Can Mn:PIN-PMN-PT piezocrystal replace hard piezoceramic in power ultrasonic devices?

Mn:PIN-PMN-PT piezocrystal is investigated to determine whether its enhanced energy density makes it a candidate transducer material for power ultrasonics applications. To this end, the electromechanical and vibrational characteristics of a simple configuration of a bolted Langevin transducer (BLT) and then an ultrasonic surgical device, both incorporating Mn:PIN-PMN-PT piezocrystal, are compared with the same transducer configurations incorporating a conventional hard PZT piezoceramic commonly used in high-power ultrasonic transducers. The material properties of Mn:PIN-PMN-PT are determined using a single sample characterisation technique and these are used in finite element analysis (FEA) to design and then fabricate the BLT and ultrasonic surgical device, tuned to the first and second longitudinal modes at 20 kHz respectively. FEA is similarly used for the hard PZT versions. It is found that the superior elastic compliance of Mn:PIN-PMN-PT results in a higher radial piezo-stack deformation than the hard PZT under ultrasonic excitation of the BLT. However, the resulting longitudinal displacement amplitude of the two BLTs and two ultrasonic surgical devices is found to be equal, despite the higher figure of merit (Qkeff2) of those incorporating Mn:PIN-PMN-PT. The electrical impedance is measured at increasing excitation levels to evaluate the quality factor, Q. It is found that damping in the BLT with hard PZT is negligibly affected in the excitation range considered; however, the BLT incorporating Mn:PIN-PMN-PT exhibits a large reduction in Q. These findings indicate that, for measurements in air, the advantages of the high figure of merit of the piezocrystal material are not realised in a high-power transducer due to significantly increased damping at high excitation levels. To compare the vibrational response of the two ultrasonic surgical devices, L-C electrical impedance matching was implemented to maximise the efficiency of energy transfer from the source to the transducer under load. Results suggest that similar responses occurred for the two surgical devices in cutting tests using a low strength bone mimic material. However, the Mn:PIN-PMN-PT device exhibited better performance in cutting through higher strength ex-vivo chicken femur.

Rapid Emergence and Evolution of SARS-CoV-2 Variants in Advanced HIV Infection.

Previous studies have linked the evolution of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) genetic variants to persistent infections in people with immunocompromising conditions1-4, but the evolutionary processes underlying these observations are incompletely understood. Here we used high-throughput, single-genome amplification and sequencing (HT-SGS) to obtain up to ~103 SARS-CoV-2 spike gene sequences in each of 184 respiratory samples from 22 people with HIV (PWH) and 25 people without HIV (PWOH). Twelve of 22 PWH had advanced HIV infection, defined by peripheral blood CD4 T cell counts (i.e., CD4 counts) <200 cells/µL. In PWOH and PWH with CD4 counts ≥200 cells/µL, most single-genome spike sequences in each person matched one haplotype that predominated throughout the infection. By contrast, people with advanced HIV showed elevated intra-host spike diversity with a median of 46 haplotypes per person (IQR 14-114). Higher intra-host spike diversity immediately after COVID-19 symptom onset predicted longer SARS-CoV-2 RNA shedding among PWH, and intra-host spike diversity at this timepoint was significantly higher in people with advanced HIV than in PWOH. Composition of spike sequence populations in people with advanced HIV fluctuated rapidly over time, with founder sequences often replaced by groups of new haplotypes. These population-level changes were associated with a high total burden of intra-host mutations and positive selection at functionally important residues. In several cases, delayed emergence of detectable serum binding to spike was associated with positive selection for presumptive antibody-escape mutations. Taken together, our findings show remarkable intra-host genetic diversity of SARS-CoV-2 in advanced HIV infection and suggest that adaptive intra-host SARS-CoV-2 evolution in this setting may contribute to the emergence of new variants of concern (VOCs).

Effect of longitudinal-bending elliptical ultrasonic vibration assistance on electrosurgical cutting and hemostasis.

