Publications by authors named "Amanda Walker"

99 Publications

Use of Reflectance Confocal Microscopy for Hidrocystomas: An Emerging, Cost-Effective, and Powerful Tool.

Case Rep Dermatol Med 2021 9;2021:5543803. Epub 2021 Apr 9.

University of Utah School of Medicine, Department of Dermatology, Salt Lake City, UT 84132, USA.

Reflectance confocal microscopy (RCM) is an emerging and noninvasive imaging tool in dermatological practice. Benefits of this modality include differentiation between benign and malignant skin lesions, prevention of unnecessary biopsies, and cost effectiveness. However, RCM findings for benign lesions are rarely reported in the literature. We describe a case of reflectance confocal microscopy findings of a hidrocystoma and review potential applications of this imaging technique in everyday clinical practice.
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http://dx.doi.org/10.1155/2021/5543803DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8052164PMC
April 2021

Reversible ON- and OFF-switch chimeric antigen receptors controlled by lenalidomide.

Sci Transl Med 2021 Jan;13(575)

Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.

Cell-based therapies are emerging as effective agents against cancer and other diseases. As autonomous "living drugs," these therapies lack precise control. Chimeric antigen receptor (CAR) T cells effectively target hematologic malignancies but can proliferate rapidly and cause toxicity. We developed ON and OFF switches for CAR T cells using the clinically approved drug lenalidomide, which mediates the proteasomal degradation of several target proteins by inducing interactions between the CRL4 E3 ubiquitin ligase and a C2H2 zinc finger degron motif. We performed a systematic screen to identify "super-degron" tags with enhanced sensitivity to lenalidomide-induced degradation and used these degradable tags to generate OFF-switch degradable CARs. To create an ON switch, we engineered a lenalidomide-inducible dimerization system and developed split CARs that required both lenalidomide and target antigen for activation. Subtherapeutic lenalidomide concentrations controlled the effector functions of ON- and OFF-switch CAR T cells. In vivo, ON-switch split CARs demonstrated lenalidomide-dependent antitumor activity, and OFF-switch degradable CARs were depleted by drug treatment to limit inflammatory cytokine production while retaining antitumor efficacy. Together, the data showed that these lenalidomide-gated switches are rapid, reversible, and clinically suitable systems to control transgene function in diverse gene- and cell-based therapies.
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http://dx.doi.org/10.1126/scitranslmed.abb6295DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8045771PMC
January 2021

Analysis of Patient-Reported Outcome Utilization Within National Clinical Trials Network Cooperative Group Radiation Oncology Trials Over the Past 2 Decades.

Int J Radiat Oncol Biol Phys 2021 Apr 13;109(5):1151-1160. Epub 2020 Dec 13.

Department of Radiation Oncology, University of Cincinnati Cancer Center, University of Cincinnati, Cincinnati, Ohio. Electronic address:

Purpose: When treating cancer, both quantity and quality of life are valuable, though oncology trials have long placed greater emphasis on the former. The goal of this work was to evaluate how patient-reported outcomes (PROs) have been incorporated into radiation therapy trials within the National Clinical Trials Network over the last 2 decades to measure quality of life and to assess how PRO data have been disseminated in publications upon trial conclusion.

Methods And Materials: This cross-sectional study analyzed the frequency of use of PROs in National Clinical Trials Network cooperative group radiation therapy phase 2 and 3 clinical trials over the past 2 decades. A literature review was performed to determine the publication outcomes of PRO data, including only trials that used PROs in their design and were mature enough to have published results.

Results: Fifty-seven (56.4%) of the 101 trials included in this study included PROs in their design. Brain and head and neck trials demonstrated the largest proportional incorporation of PROs (81.8% and 76.9%, respectively), and thoracic and breast trials used the fewest (18.8% and 37.5%, respectively). The EQ-5D family of questionnaires was the most commonly used PROs, used in 22.8% of trials included. The literature review demonstrated a pattern of increased publication of PRO data alongside survival endpoints in manuscripts derived from these trials over time.

Conclusions: Though there is room for improvement, the field of radiation oncology has embraced the incorporation of PROs into multicenter, high-impact clinical trials over the past 2 decades and has increased its publication of this data alongside survival data from these trials.
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http://dx.doi.org/10.1016/j.ijrobp.2020.12.007DOI Listing
April 2021

Drug-Radiotherapy Combinations in 2020-A Landmark Year?

JAMA Oncol 2021 Mar;7(3):349-350

Department of Radiation Oncology and Molecular Radiation Sciences, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Bethesda, Maryland.

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http://dx.doi.org/10.1001/jamaoncol.2020.6139DOI Listing
March 2021

Lessons to Learn From a Successful Virtual Mock Oral Examination Pilot Experience.

Adv Radiat Oncol 2021 Jan-Feb;6(1):100534. Epub 2020 Aug 8.

National Capital Consortium Radiation Oncology Residency, Uniformed Services University of the Health Sciences, Bethesda, Maryland.

oronavirus (COVID-19) has caused marked impact on graduate medical education for all medical specialties. Radiation Oncology and the American Board of Radiology have also had to rapidly adapt to converting education and examinations to virtual platforms. We describe our small pilot experience in transitioning our in-person mock oral examinations to a virtual platform. Survey-based assessment revealed excellent feedback regarding ease of use and educational usefulness. Our mock oral examinations pilot experience adds to evidence that virtual mock oral examinations are an important considerationfor Radiation Oncology education and a feasible alternative to an in-person oral examination.
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http://dx.doi.org/10.1016/j.adro.2020.07.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7414305PMC
August 2020

Developing Consensus-Based Outcome Domains for Trials in Children and Adolescents With CKD: An International Delphi Survey.

