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.

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.

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.

Chondroprotection of articular cartilage integrity: Utilizing ultrasonic scalpel and hyperosmolar irrigation solution during cutting.

Objectives: Ultrasonic (US) cutting of cartilage in orthopaedic surgery has received little attention despite its potential to reduce chondrocyte death which could enhance cartilage repair. We aimed to investigate whether an ultrasonically-vibrating scalpel to cut human articular cartilage could reduce chondrocyte death, and to determine if hyper-osmolarity could provide chondroprotection during the procedure. Methods: A scalpel (no. 15) was mounted on an ultrasonic transducer to resonate at 35 â€‹kHz with 30 â€‹µm vibrational displacement. Thirty-six fresh human femoral cartilage samples were divided into four groups based on ultrasonic activation (US or non-US) and saline osmolarity (300 or 600 mOsm/L). Cell viability was assessed using a live/dead cell assay and analysed quantitatively by confocal microscopy. Histology illustrated tissue surface changes at the cut site. Results: The overall chondrocyte death percentage at both the US and non-US cut sites showed comparable results (p â€‹> â€‹0.05) in both osmolarities. However, the zone of chondrocyte death was reduced by 31 â€‹± â€‹5% and 36 â€‹± â€‹6%, respectively, when comparing US cutting at 300 mOsm/L and 600 mOsm/L to the control group (non-US cutting; 300 mOsm/L) (p â€‹< â€‹0.05). The width of the cut was consistent at both sites, regardless of the method of cutting. Conclusion: Cutting human cartilage with US in the presence of 300 or 600 mOsm/L media was chondroprotective compared to normal (non-US) scalpel cutting in 300 mOsm/L medium. These results suggest chondroprotection can be achieved while cutting using a US scalpel and raised osmolarity, potentially improving cartilage regeneration and repair following injury.

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).

Rapid intra-host diversification and evolution of SARS-CoV-2 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 conditions, but the processes responsible for these observations are incompletely understood. Here we use high-throughput, single-genome amplification and sequencing (HT-SGS) to sequence SARS-CoV-2 spike genes from people with HIV (PWH, n = 22) and people without HIV (PWOH, n = 25). In PWOH and PWH with CD4 T cell counts (i.e., CD4 counts) ≥ 200 cells/µL, we find that most SARS-CoV-2 genomes sampled in each person share one spike sequence. By contrast, in people with advanced HIV infection (i.e., CD4 counts < 200 cells/µL), HT-SGS reveals a median of 46 distinct linked groupings of spike mutations per person. Elevated intra-host spike diversity in people with advanced HIV infection is detected immediately after COVID-19 symptom onset, and early intra-host spike diversity predicts SARS-CoV-2 shedding duration among PWH. Analysis of longitudinal timepoints reveals rapid fluctuations in spike sequence populations, replacement of founder sequences by groups of new haplotypes, and positive selection at functionally important residues. These findings demonstrate 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.

Administration of anti-HIV-1 broadly neutralizing monoclonal antibodies with increased affinity to Fcγ receptors during acute SHIVAD8-EO infection.

Anti-HIV-1 broadly neutralizing antibodies (bNAbs) have the dual potential of mediating virus neutralization and antiviral effector functions through their Fab and Fc domains, respectively. So far, bNAbs with enhanced Fc effector functions in vitro have only been tested in NHPs during chronic simian-HIV (SHIV) infection. Here, we investigate the effects of administering in acute SHIVAD8-EO infection either wild-type (WT) bNAbs or bNAbs carrying the S239D/I332E/A330L (DEL) mutation, which increases binding to FcγRs. Emergence of virus in plasma and lymph nodes (LNs) was delayed by bNAb treatment and occurred earlier in monkeys given DEL bNAbs than in those given WT bNAbs, consistent with faster clearance of DEL bNAbs from plasma. DEL bNAb-treated monkeys had higher levels of circulating virus-specific IFNγ single-producing CD8+ CD69+ T cells than the other groups. In LNs, WT bNAbs were evenly distributed between follicular and extrafollicular areas, but DEL bNAbs predominated in the latter. At week 8 post-challenge, LN monocytes and NK cells from DEL bNAb-treated monkeys upregulated proinflammatory signaling pathways and LN T cells downregulated TNF signaling via NF-κB. Overall, bNAbs with increased affinity to FcγRs shape innate and adaptive cellular immunity, which may be important to consider in future strategies of passive bNAb therapy.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Phase I study of low-dose interleukin-2, fludarabine, and cyclophosphamide for previously untreated indolent lymphoma and chronic lymphocytic leukemia.

PURPOSE: Fludarabine and cyclophosphamide is an effective combination but increases the risk of opportunistic infections due to depressed lymphocyte counts. In an attempt to preserve CD4 counts, we conducted a phase I, double-blind, placebo-controlled trial of recombinant interleukin-2 (IL-2) added to fludarabine and cyclophosphamide in patients with treatment-naive indolent lymphomas or chronic lymphocytic leukemia. EXPERIMENTAL DESIGN: Subcutaneous IL-2 (days 1-21 of each 28-day cycle) was combined with cyclophosphamide (600 mg/m2, day 8) and fludarabine (20 mg/m2, days 8-12) at four dose levels: 0.8, 1.0, 1.2, and 1.4 x 10(6) IU/m2/d. IL-2 dose was escalated in cohorts of four to six patients, with one patient per cohort receiving placebo. RESULTS: Twenty-three patients, median age 50, were enrolled, of whom 30% had chronic lymphocytic leukemia/small lymphocytic lymphoma and 52% had follicular lymphomas. The combination was generally well tolerated, with mainly hematologic toxicities. CD4 counts typically declined substantially during the early weeks of treatment and remained suppressed for months afterward. In the 18 evaluable patients who received IL-2, the mean absolute CD4 count was 999 cells/microL (range, 97-3,776) pretreatment, 379 cells/microL (range, 54-2,599) at day 14, and 98 cells/microL (range, 17-291) at end of treatment. In longitudinal linear models, the changes in CD4 counts were not significantly different across IL-2 dose levels. CONCLUSIONS: The addition of low-dose IL-2 to fludarabine and cyclophosphamide does not seem immunoprotective. New approaches are needed to reduce the cellular immunosuppression and infectious complications associated with purine analogues.