'Different things at different times': Wellbeing strategies and processes identified by parents of children who have an intellectual disability or who are autistic, or both

Background: Most parents of children with an intellectual disability or who are autistic identify positives in their family life and their own wellbeing, in addition to reported mental health challenges. Several models and interventions have been developed in relation to parent carer wellbeing. Few studies have asked parent carers how they support their own wellbeing. Method: Adopting an interpretive phenomenological approach this study utilised semi-structured interviews. Seventeen parent carers were asked and what supported their emotional wellbeing. Template Analysis was applied to develop themes. Results: All participants identified factors that supported their wellbeing. Themes included strategies that countered stress time for themselves, relaxation, 'parking' difficulties) and broader wellbeing strategies (finding meaning life direction, greater understanding of child). An ongoing process of supporting wellbeing by 'Reorienting and finding balance' appeared central. Conclusions: Self-identified, multi-dimensional strategies benefit parents' emotional wellbeing and should be considered in the context of support provided to families

Using serum CA125 to assess the activity of potential cytostatic agents in ovarian cancer

Objective: New strategies are required to rapidly identify novel cytostatic agents before embarking on large randomized trials. This study investigates whether a change in rate of rise (slope) of serum CA125 from before to after starting a novel agent could be used to identify cytostatic agents. Tamoxifen was used to validate this hypothesis. Methods: Asymptomatic patients with relapsed ovarian cancer who had responded to chemotherapy were enrolled and had CA125 measurements taken every 4 weeks, then more frequently when rising. Once levels reached 4 times the upper limit of normal or nadir, they started continuous tamoxifen 20 mg daily, as well as fortnightly CA125 measurements until symptomatic progression. Because of the potentially nonlinear relationship of CA125 over time, it was felt that to enable normal approximations to be utilized a natural logarithmic standard transformation [ln(CA125)] was the most suitable to improve linearity above the common logarithmic transformation to base 10. Results: From 235 recruited patients, 81 started tamoxifen and had at least 4 CA125 measurements taken before and 4 CA125 measurements taken after starting tamoxifen, respectively. The mean regression slopes from using at least 4 1n(CA125) measurements immediately before and after starting tamoxifen were 0I0149 and 0I0093 [ln(CA125)/d], respectively. This difference is statistically significant, P = 0I001. Therefore, in a future trial with a novel agent, at least as effective as tamoxifen, using this effect size, the number of evaluable patients needed, at significance level of 5% and power of 80%, is 56. Conclusions: Further validation of this methodology is required, but there is potential to use comparison of mean regression slopes of ln(CA125) as an interim analysis measure of efficacy for novel cytostatic agents in relapsed ovarian cancer.Peer reviewedFinal Accepted Versio

Parallel perfusion imaging processing using GPGPU

AbstractBackground and purposeThe objective of brain perfusion quantification is to generate parametric maps of relevant hemodynamic quantities such as cerebral blood flow (CBF), cerebral blood volume (CBV) and mean transit time (MTT) that can be used in diagnosis of acute stroke. These calculations involve deconvolution operations that can be very computationally expensive when using local Arterial Input Functions (AIF). As time is vitally important in the case of acute stroke, reducing the analysis time will reduce the number of brain cells damaged and increase the potential for recovery.MethodsGPUs originated as graphics generation dedicated co-processors, but modern GPUs have evolved to become a more general processor capable of executing scientific computations. It provides a highly parallel computing environment due to its large number of computing cores and constitutes an affordable high performance computing method. In this paper, we will present the implementation of a deconvolution algorithm for brain perfusion quantification on GPGPU (General Purpose Graphics Processor Units) using the CUDA programming model. We present the serial and parallel implementations of such algorithms and the evaluation of the performance gains using GPUs.ResultsOur method has gained a 5.56 and 3.75 speedup for CT and MR images respectively.ConclusionsIt seems that using GPGPU is a desirable approach in perfusion imaging analysis, which does not harm the quality of cerebral hemodynamic maps but delivers results faster than the traditional computation

Kepler eclipsing binary stars. VII. the catalogue of eclipsing binaries found in the entire Kepler data set

The primary Kepler Mission provided nearly continuous monitoring of ~200,000 objects with unprecedented photometric precision. We present the final catalog of eclipsing binary systems within the 105 deg2 Kepler field of view. This release incorporates the full extent of the data from the primary mission (Q0-Q17 Data Release). As a result, new systems have been added, additional false positives have been removed, ephemerides and principal parameters have been recomputed, classifications have been revised to rely on analytical models, and eclipse timing variations have been computed for each system. We identify several classes of systems including those that exhibit tertiary eclipse events, systems that show clear evidence of additional bodies, heartbeat systems, systems with changing eclipse depths, and systems exhibiting only one eclipse event over the duration of the mission. We have updated the period and galactic latitude distribution diagrams and included a catalog completeness evaluation. The total number of identified eclipsing and ellipsoidal binary systems in the Kepler field of view has increased to 2878, 1.3% of all observed Kepler targets

Timing the Landmark Events in the Evolution of Clear Cell Renal Cell Cancer: TRACERx Renal.

