Lenalidomide, bortezomib and dexamethasone induction therapy for the treatment of newly diagnosed multiple myeloma : a practical review

For patients with newly diagnosed multiple myeloma, survival outcomes continue to improve significantly: however, nearly all patients will relapse following induction treatment. Optimisation of induction therapy is essential to provide longer term disease control and the current standard of care for most patients incorporates an immunomodulatory agent and proteasome inhibitor, most commonly lenalidomide and bortezomib in combination with dexamethasone (RVD), with maintenance until progression. Historically there has been limited access to RVD as an induction strategy outside of the United States; fortunately, there is now increasing access worldwide. This review discusses the rationale for use of RVD as induction therapy and aims to provide guidance in prescribing this regimen in order to optimise efficacy while minimising the toxicities of treatment. We also highlight the increasing evidence for the utility of addition of a monoclonal antibody to the RVD backbone to deepen responses and potentially provide longer disease control.Peer reviewe

Superconducting Heater Cryotron-Based Reconfigurable Logic Towards Cryogenic IC Camouflaging

Superconducting electronics are among the most promising alternatives to conventional CMOS technology thanks to the ultra-fast speed and ultra-high energy efficiency of the superconducting devices. Having a cryogenic control processor is also a crucial requirement for scaling the existing quantum computers up to thousands of qubits. Despite showing outstanding speed and energy efficiency, Josephson junction-based circuits suffer from several challenges such as flux trapping leading to limited scalability, difficulty in driving high impedances, and so on. Three-terminal cryotron devices have been proposed to solve these issues which can drive high impedances (>100 k{\Omega}) and are free from any flux trapping issue. In this work, we develop a reconfigurable logic circuit using a heater cryotron (hTron). In conventional approaches, the number of devices to perform a logic operation typically increases with the number of inputs. However, here, we demonstrate a single hTron device-based logic circuit that can be reconfigured to perform 1-input copy and NOT, 2-input AND and OR, and 3-input majority logic operations by choosing suitable biasing conditions. Consequently, we can perform any processing task with a much smaller number of devices. Also, since we can perform different logic operations with the same circuit (same layout), we can develop a camouflaged system where all the logic gates will have the same layout. Therefore, this proposed circuit will ensure enhanced hardware security against reverse engineering attacks.Comment: 12 pages, 5 figure

Machine Learning-powered Compact Modeling of Stochastic Electronic Devices using Mixture Density Networks

The relentless pursuit of miniaturization and performance enhancement in electronic devices has led to a fundamental challenge in the field of circuit design and simulation: how to accurately account for the inherent stochastic nature of certain devices. While conventional deterministic models have served as indispensable tools for circuit designers, they fall short when it comes to capture the subtle yet critical variability exhibited by many electronic components. In this paper, we present an innovative approach that transcends the limitations of traditional modeling techniques by harnessing the power of machine learning, specifically Mixture Density Networks (MDNs), to faithfully represent and simulate the stochastic behavior of electronic devices. We demonstrate our approach to model heater cryotrons, where the model is able to capture the stochastic switching dynamics observed in the experiment. Our model shows 0.82% mean absolute error for switching probability. This paper marks a significant step forward in the quest for accurate and versatile compact models, poised to drive innovation in the realm of electronic circuits

Multiplexed gradient descent: Fast online training of modern datasets on hardware neural networks without backpropagation

We present multiplexed gradient descent (MGD), a gradient descent framework designed to easily train analog or digital neural networks in hardware. MGD utilizes zero-order optimization techniques for online training of hardware neural networks. We demonstrate its ability to train neural networks on modern machine learning datasets, including CIFAR-10 and Fashion-MNIST, and compare its performance to backpropagation. Assuming realistic timescales and hardware parameters, our results indicate that these optimization techniques can train a network on emerging hardware platforms orders of magnitude faster than the wall-clock time of training via backpropagation on a standard GPU, even in the presence of imperfect weight updates or device-to-device variations in the hardware. We additionally describe how it can be applied to existing hardware as part of chip-in-the-loop training, or integrated directly at the hardware level. Crucially, the MGD framework is highly flexible, and its gradient descent process can be optimized to compensate for specific hardware limitations such as slow parameter-update speeds or limited input bandwidth

Orthotic management of instability of the knee related to neuromuscular and central nervous system disorders: qualitative interview study of patient perspectives

Objectives: Adults with knee instability related to neuromuscular disorders or central nervous conditions often experience mobility problems and rely on orthoses to improve function and mobility. Patient views of device effectiveness and acceptability are underexplored. Our study aimed to elicit device users’ perspectives regarding fitting, acceptability, effectiveness and use of orthoses, and identify important treatment outcomes. / Design: Qualitative descriptive study using in-depth semistructured interviews. Interview transcriptions were coded and thematically analysed, using ‘Framework’. / Setting and participants: A purposive sample of 24 adult users of orthotic devices. Nineteen patients were recruited across three National Health Service sites, and five people through charities/patient support groups in England. Half of the participants had been diagnosed with poliomyelitis, and the remainder with multiple sclerosis, Charcot-Marie-Tooth disease, spinal injury or spina bifida, and stroke. The median age of participants was 64.5 years (range 36–80 years). / Results: Patients’ medical condition impacted significantly on daily life. Participants relied on orthotic devices to enable engagement in daily activities. Patient goals for mobility were linked to individual circumstances. Desired treatment outcomes included reduction in pain, trips and falls, with improved balance and stability. Effectiveness, reliability, comfort and durability were the most valued features of orthoses and associated with reported use. Obtaining suitable footwear alongside orthotic devices was a significant concern. Time pressures during device fitting were viewed negatively. / Conclusions: Orthotic devices for knee instability play a crucial role in promoting, maintaining and enhancing physical and psychological health and well-being, enabling patients to work, engage in family life and enjoy social activities. Future research should consider how best to measure the impact of orthotic devices on patient quality of life and daily functioning outside the clinic setting, as well as device use and any adverse effects. / Trial registration number: This qualitative study was retrospectively registered as Current Controlled Trials ISRCTN65240228