Am J Kidney Dis 2020 10 10;76(4):533-545. Epub 2020 Jul 10.

Khoo Teck Puat-National University Children's Medical Institute, National University Hospital, Singapore.

Rationale & Objective: The inconsistency in outcomes reported and lack of patient-reported outcomes across trials in children with chronic kidney disease (CKD) limits shared decision making. As part of the Standardized Outcomes in Nephrology (SONG)-Kids initiative, we aimed to generate a consensus-based prioritized list of critically important outcomes to be reported in all trials in children with CKD.

Study Design: An online 2-round Delphi survey in English, French, and Hindi languages.

Settings & Participants: Patients (aged 8-21 years), caregivers/family, and health care professionals (HCPs) rated the importance of outcomes using a 9-point Likert scale (7-9 indicating critical importance) and completed a Best-Worst Scale.

Analytical Approach: We assessed the absolute and relative importance of outcomes. Comments were analyzed thematically.

Results: 557 participants (72 [13%] patients, 132 [24%] caregivers, and 353 [63%] HCPs) from 48 countries completed round 1 and 312 (56%) participants (28 [40%] patients, 64 [46%] caregivers, and 220 [56%] HCPs) completed round 2. Five outcomes were common in the top 10 for each group: mortality, kidney function, life participation, blood pressure, and infection. Caregivers and HCPs rated cardiovascular disease higher than patients. Patients gave lower ratings to all outcomes compared with caregivers/HCPs except they rated life participation (round 2 mean difference, 0.1), academic performance (0.1), mobility (0.4), and ability to travel (0.4) higher than caregivers and rated ability to travel (0.4) higher than HCPs. We identified 3 themes: alleviating disease and treatment burden, focusing on the whole child, and resolving fluctuating and conflicting goals.

Limitations: Most participants completed the survey in English.

Conclusions: Mortality, life participation, kidney function, and blood pressure were consistently highly prioritized by patients, caregivers, and HCPs. Patients gave higher priority to some lifestyle-related outcomes compared with caregivers/HCPs. Establishing critically important outcomes for all trials in children with CKD may improve consistent reporting of survival, kidney health, and clinical and life impact outcomes that are meaningful for decision making.
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http://dx.doi.org/10.1053/j.ajkd.2020.03.014DOI Listing
October 2020

Establishing core outcome domains in pediatric kidney disease: report of the Standardized Outcomes in Nephrology-Children and Adolescents (SONG-KIDS) consensus workshops.

Kidney Int 2020 09 4;98(3):553-565. Epub 2020 Jul 4.

Department of Nephrology and Murdoch Children's Research Institute, Royal Children's Hospital, Melbourne, Victoria, Australia; Department of Pediatrics, University of Melbourne, Melbourne, Victoria, Australia.

Trials in children with chronic kidney disease do not consistently report outcomes that are critically important to patients and caregivers. This can diminish the relevance and reliability of evidence for decision making, limiting the implementation of results into practice and policy. As part of the Standardized Outcomes in Nephrology-Children and Adolescents (SONG-Kids) initiative, we convened 2 consensus workshops in San Diego, California (7 patients, 24 caregivers, 43 health professionals) and Melbourne, Australia (7 patients, 23 caregivers, 49 health professionals). This report summarizes the discussions on the identification and implementation of the SONG-Kids core outcomes set. Four themes were identified; survival and life participation are common high priority goals, capturing the whole child and family, ensuring broad relevance across the patient journey, and requiring feasible and valid measures. Stakeholders supported the inclusion of mortality, infection, life participation, and kidney function as the core outcomes domains for children with chronic kidney disease.
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http://dx.doi.org/10.1016/j.kint.2020.05.054DOI Listing
September 2020

Biosynthesis and regulation of flavonoids in buckwheat.

Breed Sci 2020 Mar 17;70(1):74-84. Epub 2019 Dec 17.

CSIRO Agriculture & Food, Wine Innovation West, Hartley Grove, Waite Campus, SA 5064, Australia.

Buckwheat contains an abundance of antioxidants such as polyphenols and is considered a functional food. Among polyphenols, flavonoids have multiple functions in various aspects of plant growth and in flower and leaf colors. Flavonoids have antioxidant properties, and are thought to prevent cancer and cardiovascular disease. Here, we summarize the flavonoids present in various organs and their synthesis in buckwheat. We discuss the use of this information to breed highly functional and high value cultivars.
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http://dx.doi.org/10.1270/jsbbs.19041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7180151PMC
March 2020

The grapevine NaE sodium exclusion locus encodes sodium transporters with diverse transport properties and localisation.

J Plant Physiol 2020 Mar - Apr;246-247:153113. Epub 2020 Jan 17.

