of matrix array aperture size, element count, and beamforming approaches on defined image metrics. With a numerical Vokurka model, matrix array acquisitions of cavitation signals were simulated. In the experimental part, two 32 × 32 matrix arrays with different pitches and aperture sizes were used. After being reconstructed into 3D cavitation maps, defined metrics were calculated for a quantitative comparison of experimental and numerical data. The numerical results showed that the enlargement of the aperture from 5 to 40 mm resulted in an improvement of the full width at half maximum (FWHM) by factors of 6 and 13 (in lateral and axial dimension, respectively). A larger array sparsity influenced the point spread function (PSF) only slightly, while the grating lobe level (GLL) remained more than 12 dB below the main lobe. These results were successfully experimentally confirmed. To further reduce the GLL caused by array sparsity, we adapted a non-linear filter from optoacoustics for use in PAM. In combination with the delay, multiply, sum, and integrate (DMSAI) algorithm, the GLL was decreased by 20 dB for 64-element reconstructions, resulting in levels that were identical to the fully populated matrix reconstruction levels.

Alzheimer's disease brain endothelial-like cells reveal differential drug transporter expression and modulation by potentially therapeutic focused ultrasound.

The blood-brain barrier (BBB) has a key function in maintaining homeostasis in the brain, partly modulated by transporters, which are highly expressed in brain endothelial cells (BECs). Transporters mediate the uptake or efflux of compounds to and from the brain and they can also challenge the delivery of drugs for the treatment of Alzheimer's disease (AD). Currently there is a limited understanding of changes in BBB transporters in AD. To investigate this, we generated brain endothelial-like cells (iBECs) from induced pluripotent stem cells (iPSCs) with familial AD (FAD) Presenilin 1 (PSEN1) mutation and identified AD-specific differences in transporter expression compared to control (ctrl) iBECs. We first characterized the expression levels of 12 BBB transporters in AD-, Ctrl-, and isogenic (PSEN1 corrected) iBECs to identify any AD specific differences. We then exposed the cells to focused ultrasound (FUS) in the absence (FUSonly) or presence of microbubbles (MB) (FUS+MB), which is a novel therapeutic method that can be used to transiently open the BBB to increase drug delivery into the brain, however its effects on BBB transporter expression are largely unknown. Following FUSonly and FUS+MB, we investigated whether the expression or activity of key transporters could be modulated. Our findings demonstrate that PSEN1 mutant FAD (PSEN1AD) possess phenotypical differences compared to control iBECs in BBB transporter expression and function. Additionally, we show that FUSonly and FUS+MB can modulate BBB transporter expression and functional activity in iBECs, having potential implications on drug penetration and amyloid clearance. These findings highlight the differential responses of patient cells to FUS treatment, with patient-derived models likely providing an important tool for modelling therapeutic effects of FUS.