Clear cell renal cell carcinoma (ccRCC) is characterized by near-universal loss of the short arm of chromosome 3, deleting several tumor suppressor genes. We analyzed whole genomes from 95 biopsies across 33 patients with clear cell renal cell carcinoma. We find hotspots of point mutations in the 5' UTR of TERT, targeting a MYC-MAX-MAD1 repressor associated with telomere lengthening. The most common structural abnormality generates simultaneous 3p loss and 5q gain (36% patients), typically through chromothripsis. This event occurs in childhood or adolescence, generally as the initiating event that precedes emergence of the tumor's most recent common ancestor by years to decades. Similar genomic changes drive inherited ccRCC. Modeling differences in age incidence between inherited and sporadic cancers suggests that the number of cells with 3p loss capable of initiating sporadic tumors is no more than a few hundred. Early development of ccRCC follows well-defined evolutionary trajectories, offering opportunity for early intervention

Deterministic Evolutionary Trajectories Influence Primary Tumor Growth: TRACERx Renal.

The evolutionary features of clear-cell renal cell carcinoma (ccRCC) have not been systematically studied to date. We analyzed 1,206 primary tumor regions from 101 patients recruited into the multi-center prospective study, TRACERx Renal. We observe up to 30 driver events per tumor and show that subclonal diversification is associated with known prognostic parameters. By resolving the patterns of driver event ordering, co-occurrence, and mutual exclusivity at clone level, we show the deterministic nature of clonal evolution. ccRCC can be grouped into seven evolutionary subtypes, ranging from tumors characterized by early fixation of multiple mutational and copy number drivers and rapid metastases to highly branched tumors with >10 subclonal drivers and extensive parallel evolution associated with attenuated progression. We identify genetic diversity and chromosomal complexity as determinants of patient outcome. Our insights reconcile the variable clinical behavior of ccRCC and suggest evolutionary potential as a biomarker for both intervention and surveillance

Fc-Optimized Anti-CD25 Depletes Tumor-Infiltrating Regulatory T Cells and Synergizes with PD-1 Blockade to Eradicate Established Tumors

CD25 is expressed at high levels on regulatory T (Treg) cells and was initially proposed as a target for cancer immunotherapy. However, anti-CD25 antibodies have displayed limited activity against established tumors. We demonstrated that CD25 expression is largely restricted to tumor-infiltrating Treg cells in mice and humans. While existing anti-CD25 antibodies were observed to deplete Treg cells in the periphery, upregulation of the inhibitory Fc gamma receptor (FcγR) IIb at the tumor site prevented intra-tumoral Treg cell depletion, which may underlie the lack of anti-tumor activity previously observed in pre-clinical models. Use of an anti-CD25 antibody with enhanced binding to activating FcγRs led to effective depletion of tumor-infiltrating Treg cells, increased effector to Treg cell ratios, and improved control of established tumors. Combination with anti-programmed cell death protein-1 antibodies promoted complete tumor rejection, demonstrating the relevance of CD25 as a therapeutic target and promising substrate for future combination approaches in immune-oncology

Fc Effector Function Contributes to the Activity of Human Anti-CTLA-4 Antibodies.

With the use of a mouse model expressing human Fc-gamma receptors (FcγRs), we demonstrated that antibodies with isotypes equivalent to ipilimumab and tremelimumab mediate intra-tumoral regulatory T (Treg) cell depletion in vivo, increasing the CD8+ to Treg cell ratio and promoting tumor rejection. Antibodies with improved FcγR binding profiles drove superior anti-tumor responses and survival. In patients with advanced melanoma, response to ipilimumab was associated with the CD16a-V158F high affinity polymorphism. Such activity only appeared relevant in the context of inflamed tumors, explaining the modest response rates observed in the clinical setting. Our data suggest that the activity of anti-CTLA-4 in inflamed tumors may be improved through enhancement of FcγR binding, whereas poorly infiltrated tumors will likely require combination approaches