ARC Centre of Excellence in Plant Energy Biology, School of Agriculture, Food and Wine & Waite Research Institute, University of Adelaide, Glen Osmond, 5064, Australia; ARC Industrial Transformation Training Centre for Innovative Wine Production, School of Agriculture, Food and Wine & Waite Research Institute, University of Adelaide, Glen Osmond, 5064, Australia. Electronic address:

Grapevine (Vitis vinifera L.) is a valuable crop for human consumption and wine production, and is prone to suffering from salinity stress in arid regions or when exposed to low quality irrigation water. A previous study identified a quantitative trait locus (QTL) NaE, containing six High-affinity Potassium Transporter 1 genes, that was associated with shoot Na exclusion in grapevine. While HKT1;1 was predicted to be the most likely gene within this QTL to encode for this important salinity tolerance sub-trait, four other HKTs within the QTL remained uncharacterised; VviHKT1;2 encodes a truncated transcript unlikely to form a functional transporter. In this study, two allelic variants for each of VviHKT1;6, VviHKT1;7 and VviHKT1;8 from the heterozygous grapevine variety Cabernet Sauvignon were functionally characterised. Using the Xenopus laevis oocyte heterologous expression system, as well as transient expression in tobacco leaves, we found that the VviHKT1;6 and VviHKT1;7 alleles encoded plasma membrane localised proteins that facilitated significant non-rectifying Na transport. Conversely, proteins encoded by the VviHKT1;8 alleles were inwardly-rectifying, weak Na transporters that localised to intracellular organelles. Mining of previous RNA-seq gene expression data suggested that VviHKT1;6-8 are weakly expressed in grapevine roots, flower buds, and seeds under normal conditions and different nutrient regimes. We propose that VviHKT1;6 and VviHKT1;7 are likely to have a less significant role in grapevine leaf Na exclusion than VviHKT1;1, and that VviHKT1;8 is involved in endomembrane Na transport.
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http://dx.doi.org/10.1016/j.jplph.2020.153113DOI Listing
August 2020

A whole canopy gas exchange system for the targeted manipulation of grapevine source-sink relations using sub-ambient CO.

BMC Plant Biol 2019 Dec 3;19(1):535. Epub 2019 Dec 3.

National Wine and Grape Industry Centre, Wagga Wagga, New South Wales, 2678, Australia.

Background: Elucidating the effect of source-sink relations on berry composition is of interest for wine grape production as it represents a mechanistic link between yield, photosynthetic capacity and wine quality. However, the specific effects of carbohydrate supply on berry composition are difficult to study in isolation as leaf area or crop adjustments can also change fruit exposure, or lead to compensatory growth or photosynthetic responses. A new experimental system was therefore devised to slow berry sugar accumulation without changing canopy structure or yield. This consisted of six transparent 1.2 m chambers to enclose large pot-grown grapevines, and large soda-lime filled scrubbers that reduced carbon dioxide (CO) concentration of day-time supply air by approximately 200 ppm below ambient.

Results: In the first full scale test of the system, the chambers were installed on mature Shiraz grapevines for 14 days from the onset of berry sugar accumulation. Three chambers were run at sub-ambient CO for 10 days before returning to ambient. Canopy gas exchange, and juice hexose concentrations were determined. Net CO exchange was reduced from 65.2 to 30 g vine day, or 54%, by the sub-ambient treatment. At the end of the 10 day period, total sugar concentration was reduced from 95 to 77 g L from an average starting value of 23 g L, representing a 25% reduction. Scaling to a per vine basis, it was estimated that 223 g of berry sugars accumulated under ambient supply compared to 166 g under sub-ambient, an amount equivalent to 50 and 72% of total C assimilated.

Conclusions: Through supply of sub-ambient CO using whole canopy gas exchange chambers system, an effective method was developed for reducing photosynthesis and slowing the rate of berry sugar accumulation without modifying yield or leaf area. While in this case developed for further investigations of grape and wine composition, the system has broader applications for the manipulation and of study of grapevine source-sink relations.
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http://dx.doi.org/10.1186/s12870-019-2152-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6889647PMC
December 2019

Self-reported sleep disturbances are associated with poorer cognitive performance in older adults with hypertension: a multi-parameter risk factor investigation.

Int Psychogeriatr 2020 Jul;32(7):815-825

Department of Psychiatry, University of California, San Diego, USA.

Objectives: Given the evidence of multi-parameter risk factors in shaping cognitive outcomes in aging, including sleep, inflammation, cardiometabolism, and mood disorders, multidimensional investigations of their impact on cognition are warranted. We sought to determine the extent to which self-reported sleep disturbances, metabolic syndrome (MetS) factors, cellular inflammation, depressive symptomatology, and diminished physical mobility were associated with cognitive impairment and poorer cognitive performance.

Design: This is a cross-sectional study.

Setting: Participants with elevated, well-controlled blood pressure were recruited from the local community for a Tai Chi and healthy-aging intervention study.

Participants: One hundred forty-five older adults (72.7 ± 7.9 years old; 66% female), 54 (37%) with evidence of cognitive impairment (CI) based on Montreal Cognitive Assessment (MoCA) score ≤24, underwent medical, psychological, and mood assessments.

Measurements: CI and cognitive domain performance were assessed using the MoCA. Univariate correlations were computed to determine relationships between risk factors and cognitive outcomes. Bootstrapped logistic regression was used to determine significant predictors of CI risk and linear regression to explore cognitive domains affected by risk factors.

Results: The CI group were slower on the mobility task, satisfied more MetS criteria, and reported poorer sleep than normocognitive individuals (all p < 0.05). Multivariate logistic regression indicated that sleep disturbances, but no other risk factors, predicted increased risk of evidence of CI (OR = 2.00, 95% CI: 1.26-4.87, 99% CI: 1.08-7.48). Further examination of MoCA cognitive subdomains revealed that sleep disturbances predicted poorer executive function (β = -0.26, 95% CI: -0.51 to -0.06, 99% CI: -0.61 to -0.02), with lesser effects on visuospatial performance (β = -0.20, 95% CI: -0.35 to -0.02, 99% CI: -0.39 to 0.03), and memory (β = -0.29, 95% CI: -0.66 to -0.01, 99% CI: -0.76 to 0.08).