Electrosurgical devices are widely used for tissue cutting and hemostasis in minimally invasive surgery (MIS) for their high precision and low trauma. However, tissue adhesion and the resulting thermal injury can cause infection and impede the wound-healing process. This paper proposes a longitudinal-bending elliptical ultrasonic vibration-assisted (EUV-A) electrosurgical cutting system that incorporates an ultrasonic vibration in the direction of the cut by introducing an elliptical motion of the surgical tip. Compared with a solely longitudinal ultrasonic vibration-assisted (UV-A) electrosurgical device, the EUV-A electrode contacts the tissue intermittently, thus allowing for a cooler cut and preventing tissue accumulation. The experimental results reveal that the EUV-A electrode demonstrates better performance than the UV-A electrode for both anti-adhesion and thermal injury through in vitro experiments in porcine samples. The tissue removal mechanism of EUV-A electrosurgical cutting is modeled to investigate its anti-adhesion effect. In addition, lower adhesion, lower temperature, and faster cutting are demonstrated through in vivo experiments in rabbit samples. Results show that the EUV-A electrode causes lower thermal injury, indicative of faster postoperative healing. Finally, efficacy of the hemostatic effect of the EUV-A electrode is demonstrated in vivo for vessels up to 3.5 mm (equivalent to that of electrocautery). The study reveals that the EUV-A electrosurgical cutting system can achieve safe tissue incision and hemostasis.

Traditional Multiwell Plates and Petri Dishes Limit the Evaluation of the Effects of Ultrasound on Cells In Vitro.

Ultrasound accelerates healing in fractured bone; however, the mechanisms responsible are poorly understood. Experimental setups and ultrasound exposures vary or are not adequately characterized across studies, resulting in inter-study variation and difficulty in concluding biological effects. This study investigated experimental variability introduced through the cell culture platform used. Continuous wave ultrasound (45 kHz; 10, 25 or 75 mW/cm2, 5 min/d) was applied, using a Duoson device, to Saos-2 cells seeded in multiwell plates or Petri dishes. Pressure field and vibration quantification and finite-element modelling suggested formation of complex interference patterns, resulting in localized displacement and velocity gradients, more pronounced in multiwell plates. Cell experiments revealed lower metabolic activities in both culture platforms at higher ultrasound intensities and absence of mineralization in certain regions of multiwell plates but not in Petri dishes. Thus, the same transducer produced variable results in different cell culture platforms. Analysis on Petri dishes further revealed that higher intensities reduced vinculin expression and distorted cell morphology, while causing mitochondrial and endoplasmic reticulum damage and accumulation of cells in sub-G1 phase, leading to cell death. More defined experimental setups and reproducible ultrasound exposure systems are required to study the real effect of ultrasound on cells for development of effective ultrasound-based therapies not just limited to bone repair and regeneration.

A longitudinal-torsional mode ultrasonic needle for deep penetration into bone.

This work presents a longitudinal-torsional (L-T) composite mode ultrasonic needle device for deep bone penetration. The L-T needle is a geometrically modified version of an L-mode needle whose efficacy as a prototype ultrasonic bone biopsy device has been previously demonstrated by the authors. Finite element analysis (FEA) aided in the design of the L-T needle, with the aim of maximising the achievable torsional displacement while matching the longitudinal displacement achieved by the L-mode needle. Experimental modal analysis (EMA) of the fabricated ultrasonic device was used to identify the modal parameters and validate the FEA model. Harmonic analysis then provided an insight into how the inherent nonlinearities of the high-power transducer are affected by incorporating the geometrical features that degenerate the L mode into an L-T mode. High power characterisation shows that the longitudinal displacement amplitude of the L-T mode needle is larger than that of the L-mode needle. Comparative penetration tests in fresh Wistar rat skull were evaluated by investigating cell death and cell survival. The region of statistically significant cell death was small for both devices, with the combined axial and shear motion of the L-T device causing increased osteocyte necrosis within this region. Nevertheless, the results suggest a promising environment for post-operative healing. It is shown how this technology offers a potential technique for a surgical approach to the petrous apex, an application that requires a deep penetration into bone.

Incorporating direct metal laser sintered complex shaped Ti-6Al-4V components in ultrasonic surgical devices.

