Development of a core outcome set for clinical trials in childhood asthma: a survey of clinicians, parents, and young people

In clinical trials in childhood asthma, outcomes reflecting short-term disease activity are frequently measured, whilst functional status, quality of life (QoL), and long-term treatment effects are rarely assessed. There is also non-uniformity across studies in the selection and measurement of outcomes within these domains. The development of a core outcome set has the potential to reduce heterogeneity between trials, lead to research that is more likely to have measured relevant outcomes, and enhance the value of evidence synthesis by reducing the risk of outcome reporting bias and ensuring that all trials contribute usable information

A 4.3 GHz BiCMOS VCO with multiple 360° variable phase outputs using the vector sum method

A 4.3 GHz voltage controlled oscillator (VCO) with multiple independently tunable phase outputs is presented. The VCO is realized by coupling two LC oscillators together in order to obtain quadrature signals and is tunable between 4.12 and 4.74 GHz. The variable phase outputs are achieved by varying the amplitudes of the in-phase and quadrature signals independently and then combining these signals together. By using multiple Gilbert cells as variable gain amplifiers (VGAs), multiple tunable phase outputs are achieved with the use of only one quadrature VCO. The VGAs are controlled using a custom non-linear digital-toanalog converter. The entire circuit is designed using a 3.3 V SiGe BiCMOS process. A maximum phase noise of -108.17 dBc/Hz was measured over the entire tuning range at a 1 MHz offset. The outputs of the VCO can be used as local oscillators that achieve phase shifting during radio frequency up or down conversion.Armscor S. A. Ltd and the Business Unit: Defence, Peace, Safety and Security (DPSS), Council for Scientific and Industrial Research (CSIR), South Africa.http://www.springerlink.com/content/0925-1030ai201

Hematological Changes in Women and Infants Exposed to an AZT-Containing Regimen for Prevention of Mother-to-child-transmission of HIV in Tanzania.

Tanzanian guidelines for prevention of mother-to-child-transmission of HIV (PMTCT) recommend an antiretroviral combination regimen involving zidovudine (AZT) during pregnancy, single-dosed nevirapine at labor onset, AZT plus Lamivudine (3TC) during delivery, and AZT/3TC for 1-4 weeks postpartum. As drug toxicities are a relevant concern, we assessed hematological alterations in AZT-exposed women and their infants. A cohort of HIV-positive women, either with AZT intake (n = 82, group 1) or without AZT intake (n = 62, group 2) for PMTCT during pregnancy, was established at Kyela District Hospital, Tanzania. The cohort also included the infants of group 1 with an in-utero AZT exposure ≥4 weeks, receiving AZT for 1 week postpartum (n = 41), and infants of group 2 without in-utero AZT exposure, receiving a prolonged 4-week AZT tail (n = 58). Complete blood counts were evaluated during pregnancy, birth, weeks 4-6 and 12. For women of group 1 with antenatal AZT intake, we found a statistically significant decrease in hemoglobin level, red blood cells, white blood cells, granulocytes, as well as an increase in red cell distribution width and platelet count. At delivery, the median red blood cell count was significantly lower and the median platelet count was significantly higher in women of group 1 compared to group 2. At birth, infants from group 1 showed a lower median hemoglobin level and granulocyte count and a higher frequency of anemia and granulocytopenia. At 4-6 weeks postpartum, the mean neutrophil granulocyte count was significantly lower and neutropenia was significantly more frequent in infants of group 2. AZT exposure during pregnancy as well as after birth resulted in significant hematological alterations for women and their newborns, although these changes were mostly mild and transient in nature. Research involving larger cohorts is needed to further analyze the impact of AZT-containing regimens on maternal and infant health

Defining and evaluating novel procedures for involving patients in Core Outcome Set research: creating a meaningful long list of candidate outcome domains