Conclusions: Our results indicate that the deleterious impact of self-reported sleep disturbances on cognitive performance was prominent over other risk factors and illustrate the importance of clinician evaluation of sleep in patients with or at risk of diminished cognitive performance. Future, longitudinal studies implementing a comprehensive neuropsychological battery and objective sleep measurement are warranted to further explore these associations.
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http://dx.doi.org/10.1017/S1041610219001492DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8011648PMC
July 2020

Optimizing Mycophenolic Acid Exposure in Kidney Transplant Recipients: Time for Target Concentration Intervention.

Transplantation 2019 10;103(10):2012-2030

Department of Paediatrics, The University of Melbourne, Melbourne, VIC, Australia.

The immunosuppressive agent mycophenolate is used extensively in kidney transplantation, yet dosing strategy applied varies markedly from fixed dosing ("one-dose-fits-all"), to mycophenolic acid (MPA) trough concentration monitoring, to dose optimization to an MPA exposure target (as area under the concentration-time curve [MPA AUC0-12]). This relates in part to inconsistent results in prospective trials of concentration-controlled dosing (CCD). In this review, the totality of evidence supporting mycophenolate CCD is examined: pharmacological characteristics, observational data linking exposure to efficacy and toxicities, and randomized controlled trials of CCD, with attention to dose optimization method and exposure achieved. Fixed dosing of mycophenolate consistently leads to underexposure associated with rejection, as well as overexposure associated with toxicities. When CCD is driven by pharmacokinetic calculation to a target concentration (target concentration intervention), MPA exposure is successfully controlled and clinical benefits are seen. There remains a need for consensus on practical aspects of mycophenolate target concentration intervention in contemporary tacrolimus-containing regimens and future research to define maintenance phase exposure targets. However, given ongoing consequences of both overimmunosuppression and underimmunosuppression in kidney transplantation, impacting short- and long-term outcomes, these should be a priority. The imprecise "one-dose-fits-all" approach should be replaced by the clinically proven MPA target concentration strategy.
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http://dx.doi.org/10.1097/TP.0000000000002762DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6756255PMC
October 2019

First isolation of Flavobacterium psychrophilum associated with reports of moribund wild European eel (Anguilla anguilla) in Scotland.

J Fish Dis 2019 Nov 27;42(11):1509-1521. Epub 2019 Aug 27.

Marine Laboratory, Marine Scotland Science, Aberdeen, UK.

In late April 2015, the River Dee Trust informed Marine Scotland Science, Fish Health Inspectorate (FHI), that there had been observations of dead and moribund European eels on the River Dee. Later in May, the Spey Fishery Board also reported a number of moribund European eels in a rotary screw smolt trap on the River Spey. In total, 10 cases involving moribund eels were investigated in 2015 and one case in 2016. In addition, a health screen was conducted to investigate the potential presence of Flavobacterium psychrophilum in healthy eels and Atlantic salmon from the River Dee in 2015. Externally, the diseased eels demonstrated white patches in different locations of the body. In all cases, F. psychrophilum was detected by bacterial isolation and/or molecular methods. Three isolates were further characterized by whole-genome sequencing (WGS) as belonging to sequence type 15 (ST15). Histological examination of diseased European eels revealed lesions at the level of the integument. The pathogen screen for F. psychrophilum in wild healthy fish tested negative by PCR. Further investigation is required to understand the pathogenicity of this bacterium on the health of eels and the potential impact on the wild salmonid population.
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http://dx.doi.org/10.1111/jfd.13069DOI Listing
November 2019

The MYB5-driven MBW complex recruits a WRKY factor to enhance the expression of targets involved in vacuolar hyper-acidification and trafficking in grapevine.

Plant J 2019 09 27;99(6):1220-1241. Epub 2019 Jun 27.

Department of Biotechnology, University of Verona, Verona, Italy.

The accumulation of secondary metabolites and the regulation of tissue acidity contribute to the important traits of grape berry and influence plant performance in response to abiotic and biotic factors. In several plant species a highly conserved MYB-bHLH-WD (MBW) transcriptional regulatory complex controls flavonoid pigment synthesis and transport, and vacuolar acidification in epidermal cells. An additional component, represented by a WRKY-type transcription factor, physically interacts with the complex increasing the expression of some target genes and adding specificity for other targets. Here we investigated the function of MBW(W) complexes involving two MYBs (VvMYB5a and VvMYB5b) and the WRKY factor VvWRKY26 in grapevine (Vitis vinifera L.). Using transgenic grapevine plants we showed that these complexes affected different aspects of morphology, plant development, pH regulation, and pigment accumulation. Transcriptomic analysis identified a core set of putative target genes controlled by VvMYB5a, VvMYB5b, and VvWRKY26 in different tissues. Our data indicated that VvWRKY26 enhances the expression of selected target genes induced by VvMYB5a/b. Among these targets are genes involved in vacuolar hyper-acidification, such as the P-type ATPases VvPH5 and VvPH1, and trafficking, and genes involved in the biosynthesis of flavonoids. In addition, VvWRKY26 is recruited specifically by VvMYB5a, reflecting the functional diversification of VvMYB5a and VvMYB5b. The expression of MBWW complexes in vegetative organs, such as leaves, indicates a possible function of vacuolar hyper-acidification in the repulsion of herbivores and/or in developmental processes, as shown by defects in transgenic grape plants where the complex is inactivated.
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http://dx.doi.org/10.1111/tpj.14419DOI Listing
September 2019

NAV-KIDS trial: protocol for a multi-centre, staggered randomised controlled trial of a patient navigator intervention in children with chronic kidney disease.