Additive manufacturing (AM) offers opportunities to design more complex shapes of the Ti-6Al-4V parts commonly used in high-power ultrasonic surgical devices. Moreover, AM metal printing will be essential to the realization of miniature ultrasonic devices incorporating internal structures for minimally invasive surgical procedures. However, it is necessary first to verify the ultrasonic vibrational behavior of devices with three-dimensional (3D) printed metal parts. Therefore, two different prototype devices are fabricated, with CNC machined mill annealed and 3D printed Ti-6Al-4V parts. Both devices, an ultrasonic bone needle and a miniature ultrasonic scalpel, incorporate complex geometries but can be manufactured using subtractive processes so that the comparative effects of 3D printing on the vibrational performance of the devices can be elucidated. The metal microstructure is investigated through measurements of longitudinal and shear acoustic velocities and scanning electron microscopy. Comparisons of electrical impedance, frequency and modal responses, and the vibrational response at increasing levels of excitation enable evaluation of the efficacy of incorporating 3D printed Ti-6Al-4V parts. Results show that whereas the bone needle exhibited comparable vibrational responses for the measurement techniques used, the 3D printed bone cutting device exhibited a more dense modal response and developed cracks at high excitation levels.

Limits and Opportunities for Miniaturizing Ultrasonic Surgical Devices Based on a Langevin Transducer.

Minimally invasive surgery offers opportunities for reduced morbidities, faster postoperative recovery, and reduced costs, and is a major focus of surgical device innovation. For ultrasonic surgical devices, which offer benefits of high precision, low force, and tissue selectivity in surgical procedures, there exist laparoscopic ultrasonic shears for minimally invasive surgeries that combine tissue cutting with vessel hemostasis and sealing functions. Another approach to laparoscopy that could enable new procedures, and increase the sites of surgeries that could be reached by an ultrasonic device, involves integrating a miniature ultrasonic tool with a flexible surgical robot. However, miniaturization presents challenges in delivering the ultrasonic vibrational energy required to cut hard and soft tissues, partly due to the concomitant small volume of piezoelectric material. This article aims to provide insights into the trade-offs between transducer size, volume of piezoceramic material, resonance frequency, and the achievable displacement amplitude of devices that, consistent with current ultrasonic surgical tools, are based on a bolted Langevin transducer (BLT) and tip. Different configurations of BLTs are studied, including a cascaded version, simple bar versions, and BLTs with different front mass geometries. Results show that a BLT with a larger number of piezoceramic rings exhibits a higher coupling coefficient [Formula: see text] but with the compromise of a lower mechanical Q and stronger nonlinear response at increasing excitation levels. Displacement amplitude is reduced considerably when a BLT is excited at a higher harmonic, where the PZT rings are maintained at a nodal plane, and the resonance frequency shift at increasing excitation levels increases significantly. The electromechanical and dynamic characteristics of a cascaded transducer excited in its third longitudinal mode (L3) are almost equivalent to a much shorter version of a BLT driven at the same frequency but in its first longitudinal mode (L1), showing that a cascaded BLT can be a realistic proxy for studying the dynamics of small BLT devices. A new figure of merit is proposed that is the product of Q , [Formula: see text], and gain, which [Formula: see text] accounts for the gain of cylindrical BLTs which is shown not to be unity. It also proves effective as it incorporates the key factors affecting the achievable displacement amplitude of a BLT, including for BLTs with gain profiles in the front mass. The order of highest to lowest amplitude of a series of six gain-profile BLTs matches the order estimated by the figure of merit. It is shown that a BLT with a stepped profile front mass can achieve displacement that has the potential to cut hard or soft tissue and exhibits the smallest shifts in resonance frequency at increasing excitation levels.

Safety of venetoclax rapid dose escalation in CLL patients previously treated with B-cell receptor signaling antagonists.