Background Tinnitus is a complex audiological condition affecting many different domains of everyday life. Clinical trials of tinnitus interventions measure and report those outcome domains inconsistently and this hinders direct comparison between study findings. To address this problem, an ongoing project is developing a Core Outcome Set; an agreed list of outcome domains to be measured and reported in all future trials. Part of this project uses a consensus methodology (‘Delphi’ survey), whereby all relevant stakeholders identify important and critical outcome domains from a long list of candidates. This article addresses a gap in the patient involvement literature by describing and reflecting on our involvement of patients to create a meaningful long list of candidate outcome domains. Methods Two Public Research Partners with lived experience of tinnitus reviewed an initial list of 124 outcome domains over two face-to-face workshops. With the Study Management Team, they interpreted each candidate outcome domain and generated a plain language description. Following this, the domain names and descriptions underwent an additional lay review by 14 patients and 5 clinical experts, via an online survey platform. Results Insights gained from the workshops and survey feedback prompted substantial, unforeseen modifications to the long list. These included the reduction of the number of outcome domains (from 124 to 66) via the exclusion of broad concepts and consolidation of equivalent domains or domains outside the scope of the study. Reviewers also applied their lived experience of tinnitus to bring clarity and relevance to domain names and plain language descriptions. Four impacts on the Delphi survey were observed: recruitment exceeded the target by 171%, there were equivalent numbers of patient and professional participants (n=358 and n=312, respectively), feedback was mostly positive, and retention was high (87%). Conclusions Patient involvement was an integral and transformative step of the study design process. Patient involvement was impactful because the online Delphi survey was successful in recruiting and retaining participants, and there were many comments about a positive participatory experience. Seven general methodological features are highlighted which fit with general principles of good patient involvement. These can benefit other Core Outcome Set developers

Flow-cytometric monitoring of disease-associated expression of 9-O-acetylated sialoglycoproteins in combination with known CD antigens, as an index for MRD in children with acute lymphoblastic leukaemia: a two-year longitudinal follow-up study

<p>Abstract</p> <p>Background</p> <p>Over expression of 9-<it>O-</it>acetylated sialoglycoproteins (Neu5,9Ac₂-GPs, abbreviated as <it>O</it>AcSGP) has been demonstrated as a disease-associated antigen on the lymphoblasts of childhood acute lymphoblastic leukaemia (ALL). Achatinin-H, a lectin, has selective affinity towards terminal 9-<it>O-</it>acetylated sialic acids-α2-6-<it>N</it>acetylated galactosamine. Exploring this affinity, enhanced expression of <it>O</it>AcSGP was observed, at the onset of disease, followed by its decrease with chemotherapy and reappearance with relapse. In spite of treatment, patients retain the diseased cells referred to as minimal residual disease (MRD) responsible for relapse. Our aim was to select a suitable template by using the differential expression of <it>O</it>AcSGP along with other known CD antigens to monitor MRD in peripheral blood (PB) and bone marrow (BM) of Indian patients with B- or T-ALL during treatment and correlate it with the disease status.</p> <p>Methods</p> <p>A two-year longitudinal follow-up study was done with 109 patients from the onset of the disease till the end of chemotherapy, treated under MCP841protocol. Paired samples of PB (n = 1667) and BM (n = 999) were monitored by flow cytometry. Three templates selected for this investigation were <it>O</it>AcSGP⁺CD10⁺CD19⁺or <it>O</it>AcSGP⁺CD34⁺CD19⁺for B-ALL and <it>O</it>AcSGP⁺CD7⁺CD3⁺for T-ALL.</p> <p>Results</p> <p>Using each template the level of MRD detection reached 0.01% for a patient in clinical remission (CR). 81.65% of the patients were in CR during these two years while the remaining relapsed. Failure in early clearance of lymphoblasts, as indicated by higher MRD, implied an elevated risk of relapse. Soaring MRD during the chemotherapeutic regimen predicted clinical relapse, at least a month before medical manifestation. Irrespective of B- or T-lineage ALL, the MRD in PB and BM correlated well.</p> <p>Conclusion</p> <p>A range of MRD values can be predicted for the patients in CR, irrespective of their lineage, being 0.03 ± 0.01% (PB) and 0.05 ± 0.015% (BM). These patients may not be stated as normal with respect to the presence of MRD. Hence, MRD study beyond two-years follow-up is necessary to investigate further reduction in MRD, thereby ensuring their disease-free survival. Therefore, we suggest use of these templates for MRD detection, during and post-chemotherapy for proper patient management strategies, thereby helping in personalizing the treatment.</p