BMC Nephrol 2019 04 18;20(1):134. Epub 2019 Apr 18.

Centre for Kidney Research at The Children's Hospital at Westmead, Westmead, New South Wales, Australia.

Background: Chronic kidney disease (CKD) is a devastating illness associated with increased mortality, reduced quality of life, impaired growth, neurocognitive impairment and psychosocial maladjustment in children. There is growing evidence of socioeconomic disparities in health outcomes among children with CKD. Patient navigators are trained non-medical personnel who assist patients with chronic conditions journey through the continuum of care and transit across different care settings. They help vulnerable and underserved populations to better understand their diagnosis, treatment options, and available resources, guide them through complex medical systems, and help them to overcome barriers to health care access. Given the complexity and chronicity of the disease process and concerns that current models of care may not adequately support the provision of high-level care in children with CKD from socioeconomically disadvantaged backgrounds, a patient navigator program may improve the provision of care and overall health of children with CKD.

Methods: The NAV-KIDS trial is a multi-centre, staggered entry, waitlisted randomised controlled trial assessing the health benefits and costs of a patient navigator program in children with CKD (stages 3-5, on dialysis, and with kidney transplants), who are of low socioeconomic backgrounds. Across 5 sites, 210 patients aged from 3 to 17 years will be randomised to immediate receipt of a patient navigator intervention for 24 weeks or waitlisting with standard care until receipt of a patient navigator at 24 weeks. The primary outcome is child self-rated health (SRH) 6-months after completion of the intervention. Other outcomes include utility-based quality of life, caregiver SRH, satisfaction with healthcare, progression of kidney dysfunction, other biomarkers, missed school days, hospitalisations and mortality. The trial also includes an economic evaluation and process evaluation, which will assess the cost-effectiveness, fidelity and barriers and enablers of implementing a patient navigator program in this setting.

Discussion: This study will provide clear evidence on the effectiveness and cost-effectiveness of a new intervention aiming to improve overall health and well-being for children with CKD from socioeconomically disadvantaged backgrounds, through a high quality, well-powered clinical trial.

Trial Registration: Prospectively registered (12/07/2018) on the Australian New Zealand Clinical Trials Registry ( ACTRN12618001152213 ).
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http://dx.doi.org/10.1186/s12882-019-1325-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6471999PMC
April 2019

Major Device-Dependence of Measured Hypertensive Status From 24-Hour Ambulatory Blood Pressure Monitoring After Aortic Coarctation Repair.

Heart Lung Circ 2019 Jul 6;28(7):1082-1089. Epub 2018 Jun 6.

Department of Cardiac Surgery, The Royal Children's Hospital, Melbourne, Vic, Australia; Department of Paediatrics, University of Melbourne, Melbourne, Vic, Australia; Heart Research, Clinical Sciences, Murdoch Children's Research Institute, Melbourne, Vic, Australia. Electronic address:

Background: Twenty-four-hour (24-hr) ambulatory blood pressure monitoring (ABPM) is often considered the gold standard to detect hypertension. We aimed to determine the short-term progression of 24-hour blood pressure after coarctation repair and to compare ABPM between two different devices.

Methods: We performed a cross-sectional study using 24-hour ABPM (Oscar 2) in 47 patients aged 16-48 years with previous paediatric coarctation repair and not on antihypertensive medication. Results were compared to a previous ABPM using paired analyses. A subset (10/47, 21%) had an additional previous ABPM performed using a Spacelabs device.

Results: After a mean follow-up of 27±6 years after repair, hypertension and prehypertension on Oscar 2 ABPM was present in 57% (27/47) and 11% (5/47), respectively. Mean follow-up time between Oscar 2 ABPMs was 3.9±1.4 years, and between first Oscar 2 and Spacelabs and between Spacelabs and second Oscar 2 ABPM was 1.4±0.8 and 1.8±0.3 years, respectively. There was no difference in the proportion of hypertensive patients between Oscar 2 ABPMs (55% [26/47] vs. 57% [27/47], p=1.0) but 17 patients (17/47, 36%) had a reclassification of 24-hour ABPM status. Mean 24-hour systolic blood pressure was higher in both Oscar 2 ABPMs compared to Spacelabs (142.4±11.7 vs. 120.4±11.8mmHg, p=0.0001; and 137.4±12.2 vs. 120.4±11.8mmHg, p=0.0001; respectively).

Conclusion: There was high intra-device reproducibility of 24-hour ABPM results using an Oscar 2 device but poor inter-device reproducibility in patients with repaired coarctation. Device-specific reference values may be required to ensure reliable 24-hour ABPM interpretation.
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http://dx.doi.org/10.1016/j.hlc.2018.05.189DOI Listing
July 2019

Identifying Important Outcomes for Young People With CKD and Their Caregivers: A Nominal Group Technique Study.

Am J Kidney Dis 2019 07 15;74(1):82-94. Epub 2019 Mar 15.

Division of Nephrology, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India.