Venetoclax has efficacy in patients relapsing after B-cell receptor pathway inhibitors (BCRis); however, because of the risk of tumor lysis syndrome (TLS), a 5-week dose ramp-up is required to attain the target dose. Patients relapsing after BCRis frequently have proliferative disease, requiring a faster time to target dose than this scheme allows. This limitation can potentially be overcome with rapid dose escalation (RDE). We analyzed 33 chronic lymphocytic leukemia patients who underwent venetoclax RDE after prior BTKi treatment. Median time to target dose was 9 days. Seventeen patients (52%) developed laboratory TLS, and 5 (15%) developed clinical TLS, all as a result of renal injury. TLS was seen in more patients with a higher initial tumor burden. TLS occurred at all dose levels, with most episodes occurring at the 50- and 100-mg doses. Most interestingly, a decrease in absolute lymphocyte count (ALC) from pre-venetoclax dose to 24 hours post-venetoclax dose of 10 × 103/µL was associated with an increased risk of TLS (hazard ratio, 1.32; P = .02), after controlling for venetoclax dose level. Venetoclax RDE with close in-hospital monitoring at experienced centers and in select patients is feasible. The rapidity with which ALC drops helps predict TLS and could help guide dose-escalation decisions.

Phase II Study of Combination Obinutuzumab, Ibrutinib, and Venetoclax in Treatment-Naïve and Relapsed or Refractory Chronic Lymphocytic Leukemia.

PURPOSE: The development of highly effective targeted agents for chronic lymphocytic leukemia offers the potential for fixed-duration combinations that achieve deep remissions without cytotoxic chemotherapy. PATIENTS AND METHODS: This phase II study tested a combination regimen of obinutuzumab, ibrutinib, and venetoclax for a total of 14 cycles in both patients with treatment-naïve (n = 25) and relapsed or refractory (n = 25) chronic lymphocytic leukemia to determine the response to therapy and safety. RESULTS: The primary end point was the rate of complete remission with undetectable minimal residual disease by flow cytometry in both the blood and bone marrow 2 months after completion of treatment, which was 28% in both groups. The overall response rate at that time was 84% in treatment-naïve patients and 88% in relapsed or refractory patients. At that time, 67% of treatment-naïve patients and 50% of relapsed or refractory patients had undetectable minimal residual disease in both the blood and marrow. At a median follow-up of 24.2 months in treatment-naïve patients and 21.5 months in relapsed or refractory patients, the median progression-free and overall survival times were not yet reached, with only 1 patient experiencing progression and 1 death. Neutropenia and thrombocytopenia were the most frequent adverse events, followed by hypertension. Grade 3 or 4 neutropenia was experienced by 66% of patients, with more events in the relapsed or refractory cohort. There was only 1 episode of neutropenic fever. A favorable impact on both perceived and objective cognitive performance during treatment was observed. CONCLUSION: The combination regimen of obinutuzumab, ibrutinib, and venetoclax offers time-limited treatment that results in deep remissions and is now being studied in phase III cooperative group trials.

Full and Half-Wavelength Ultrasonic Percussive Drills.

Ultrasonic percussive drills are a leading technology for small rock drilling applications where power and weight-on-bit are at a premium. The concept uses ultrasonic vibrations to excite an oscillatory motion in a free-mass, which then delivers impulsive blows to a drilling-bit. This is a relatively complex dynamic problem involving the transducer, the free-mass, the drilling-bit and, to a certain extent, the rock surface itself. This paper examines the performance of a full-wavelength transducer compared to a half-wavelength system, which may be more attractive due to mass and dimensional drivers. To compare the two approaches, 3-D finite-element models of the ultrasonic percussive stacks using full and half-wavelength ultrasonic transducers are created to assess delivered impulse at similar power settings. In addition, impact-induced stress levels are evaluated to optimize the design of drill tools at a range of internal spring rates before, finally, experimental drilling is conducted. The results suggest that full-wavelength systems will yield much more effective impulse but, interestingly, their actual drilling performance was only marginally better than half-wavelength equivalents.

Phase 1b study of obinutuzumab, ibrutinib, and venetoclax in relapsed and refractory chronic lymphocytic leukemia.

