The use of erythropoiesis-stimulating agents with ruxolitinib in patients with myelofibrosis in COMFORT-II: an open-label, phase 3 study assessing efficacy and safety of ruxolitinib versus best available therapy in the treatment of myelofibrosis

BACKGROUND: Anemia is considered a negative prognostic risk factor for survival in patients with myelofibrosis. Most patients with myelofibrosis are anemic, and 35-54 % present with anemia at diagnosis. Ruxolitinib, a potent inhibitor of Janus kinase (JAK) 1 and JAK2, was associated with an overall survival benefit and improvements in splenomegaly and patient-reported outcomes in patients with myelofibrosis in the two phase 3 COMFORT studies. Consistent with the ruxolitinib mechanism of action, anemia was a frequently reported adverse event. In clinical practice, anemia is sometimes managed with erythropoiesis-stimulating agents (ESAs). This post hoc analysis evaluated the safety and efficacy of concomitant ruxolitinib and ESA administration in patients enrolled in COMFORT-II, an open-label, phase 3 study comparing the efficacy and safety of ruxolitinib with best available therapy for treatment of myelofibrosis. Patients were randomized (2:1) to receive ruxolitinib 15 or 20 mg twice daily or best available therapy. Spleen volume was assessed by magnetic resonance imaging or computed tomography scan.

RESULTS: Thirteen of 146 ruxolitinib-treated patients had concomitant ESA administration (+ESA). The median exposure to ruxolitinib was 114 weeks in the +ESA group and 111 weeks in the overall ruxolitinib arm; the median ruxolitinib dose intensity was 33 mg/day for each group. Six weeks before the first ESA administration, 10 of the 13 patients had grade 3/4 hemoglobin abnormalities. These had improved to grade 2 in 7 of the 13 patients by 6 weeks after the first ESA administration. The rate of packed red blood cell transfusions per month within 12 weeks before and after first ESA administration remained the same in 1 patient, decreased in 2 patients, and increased in 3 patients; 7 patients remained transfusion independent. Reductions in splenomegaly were observed in 69 % of evaluable patients (9/13) following first ESA administration.

CONCLUSIONS: Concomitant use of an ESA with ruxolitinib was well tolerated and did not affect the efficacy of ruxolitinib. Further investigations evaluating the effects of ESAs to alleviate anemia in ruxolitinib-treated patients are warranted (ClinicalTrials.gov identifier, NCT00934544; July 6, 2009).

Communication Nonlinearities Techniques for Analysis of Passive Intermodulation

The X-parameter based nonlinear modelling tools have been adopted as the foundation for the advanced methodology
of experimental characterisation and design of passive nonlinear devices. Based upon the formalism of the Xparameters,
it provides a unified framework for co-design of antenna beamforming networks, filters, phase shifters and
other passive and active devices of RF front-end, taking into account the effect of their nonlinearities. The equivalent
circuits of the canonical elements are readily incorporated in the models, thus enabling evaluation of PIM effect on the
performance of individual devices and their assemblies. An important advantage of the presented methodology is its
compatibility with the industry-standard established commercial RF circuit simulator Agilent ADS.
The major challenge in practical implementation of the proposed approach is concerned with experimental retrieval of the X-parameters for canonical passive circuit elements. To our best knowledge commercial PIM testers and practical laboratory test instruments are inherently narrowband and do not allow for simultaneous vector measurements at the PIM and harmonic frequencies. Alternatively, existing nonlinear vector analysers (NVNA) support X-parameter measurements in a broad frequency bands with a range of stimuli, but their dynamic range is insufficient for the PIM characterisation in practical circuits. Further opportunities for adaptation of the X-parameters methodology to the PIM
characterisation of passive devices using the existing test instruments are explored.

Passive Intermodulation in Distributed Circuits with Cascaded Discrete Nonlinearities

The principle aspects of passive intermodulation (PIM) characterisation in distributed printed circuits with cascaded lumped nonlinearities are presented. Mechanisms of PIM generations have been investigated experimentally and modelled using the formalism of X-parameters. The devised equivalent circuit models are applied to the analysis of microstrip lines with distributed and cascaded lumped sources of nonlinearity. The dynamic measurements have revealed that PIM generation rates in straight and meandered microstrip lines differ and significantly deviate from those expected for the respective discrete sources of nonlinearity. The obtained results indicate that multiple physical sources of nonlinearity contribute to PIM generation in printed circuits. Finally, it is demonstrated that the electrical discontinuities can have significant effect on the overall PIM response of the distributed passive circuits and cause PIM product leakage and parasitic coupling between isolated circuit elements.