Rationale & Objective: Chronic kidney disease (CKD) has wide-ranging and long-term consequences for young people and their families. The omission of outcomes that are important to young people with CKD and their caregivers limits knowledge to guide shared decision making. We aimed to identify the outcomes that are important to young people with CKD and their caregivers.

Study Design: We used the nominal group technique whereby participants identified and ranked outcomes and explained their priorities.

Settings & Participants: Young people with CKD (stages 1-5, dialysis, or transplantation) and their caregivers were purposively sampled from 6 centers across Australia, the United States, and Canada.

Analytical Approach: Importance scores were calculated (scale of 0-1), and qualitative data were analyzed thematically.

Results: 34 patients (aged 8-21 years) and 62 caregivers participated in 16 groups and identified 48 outcomes. The 5 highest ranked outcomes for patients were survival (importance score, 0.25), physical activity (0.24), fatigue (0.20), lifestyle restrictions (0.20), and growth (0.20); and for caregivers, kidney function (0.53), survival (0.28), infection (0.22), anemia (0.20), and growth (0.17). 12 themes were identified reflecting their immediate and current priorities (wanting to feel normal, strengthening resilience, minimizing intrusion into daily life, imminent threats to life, devastating family burdens, and seeking control over health) and considerations regarding future impacts (protecting health/development, remaining hopeful, concern for limited opportunities, prognostic uncertainty, dreading painful and invasive procedures, and managing expectations).

Limitations: Only English-speaking participants were recruited.

Conclusions: Kidney function, infection, survival, and growth were the highest priorities for patients with CKD and their caregivers. Young people with CKD also prioritized highly the outcomes that directly affected their lifestyle and sense of normality, while caregiver's highest priorities concerned the long-term health of their child, current health problems, and the financial and family burdens of caring for a child with CKD.
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http://dx.doi.org/10.1053/j.ajkd.2018.12.040DOI Listing
July 2019

The anatomy and histochemistry of flight hindlimb posture in birds. II. The flexed hindlimb posture of perching birds.

J Anat 2019 05 12;234(5):668-678. Epub 2019 Mar 12.

Department of Zoology, Weber State University, Ogden, UT, USA.

During flight, birds employ one of two hindlimb postures. Perching birds utilize a flexed posture with their folded legs tucked beneath the body, whereas shorebirds and raptors use an extended posture with straightened legs trailing behind the body. Maintenance of either posture during flight requires the hindlimbs to hold their position for prolonged periods. Slow contracting fibers are known for their fatigue-resistant properties and are often found in high percentages in muscles utilized for postural actions. Given the similar actions required of the hip and knee flexors used during flight, we hypothesized that the equivalent postural muscles of perching birds (flexed posture) would contain similar percentages of slow fibers as shorebirds (extended posture). We investigated the anatomy and fiber type composition of seven hindlimb muscles in yellow-headed and red-winged blackbirds and revealed that they possess a smaller percentage of slow fibers than we found previously in the same muscles of American avocets and black-necked stilts. The comparably smaller body size of yellow-headed and red-winged blackbirds could mitigate the need for more slow fibers. In addition, the biomechanical placement of the weight force in the flexed posture may require less muscle force for postural support during flight and, therefore, fewer slow fibers.
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http://dx.doi.org/10.1111/joa.12960DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6481409PMC
May 2019

The association between socioeconomic disadvantage and parent-rated health in children and adolescents with chronic kidney disease-the Kids with CKD (KCAD) study.

Pediatr Nephrol 2019 07 20;34(7):1237-1245. Epub 2019 Feb 20.

Centre for Kidney Research, The Children's Hospital at Westmead, Sydney, Australia.

Objective: To determine the association of socioeconomic disadvantage and parent-rated health in children with chronic kidney disease (CKD).

Methods: A total of 377 children (aged 6-18 years) with CKD stages I-V (n = 199), on dialysis (n = 43), or with a kidney transplant (n = 135) were recruited from 2012 to 2016 in Australia and New Zealand. Associations of five socioeconomic status (SES) components and the global SES index with parent-rated health of the child were examined using adjusted logistic regression.

Results: The median age of participants was 12.6 years (interquartile range (IQR) 8.9-15.5). In the entire cohort, the adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for poor parent-rated health were 1.85 (1.13-3.03) for lower household income, 1.78 (1.08-2.96) for families that did not own their own home, 2.50 (1.50-4.16) for caregivers who rated their financial status as poor, 0.84 (0.51-1.38) for lower educational attainment, and 1.68 (1.04-2.72) for children whose primary caregivers were unemployed. With reference to the highest global SES index quartile, adjusted ORs for poor parent-rated health in descending order were 1.49 (0.69-3.21), 2.11 (1.06-4.20), and 2.20 (1.09-4.46), respectively. The association between low SES and poor parent-rated health was modified by CKD stage, where lower global SES index was independently associated with poor parent-rated health in children with CKD stages I-V, but not children on dialysis or with kidney transplants (p = 0.04).

Conclusions: Low SES is associated with poor parent-rated health in children with CKD stages I-V, but not children on dialysis and with kidney transplants.
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http://dx.doi.org/10.1007/s00467-019-04209-7DOI Listing
July 2019

Clostridium difficile infection in pregnant and postpartum women in 2 hospitals and a review of literature.

Am J Infect Control 2019 01 6;47(1):e7-e14. Epub 2018 Jul 6.

Public Health England, London, UK.

Background: Healthcare-associated Clostridium difficile infection (CDI) in pregnant/postpartum women is underreported, especially outside of North America. We report a cluster of cases in 2 neighboring secondary care hospitals in South-East England. The objective of this study was to identify the epidemiology and risk factors for infection.