Targeted therapies including the engineered afucosylated anti-CD20 monoclonal antibody obinutuzumab, Bruton's tyrosine kinase inhibitor ibrutinib, and B-cell lymphoma protein 2 inhibitor venetoclax have demonstrated significant clinical activity in chronic lymphocytic leukemia (CLL) and, based on their complementary mechanisms, are ideal for combination. However, combining venetoclax with other active agents raises safety concerns, as it may increase the risk for tumor lysis syndrome. To minimize this risk, we designed and implemented a fixed-duration regimen using sequentially administered obinutuzumab followed by ibrutinib (cycle 2) and venetoclax (cycle 3), for a total of fourteen 28-day cycles. This phase 1b study included 12 patients with relapsed or refractory CLL. We tested 3 dose levels of venetoclax and identified the doses of all 3 agents approved by the US Food and Drug Administration for use in the combination. Adverse events were consistent with known toxicities of the individual agents, with hematologic adverse events being most frequent. No clinically significant tumor lysis syndrome occurred. The overall response rate was 92% (95% confidence interval, 62%-100%), with 42% (5/12) achieving a complete remission or complete remission with incomplete marrow recovery. There were 6 patients with no detectable CLL in both the blood and bone marrow at the end of treatment. We found this regimen to be safe and tolerable in CLL, and capable of inducing deep responses, justifying future study in our ongoing phase 2 cohorts of relapsed or refractory and treatment-naive patients, as well as larger phase 3 trials currently in planning. This trial was registered at www.clinicaltrials.gov as #NCT02427451.

A Comparison of Two Configurations for a Dual-Resonance Cymbal Transducer.

The ability to design tuned ultrasonic devices that can be operated in the same mode at two different frequencies has the potential to benefit a range of applications, such as surgical cutting procedures where the penetration through soft then hard tissues could be enhanced by switching the operating frequency. The cymbal transducer has recently been adapted to form a prototype ultrasonic surgical cutting device that operates at a single frequency. In this paper, two different methods of configuring a dual-resonance cymbal transducer are detailed. The first approach relies on transducer fabrication using different metals for the two endcaps, thereby forming a dual-resonance transducer. The second employs transducer endcaps composed from a shape memory alloy, superelastic Nitinol. The resonance frequency of the Nitinol transducer depends on the phase microstructure of the material, switchable through the temperature or stress dependence of the Nitinol endcaps. The vibration response of each transducer is measured through electrical impedance measurements and laser Doppler vibrometry, and finite-element analysis is used to show the sensitivity of transducer modal response to the fabrication processes. Through this paper, two viable dual-resonance cymbal transducers are designed and characterized and compared to illustrate the advantages and disadvantages of the two different approaches.

BTKC481S-Mediated Resistance to Ibrutinib in Chronic Lymphocytic Leukemia.

Purpose Therapeutic targeting of Bruton tyrosine kinase (BTK) with ibrutinib in chronic lymphocytic leukemia has led to a paradigm shift in therapy, and relapse has been uncommon with current follow-up. Acquired mutations in BTK and PLCG2 can cause relapse, but data regarding the prevalence and natural history of these mutations are limited. Patients and Methods Patients accrued to four sequential studies of ibrutinib were included in these analyses. Deep sequencing for BTK and PLCG2 was performed retrospectively on patients who experienced relapse and prospectively on a screening population. Results With a median follow-up time of 3.4 years, the estimated cumulative incidence of progression at 4 years is 19% (95% CI, 14% to 24%). Baseline karyotypic complexity, presence of del(17)(p13.1), and age less than 65 years were risk factors for progression. Among patients who experienced relapse, acquired mutations of BTK or PLCG2 were found in 85% (95% CI, 71% to 94%), and these mutations were detected an estimated median of 9.3 months (95% CI, 7.6 to 11.7 months) before relapse. Of a group of 112 patients examined prospectively, eight patients have experienced relapse, and all of these patients had acquired resistance mutations before relapse. A resistance mutation was detected in an additional eight patients who have not yet met criteria for clinical relapse. Conclusion Relapse of chronic lymphocytic leukemia after ibrutinib is an issue of increasing clinical significance. We show that mutations in BTK and PLCG2 appear early and have the potential to be used as a biomarker for future relapse, suggesting an opportunity for intervention.

Ultrasonic compaction of granular geological materials.