On Passive Intermodulation Test of Analog and Digital Systems

This paper presents initial results of evaluating suitability of the conventional two-tone CW passive intermodulation (PIM) test for characterization of modulated signal distortion by passive nonlinearities in base station antennas and RF front-end. A comprehensive analysis of analog and digitally modulated waveforms in the transmission lines with weak distributed nonlinearity has been performed using the harmonic balance analysis and X-parameters in Advanced Design System (ADS) simulator. The nonlinear distortion metrics used in the conventional two-tone CW PIM test have been compared with the respective spectral metrics applied to the modulated waveforms, such as adjacent channel power ratio (ACPR) and error vector magnitude (EVM). It is shown that the results of two-tone CW PIM tests are consistent with the metrics used for assessment of signal integrity of both analog and digitally modulated waveforms.

An investigation of IAQ, thermal comfort and Sick Building Syndrome symptoms in UK energy efficient homes

Purpose
– Concern of the deterioration of indoor environmental quality as a result of energy efficient building design strategies is growing. Apprehensions of the effect of airtight, super insulated envelopes, the reduction of infiltration, and the reliance on mechanical systems to provide adequate ventilation (air supply) is promoting emerging new research in this field. The purpose of this paper is to present the results of an indoor air quality (IAQ) and thermal comfort investigation in UK energy efficient homes, through a case study investigation.

Design/methodology/approach
– The case study dwellings consisted of a row of six new-build homes which utilize mechanical ventilation with heat recovery (MVHR) systems, are built to an average airtightness of 2m3/m2/hr at 50 Pascal’s, and constructed without a central heating system. Physical IAQ measurements and occupant interviews were conducted during the summer and winter months over a 24-hour period, to gain information on occupant activities, perception of the interior environment, building-related health and building use.

Findings
– The results suggest inadequate IAQ and perceived thermal comfort, insufficient use of purge ventilation, presence of fungal growth, significant variances in heating patterns, occurrence of sick building syndrome symptoms and issues with the MVHR system.

Practical implications
– The findings will provide relevant data on the applicability of airtight, mechanically ventilated homes in a UK climate, with particular reference to IAQ.

Originality/value
– IAQ data of this nature is essentially lacking, particularly in the UK context. The findings will aid the development of effective sustainable design strategies that are appropriate to localized climatic conditions and sensitive to the health of building occupants.

Passive Intermodulation of Analog and Digital Signals on Transmission Lines with Distributed Nonlinearities: Modelling and Characterization

Passive intermodulation (PIM) often limits the performance of communication systems with analog and digitally-modulated signals and especially of systems supporting multiple carriers. Since the origins of the apparently multiple physical sources of nonlinearity causing PIM are not fully understood, the behavioral models are frequently used to describe the process of PIM generation. In this paper a polynomial model of memoryless nonlinearity is deduced from PIM measurements of a microstrip line with distributed nonlinearity with two-tone CW signals. The analytical model of nonlinearity is incorporated in Keysight Technology’s ADS simulator to evaluate the metrics of signal fidelity in the receive band for analog and digitally-modulated signals. PIM-induced distortion and cross-band interference with modulated signals are compared to those with two-tone CW signals. It is shown that conventional metrics can be applied to quantify the effect of distributed nonlinearities on signal fidelity. It is found that the two-tone CW test provides a worst-case estimate of cross-band interference for two-carrier modulated signals whereas with a three-carrier signal PIM interference in the receive band is noticeably overestimated. The simulated constellation diagrams for QPSK signals demonstrate that PIM interference exhibits the distinctive signatures of correlated distortion and this indicates that there are opportunities for mitigating PIM interference and that PIM interference cannot be treated as noise. One of the interesting results is that PIM distortion on a transmission line results in asymmetrical regrowth of output PIM interference for modulated signals.