Methods: An investigation into a cluster of cases of confirmed CDI in pregnant/postpartum women was performed over a 12-month period, from June 2016 to June 2017.

Results: Eleven cases, in 10 patients, were identified, including 1 patient who had a relapse. Eight of 10 patients developed symptoms after hospital discharge. All patients had received broad-spectrum antibiotics prior to CDI onset. Environmental vectors, such as labor room mattresses, that were found difficult to effectively decontaminate after heavy contamination with blood, feces, and other body fluids may have been possible reservoirs. An infection control care bundle was successful in preventing further cases.

Conclusions: Antibiotic use and exposure to the organism in a contaminated labor room environment are likely risk factors for healthcare-associated CDI in postpartum women. Active surveillance is necessary to prevent these infections, as these cases often present after hospital discharge.
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http://dx.doi.org/10.1016/j.ajic.2018.06.001DOI Listing
January 2019

Clinical Development of Novel Drug-Radiotherapy Combinations.

Clin Cancer Res 2019 03 29;25(5):1455-1461. Epub 2018 Nov 29.

Radiation Oncology, NIHR University College London Hospitals Biomedical Research Centre, University College London Cancer Institute, University College London, London, United Kingdom.

Radiotherapy is a fundamental component of treatment for the majority of patients with cancer. In recent decades, technological advances have enabled patients to receive more targeted doses of radiation to the tumor, with sparing of adjacent normal tissues. There had been hope that the era of precision medicine would enhance the combination of radiotherapy with targeted anticancer drugs; however, this ambition remains to be realized. In view of this lack of progress, the FDA-AACR-ASTRO Clinical Development of Drug-Radiotherapy Combinations Workshop was held in February 2018 to bring together stakeholders and opinion leaders from academia, clinical radiation oncology, industry, patient advocacy groups, and the FDA to discuss challenges to introducing new drug-radiotherapy combinations to the clinic. This article summarizes the themes and action points that were discussed. Intelligent trial design is required to increase the number of studies that efficiently meet their primary outcomes; endpoints to be considered include local control, organ preservation, and patient-reported outcomes. Novel approaches including immune-oncology or DNA-repair inhibitor agents combined with radiotherapy should be prioritized. In this article, we focus on how the regulatory challenges associated with defining a new drug-radiotherapy combination can be overcome to improve clinical outcomes for patients with cancer.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-2466DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6397668PMC
March 2019

Grape berry flavonoids: a review of their biochemical responses to high and extreme high temperatures.

J Exp Bot 2019 01;70(2):397-423

National Wine and Grape Industry Centre, Wagga Wagga, New South Wales, Australia.

Climate change scenarios predict an increase in average temperatures and in the frequency, intensity, and length of extreme temperature events in many wine regions around the world. In already warm and hot regions, such changes may compromise grape growing and the production of high quality wine as high temperature has been found to affect berry composition critically. Most recent studies focusing on the sole effect of temperature, separated from light and water, on grape berry composition found that high temperature affects a wide range of metabolites, and in particular flavonoids-key compounds for berry and wine quality. A decrease in total anthocyanins is reported in most cases, and appears to be directly associated with high temperature. Changes in anthocyanin composition, and flavonol and proanthocyanidin responses are however less consistent, and reflect the complexity of the underlying biosynthetic pathways and diversity of experimental treatments that have been used in these studies. This review examines the impact of high temperature on the biosynthesis, accumulation, and degradation of flavonoids, and attempts to reconcile the diversity of responses in relation to the latest understanding of flavonoid chemistry and molecular regulation.
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http://dx.doi.org/10.1093/jxb/ery392DOI Listing
January 2019

Buckwheat R2R3 MYB transcription factor FeMYBF1 regulates flavonol biosynthesis.

Plant Sci 2018 Sep 13;274:466-475. Epub 2018 Jul 13.

National Agriculture and Food Research Organization (NARO), Kyushu Okinawa Agricultural Research Center, Suya 2421, Koshi, Kumamoto 861-1192, Japan.

Buckwheat (Fagopyrum esculentum) contains high amounts of flavonoids, especially flavonols (e.g., rutin), which are thought to be highly beneficial for human health. Little is known, however, about the regulation of flavonol synthesis in buckwheat. We identified a buckwheat gene encoding an R2R3 MYB transcription factor, and named this gene FeMYBF1. Analysis of the deduced amino acid sequence and phylogenetic analysis suggested that FeMYBF1 encodes an ortholog of the Arabidopsis flavonol regulators AtMYB11, AtMYB12 and AtMYB111. Expression of FeMYBF1 in a flavonol-deficient Arabidopsis triple mutant (myb11 myb12 myb111) restored flavonol synthesis. Constitutive expression of FeMYBF1 driven by the CaMV 35S promoter in Arabidopsis resulted in over-accumulation of flavonol glycosides and upregulation of the expression of AtFLS1. Transient expression assays showed that FeMYBF1 activated the promoter of the Arabidopsis gene encoding AtFLS1, and the promoters of buckwheat genes related to anthocyanin and proanthocyanidin synthesis such as dihydroflavonol 4-reductase (DFR) and leucoanthocyanidin dioxygenase (LDOX) in addition to genes encoding FLS. The results indicate that FeMYBF1 regulates flavonol synthesis and may have a role in synthesis of other flavonoid compounds, and also that buckwheat may have alternative pathway of flavonol synthesis through DFR and LDOX.
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http://dx.doi.org/10.1016/j.plantsci.2018.06.025DOI Listing
September 2018

Quality of life of children and adolescents with chronic kidney disease: a cross-sectional study.