It has been shown that the compaction of granular materials for applications such as pharmaceutical tableting and plastic moulding can be enhanced by ultrasonic vibration of the compaction die. Ultrasonic vibrations can reduce the compaction pressure and increase particle fusion, leading to higher strength products. In this paper, the potential benefits of ultrasonics in the compaction of geological granular materials in downhole applications are explored, to gain insight into the effects of ultrasonic vibrations on compaction of different materials commonly encountered in sub-sea drilling. Ultrasonic vibrations are applied, using a resonant 20kHz compactor, to the compaction of loose sand and drill waste cuttings derived from oolitic limestone, clean quartz sandstone, and slate-phyllite. For each material, a higher strain for a given compaction pressure was achieved, with higher sample density compared to that in the case of an absence of ultrasonics. The relationships between the operational parameters of ultrasonic vibration amplitude and true strain rate are explored and shown to be dependent on the physical characteristics of the compacting materials.

Ultrasonic Needles for Bone Biopsy.

Bone biopsy is an invasive clinical procedure, where a bone sample is recovered for analysis during the diagnosis of a medical condition. When the architecture of the bone tissue is required to be preserved, a core-needle biopsy is taken. Although this procedure is performed while the patient is under local anaesthesia, the patient can still experience significant discomfort. Additionally, large haematoma can be induced in the soft tissue surrounding the biopsy site due to the large axial and rotational forces, which are applied through the needle to penetrate bone. It is well documented that power ultrasonic surgical devices offer the advantages of low cutting force, high accuracy, and preservation of soft tissues. This paper reports a study of the design, analysis, and test of two novel power ultrasonic needles for bone biopsy that operate using different configurations to penetrate bone. The first utilizes micrometric vibrations generated at the distil tip of a full-wavelength resonant ultrasonic device, while the second utilizes an ultrasonic-sonic approach, where vibrational energy generated by a resonant ultrasonic horn is transferred to a needle via the chaotic motion of a free-mass. It is shown that the dynamic behavior of the devices identified through experimental techniques closely match the behavior calculated through numerical and finite-element analysis methods, demonstrating that they are effective design tools for these devices. Both devices were able to recover trabecular bone from the metaphysis of an ovine femur, and the biopsy samples were found to be comparable to a sample extracted using a conventional biopsy needle. Furthermore, the resonant needle device was also able to extract a cortical bone sample from the central diaphysis, which is the strongest part of the bone, and the biopsy was found to be superior to the sample recovered by a conventional bone biopsy needle.

A Parametric Study for the Design of an Optimized Ultrasonic Percussive Planetary Drill Tool.

Traditional rotary drilling for planetary rock sampling, in situ analysis, and sample return are challenging because the axial force and holding torque requirements are not necessarily compatible with lightweight spacecraft architectures in low-gravity environments. This paper seeks to optimize an ultrasonic percussive drill tool to achieve rock penetration with lower reacted force requirements, with a strategic view toward building an ultrasonic planetary core drill (UPCD) device. The UPCD is a descendant of the ultrasonic/sonic driller/corer technique. In these concepts, a transducer and horn (typically resonant at around 20 kHz) are used to excite a toroidal free mass that oscillates chaotically between the horn tip and drill base at lower frequencies (generally between 10 Hz and 1 kHz). This creates a series of stress pulses that is transferred through the drill bit to the rock surface, and while the stress at the drill-bit tip/rock interface exceeds the compressive strength of the rock, it causes fractures that result in fragmentation of the rock. This facilitates augering and downward progress. In order to ensure that the drill-bit tip delivers the greatest effective impulse (the time integral of the drill-bit tip/rock pressure curve exceeding the strength of the rock), parameters such as the spring rates and the mass of the free mass, the drill bit and transducer have been varied and compared in both computer simulation and practical experiment. The most interesting findings and those of particular relevance to deep drilling indicate that increasing the mass of the drill bit has a limited (or even positive) influence on the rate of effective impulse delivered.

An ultrasonic orthopaedic surgical device based on a cymbal transducer.