Polynomial Model for High-Order and Multi-Carrier Passive Intermodulation Products

Passive intermodulation (PIM) often limits the performance of communication systems, particularly in the presence of multiple carriers. Since the origins of the apparently multiple physical sources of nonlinearity causing PIM in distributed circuits are not fully understood, the behavioural models are frequently employed to describe the process of PIM generation. In this paper, a memoryless nonlinear polynomial model, capable of predicting high-order multi-carrier intermodulation products, is deduced from the third-order two-tone PIM measurements on a microstrip transmission line with distributed nonlinearity. The analytical model of passive distributed nonlinearity is implemented in Keysight Technology’s ADS simulator to evaluate the adjacent band power ratio for three-tone signals. The obtained results suggest that the costly multi-carrier test setups can possibly be replaced by a simulation tool based on the properly retrieved nonlinear polynomial model.

Thermal environments and comfort in dementia friendly dwellings

This study follows on from a research project that developed guidelines for the Universal Design (UD) of Dementia Friendly Dwellings for People with Dementia, their Families and Carers. Research findings point to the need for thermal environments that support people with dementia and do not provoke stress, agitation or anxiety. Using semi-structured interviews and qualitative analysis of people with dementia this paper aims to provide insight into the questions of appropriate thermal environments. The qualitative analysis is supported by example simulated indoor environment studies that investigate comfort in common thermal environment provision scenarios in the homes of people with dementia. This paper focuses on the thermal environment, its impact on people with dementia, its therapeutic value, and its role in encouraging engagement in every day activity.
Findings from the interviews emphasize that control over their own internal environment is a priority for people with dementia. A strong preference for naturally or passively conditioned environments over mechanical conditioning is evident. Preferences are expressed for naturally ventilated environments enabling occupant instigated air movement. Repeated emphasis is placed on familiar elements including the fire and hot water bottle. Little desire is expressed for information feedback or technological displays.

Evaluation of passive ventilation provision in domestic housing retrofit

Increasing energy efficiency in the residential sector, while maintaining adequate home ventilation for health and well-being, is proving to be a challenge. This study assesses the efficacy of passive ventilation strategies designed to comply with building regulations and imposed after housing energy-efficiency retrofits. In particular, it focuses on the provision of ventilation using background through-wall vents, which remains a common strategy in a number of European countries including Ireland and the UK, where vent sizes, related to floor area, are stipulated in building regulations. A collective of social housing, with background through-wall vents installed post thermal retrofit, is taken as a case study. These homes are modelled to interrogate the impact of the passive ventilation strategy on house air exchange rate and thermal heating energy loads. The reaction of occupants to through-wall vent installation is decidedly negative and many block vents to limit thermal discomfort and heat loss. Simulation studies show significant external air ingress through vents. A wide range of effective air change rates are observed when vents are sized without reference to building airtightness, and significant energy penalties result for the leakier homes. This study evaluates the provision of passive through-wall ventilation as part of a retrofit programme and shows it to have a number of drawbacks that may impact on the health of the building and its occupants and ultimately be at odds with the aims of achieving energy efficiency in the residential sector.

Demonstration of passive plasma lensing of a laser wakefield accelerated electron bunch

We report on the first demonstration of passive all-optical plasma lensing using a two-stage setup. An intense femtosecond laser accelerates electrons in a laser wakefield accelerator (LWFA) to 100 MeVover millimeter length scales. By adding a second gas target behind the initial LWFAstage we introduce a robust and independently tunable plasma lens. We observe a density dependent reduction of the LWFA electron beam divergence from an initial value of 2.3 mrad, down to 1.4 mrad (rms), when the plasma lens is in operation. Such a plasma lens provides a simple and compact approach for divergence reduction well matched to the mm-scale length of the LWFA accelerator. The focusing forces are provided solely by the plasma and driven by the bunch itself only, making this a highly useful and conceptually new approach to electron beam focusing. Possible applications of this lens are not limited to laser plasma accelerators. Since no active driver is needed the passive plasma lens is also suited for high repetition rate focusing of electron bunches. Its understanding is also required for modeling the evolution of the driving particle bunch in particle driven wake field acceleration.