Noise-Aided Logic in an Electronic Analog of Synthetic Genetic Networks

We report the experimental verification of noise-enhanced logic behaviour in an electronic analog of a synthetic genetic network, composed of two repressors and two constitutive promoters. We observe good agreement between circuit measurements and numerical prediction, with the circuit allowing for robust logic operations in an optimal window of noise. Namely, the input-output characteristics of a logic gate is reproduced faithfully under moderate noise, which is a manifestation of the phenomenon known as Logical Stochastic Resonance. The two dynamical variables in the system yield complementary logic behaviour simultaneously. The system is easily morphed from AND/NAND to OR/NOR logi

Sensitivity of the Himalayan orography representation in simulation of winter precipitation using Regional Climate Model (RegCM) nested in a GCM

This document is the Accepted Manuscript version of the following article: Tiwari, P.R., Kar, S.C., Mohanty, U.C., Climate Dynamics (2017). The final publication is available at Springer via https://link.springer.com/article/10.1007%2Fs00382-017-3567-3. The Accepted Manuscript is under embargo. Embargo end date: 24 February 2018.The role of the Himalayan orography representationin a Regional Climate Model (RegCM4) nested inNCMRWF global spectral model is examined in simulatingthe winter circulation and associated precipitation over theNorthwest India (NWI; 23°–37.5°N and 69°–85°E) region.For this purpose, nine different set of orography representationsfor nine distinct precipitation years (three years eachfor wet, normal and dry) have been considered by increasing(decreasing) 5, 10, 15, and 20% from the mean height(CNTRL) of the Himalaya in RegCM4 model. Validationwith various observations revealed a good improvementin reproducing the precipitation intensity and distributionwith increased model height compared to the resultsobtained from CNTRL and reduced orography experiments.Further it has been found that, increase in heightby 10% (P10) increases seasonal precipitation about 20%,while decrease in height by 10% (M10) results around 28%reduction in seasonal precipitation as compared to CNTRLexperiment over NWI region. This improvement in precipitationsimulation comes due to better representation ofvertical pressure velocity and moisture transport as thesefactors play an important role in wintertime precipitationprocesses over NWI region. Furthermore, a comparison of model-simulated precipitation with observed precipitationat 17 station locations has been also carried out. Overall,the results suggest that when the orographic increment of10% (P10) is applied on RegCM4 model, it has better skillin simulating the precipitation over the NWI region andthis model is a useful tool for further regional downscalingstudies.Peer reviewe

Vestibular Perception following Acute Unilateral Vestibular Lesions.

Little is known about the vestibulo-perceptual (VP) system, particularly after a unilateral vestibular lesion. We investigated vestibulo-ocular (VO) and VP function in 25 patients with vestibular neuritis (VN) acutely (2 days after onset) and after compensation (recovery phase, 10 weeks). Since the effect of VN on reflex and perceptual function may differ at threshold and supra-threshold acceleration levels, we used two stimulus intensities, acceleration steps of 0.5°/s(2) and velocity steps of 90°/s (acceleration 180°/s(2)). We hypothesised that the vestibular lesion or the compensatory processes could dissociate VO and VP function, particularly if the acute vertiginous sensation interferes with the perceptual tasks. Both in acute and recovery phases, VO and VP thresholds increased, particularly during ipsilesional rotations. In signal detection theory this indicates that signals from the healthy and affected side are still fused, but result in asymmetric thresholds due to a lesion-induced bias. The normal pattern whereby VP thresholds are higher than VO thresholds was preserved, indicating that any 'perceptual noise' added by the vertigo does not disrupt the cognitive decision-making processes inherent to the perceptual task. Overall, the parallel findings in VO and VP thresholds imply little or no additional cortical processing and suggest that vestibular thresholds essentially reflect the sensitivity of the fused peripheral receptors. In contrast, a significant VO-VP dissociation for supra-threshold stimuli was found. Acutely, time constants and duration of the VO and VP responses were reduced - asymmetrically for VO, as expected, but surprisingly symmetrical for perception. At recovery, VP responses normalised but VO responses remained shortened and asymmetric. Thus, unlike threshold data, supra-threshold responses show considerable VO-VP dissociation indicative of additional, higher-order processing of vestibular signals. We provide evidence of perceptual processes (ultimately cortical) participating in vestibular compensation, suppressing asymmetry acutely in unilateral vestibular lesions