The thermally-coupled imager: A scalable readout architecture for superconducting nanowire single photon detectors

Although superconducting nanowire single-photon detectors (SNSPDs) are a promising technology for quantum optics, metrology, and astronomy, they currently lack a readout architecture that is scalable to the megapixel regime and beyond. In this work, we have designed and demonstrated such an architecture for SNSPDs, called the thermally-coupled imager (TCI). The TCI uses a combination of time-of-flight delay lines and thermal coupling to create a scalable architecture that can scale to large array sizes, allows neighboring detectors to operate independently, and requires only four microwave readout lines to operate no matter the size of the array. We give an overview of how the architecture functions, and demonstrate a proof-of-concept $32\times32$ imaging array. The array was able to image a free-space focused spot at 373 nm, count at 9.6 Mcps, and resolve photon location with greater than 99.83\% distinguishability

Extrapleural pneumonectomy for malignant pleural mesothelioma: Outcomes of treatment and prognostic factors

ObjectiveThis study aimed to evaluate the perioperative and long-term outcomes associated with extrapleural pneumonectomy for patients with malignant pleural mesothelioma.MethodsFrom October 1994 to April 2008, 70 patients were selected for extrapleural pneumonectomy. Univariate analysis was performed using the Kaplan–Meier method and compared using the log-rank test. Multivariate analysis with entering and removing limits of P less than .10 and P greater than .05, respectively, was used. The prognostic factors included age, gender, side of disease, asbestos exposure, histology, positron emission tomography, date of surgery, neoadjuvant chemotherapy, completeness of cytoreduction, lymph node involvement, perioperative morbidity, adjuvant radiotherapy, and pemetrexed-based chemotherapy.ResultsThe mean age of patients was 55 years (standard deviation = 10). Fifty-eight patients had epithelial tumors. Six patients received neoadjuvant chemotherapy, 28 patients received adjuvant radiotherapy, and 16 patients received postoperative pemetrexed-based chemotherapy. Forty-four patients had no lymph node involvement. The perioperative morbidity and mortality were 37% and 5.7%, respectively. Complications included hemothorax (n = 7), atrial fibrillation (n = 6), empyema (n = 4), bronchopulmonary fistula (n = 3), right-sided heart failure (n = 2), pneumonia (n = 1), constrictive pericarditis (n = 1), acute pulmonary edema (n = 1), small bowel herniation (n = 1), and disseminated intravascular coagulopathy (n = 1). The median survival was 20 months, with a 3-year survival of 30%. Asbestos exposure, negative lymph node involvement, and receipt of adjuvant radiation or postoperative pemetrexed-based chemotherapy were associated with improved survival on both univariate and multivariate analyses.ConclusionThe present study supports the use of extrapleural pneumonectomy-based multimodal therapy in carefully selected patients with malignant pleural mesothelioma

Palliative care specialists' perceptions concerning referral of haematology patients to their services : findings from a qualitative study

Background: Haematological malignancies (leukaemias, lymphomas and myeloma) are complex cancers that are relatively common, affect all ages and have divergent outcomes. Although the symptom burden of these diseases is comparable to other cancers, patients do not access specialist palliative care (SPC) services as often as those with other cancers. To determine the reasons for this, we asked SPC practitioners about their perspectives regarding the barriers and facilitators influencing haematology patient referrals. Methods: We conducted a qualitative study, set within the United Kingdom’s (UK’s) Haematological Malignancy Research Network (HMRN: www.hmrn.org), a population-based cohort in the North of England. In-depth, semistructured interviews were conducted with 20 SPC doctors and nurses working in hospital, community and hospice settings between 2012 and 2014. Interviews were digitally audio-recorded, transcribed and analysed for thematic content using the ‘Framework’ method. Results: Study participants identified a range of barriers and facilitators influencing the referral of patients with haematological malignancies to SPC services. Barriers included: the characteristics and pathways of haematological malignancies; the close patient/haematology team relationship; lack of role clarity; late end of life discussions and SPC referrals; policy issues; and organisational issues. The main facilitators identified were: establishment of interdisciplinary working patterns (co-working) and enhanced understanding of roles; timely discussions with patients and early SPC referral; access to information platforms able to support information sharing; and use of indicators to ‘flag’ patients’ needs for SPC. Collaboration between haematology and SPC was perceived as beneficial and desirable, and was said to be increasing over time. Conclusions: This is the first UK study to explore SPC practitioners’ perceptions concerning haematology patient referrals. Numerous factors were found to influence the likelihood of referral, some of which related to the organisation and delivery of SPC services, so were amenable to change, and others relating to the complex and unique characteristics and pathways of haematological cancers. Further research is needed to assess the extent to which palliative care is provided by haematology doctors and nurses and other generalists and ways in which clinical uncertainty could be used as a trigger, rather than a barrier, to referral. Keywords: Cancer, Leukaemia, Lymphoma, Myeloma, Haematology, Specialist palliative care, End of life, Hospice, Qualitativ