An ultrasonic orthopaedic surgical device is presented, where the ultrasonic actuation relies on a modification of the classical cymbal transducer. All current devices consist of a Langevin ultrasonic transducer with a tuned cutting blade attached, where resonance is required to provide sufficient vibrational amplitude to cut bone. However, this requirement restricts the geometry and offers little opportunity to propose miniaturised devices or complex blades. The class V flextensional cymbal transducer is proposed here as the basis for a new design, where the cymbal delivers the required vibrational amplitude, and the design of the attached cutting insert can be tailored for the required cut. Consequently, the device can be optimised to deliver an accurate and precise cutting capability. A prototype device is presented, based on the cymbal configuration and designed to operate at 25.5kHz with a displacement amplitude of 30µm at 300V. Measurements of vibrational and impedance responses elucidate the mechanical and electrical characteristics of the device. Subsequent cutting tests on rat femur demonstrate device performance consistent with a commercial Langevin-based ultrasonic device and show that cutting is achieved using less electrical power and a lower piezoceramic volume. Histological analysis exhibits a higher proportion of live cells in the region around the cut site for the cymbal device than for a powered sagittal or a manual saw, demonstrating the potential for the ultrasonic device to result in faster healing.

Phase I dose escalation trial of the novel proteasome inhibitor carfilzomib in patients with relapsed chronic lymphocytic leukemia and small lymphocytic lymphoma.

The proteasome complex degrades proteins involved in a variety of cellular processes and is a powerful therapeutic target in several malignancies. Carfilzomib is a potent proteasome inhibitor which induces rapid chronic lymphocytic leukemia (CLL) cell apoptosis in vitro. We conducted a phase I dose-escalation trial to determine the safety and tolerability of carfilzomib in relapsed/refractory CLL or small lymphocytic lymphoma (SLL). Nineteen patients were treated with carfilzomib initially at 20 mg/m(2), then escalated in four cohorts (27, 36, 45 and 56 mg/m(2)) on days 1, 2, 8, 9, 15 and 16 of 28-day cycles. Therapy was generally well tolerated, and no dose limiting toxicities were observed. The most common hematologic toxicities were thrombocytopenia and neutropenia. All patients evaluable for response had stable disease, including patients with del17p13 and fludarabine-resistant disease. This trial shows acceptable tolerability and limited preliminary efficacy of carfilzomib in CLL and SLL.

Understanding nonlinear vibration behaviours in high-power ultrasonic surgical devices.

Ultrasonic surgical devices are increasingly used in oral, craniofacial and maxillofacial surgery to cut mineralized tissue, offering the surgeon high accuracy with minimal risk to nerve and vessel tissue. Power ultrasonic devices operate in resonance, requiring their length to be a half-wavelength or multiple-half-wavelength. For bone surgery, devices based on a half-wavelength have seen considerable success, but longer multiple-half-wavelength endoscopic devices have recently been proposed to widen the range of surgeries. To provide context for these developments, some examples of surgical procedures and the associated designs of ultrasonic cutting tips are presented. However, multiple-half-wavelength components, typical of endoscopic devices, have greater potential to exhibit nonlinear dynamic behaviours that have a highly detrimental effect on device performance. Through experimental characterization of the dynamic behaviour of endoscopic devices, it is demonstrated how geometrical features influence nonlinear dynamic responses. Period doubling, a known route to chaotic behaviour, is shown to be significantly influenced by the cutting tip shape, whereas the cutting tip has only a limited effect on Duffing-like responses, particularly the shape of the hysteresis curve, which is important for device stability. These findings underpin design, aiming to pave the way for a new generation of ultrasonic endoscopic surgical devices.

Smart cymbal transducers with nitinol end caps tunable to multiple operating frequencies.

Cymbal flextensional transducers have principally been adopted for sensing and actuation and their performance in higher power applications has only recently been investigated. Nitinol is a shape-memory alloy (SMA) with excellent strain recovery, durability, corrosion resistance, and fatigue strength. Although it has been incorporated in many applications, the implementation of nitinol, or any of the SMAs, in power ultrasonic applications is limited. Nitinol exhibits two phenomena, the first being the superelastic effect and the second being the shape-memory effect (SME). This paper assesses two cymbal transducers, one assembled with superelastic nitinol end caps and the other with shape-memory nitinol end caps. Characterization of the nitinol alloy before the design of such transducers is vital, so that they can be tuned to the desired operating frequencies. It is shown this can be achieved for shape-memory nitinol using differential scanning calorimetry (DSC); however, it is also shown that characterizing superelastic nitinol with DSC is problematic. Two transducers are assembled whose two operating frequencies can be tuned, and their dynamic behaviors are compared. Both transducers are shown to be tunable, with limitation for high-power applications largely being associated with the bond layer.