Arch Dis Child 2019 02 17;104(2):134-140. Epub 2018 Jul 17.

Sydney School of Public Health, The University of Sydney, Sydney, New South Wales, Australia.

Objective: The aim was to compare quality of life (QoL) among children and adolescents with different stages of chronic kidney disease (CKD) and determine factors associated with changes in QoL.

Design: Cross-sectional.

Setting: The Kids with CKD study involved five of eight paediatric nephrology units in Australia and New Zealand.

Patients: There were 375 children and adolescents (aged 6-18 years) with CKD, on dialysis or transplanted, recruited between 2013 and 2016.

Main Outcome Measures: Overall and domain-specific QoL were measured using the Health Utilities Index 3 score, with a scale from -0.36 (worse than dead) to 1 (perfect health). QoL scores were compared between CKD stages using the Mann-Whitney U test. Factors associated with changes in QoL were assessed using multivariable linear and ordinal logistic regression.

Results: QoL for those with CKD stages 1-2 (n=106, median 0.88, IQR 0.63-0.96) was higher than those on dialysis (n=43, median 0.67, IQR 0.39-0.91, p<0.001), and similar to those with kidney transplants (n=135, median 0.83, IQR 0.59-0.97, p=0.4) or CKD stages 3-5 (n=91, 0.85, IQR 0.60-0.98). Reductions were most frequent in the domains of cognition (50%), pain (42%) and emotion (40%). The risk factors associated with decrements in overall QoL were being on dialysis (decrement of 0.13, 95% CI 0.02 to 0.25, p=0.02), lower family income (decrement of 0.10, 95% CI 0.03 to 0.15, p=0.002) and short stature (decrement of 0.09, 95% CI 0.01 to 0.16, p=0.02).

Conclusions: The overall QoL and domains such as pain and emotion are substantially worse in children on dialysis compared with earlier stage CKD and those with kidney transplants.
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http://dx.doi.org/10.1136/archdischild-2018-314934DOI Listing
February 2019

Child and Parental Perspectives on Communication and Decision Making in Pediatric CKD: A Focus Group Study.

Am J Kidney Dis 2018 10 3;72(4):547-559. Epub 2018 Jul 3.

Sydney School of Public Health, The University of Sydney, Sydney; Centre for Kidney Research, The Children's Hospital at Westmead, Westmead, NSW, Australia.

Background & Objectives: Effective communication and shared decision making improve quality of care and patient outcomes but can be particularly challenging in pediatric chronic disease because children depend on their parents and clinicians to manage complex health care and developmental needs. We aimed to describe the perspectives of children with chronic kidney disease (CKD) and their parents with regard to communication and decision making.

Study Design: Qualitative study.

Setting & Participants: Children with CKD (n=34) and parents (n=62) from 6 centers across 6 cities in Australia, Canada, and the United States participated in 16 focus groups.

Analytical Approach: Transcripts were analyzed thematically.

Results: We identified 4 themes: (1) disempowered by knowledge imbalance (unprepared and ill-informed, suspicion of censorship, and inadequacy as technicians), (2) recognizing own expertise (intuition and instinct unique to parental bond, emerging wisdom and confidence, identifying opportunities for control and inclusion, and empowering participation in children), (3) striving to assert own priorities (negotiating broader life impacts, choosing to defer decisional burden, overprotected and overruled, and struggling to voice own preferences), and (4) managing child's involvement (respecting child's expertise, attributing "risky" behaviors to rebellion, and protecting children from illness burden).

Limitations: Only English-speaking participants were recruited, which may limit the transferability of the findings. We collected data from child and parent perspectives; however, clinician perspectives may provide further understanding of the difficulties of communication and decision making in pediatrics.

Conclusions: Parents value partnership with clinicians and consider long-term and quality-of-life implications of their child's illness. Children with CKD want more involvement in treatment decision making but are limited by vulnerability, fear, and uncertainty. There is a need to support the child to better enable him or her to become a partner in decision making and prepare him or her for adulthood. Collaborative and informed decision making that addresses the priorities and concerns of both children and parents is needed.
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http://dx.doi.org/10.1053/j.ajkd.2018.05.005DOI Listing
October 2018

Policy and Practice-Relevant Youth Physical Activity Research Center Agenda.

J Phys Act Health 2018 08 8;15(8):626-634. Epub 2018 Jun 8.

Background: The Physical Activity Research Center developed a research agenda that addresses youth physical activity (PA) and healthy weight, and aligns with the Robert Wood Johnson Foundation's Culture of Health. This paper summarizes prioritized research studies with a focus on youth at higher risk for inactive lifestyles and childhood obesity in urban and rural communities.

Methods: Systematic literature reviews, a survey, and discussions with practitioners and researchers provided guidance on research questions to build evidence and inform effective strategies to promote healthy weight and PA in youth across race, cultural, and economic groups.

Results: The research team developed a matrix of potential research questions, identified priority questions, and designed targeted studies to address some of the priority questions and inform advocacy efforts. The studies selected examine strategies advocating for activity-friendly communities, Play Streets, park use, and PA of youth in the summer. A broader set of research priorities for youth PA is proposed.

Conclusion: Establishing the Physical Activity Research Center research agenda identified important initial and future research studies to promote and ensure healthy weight and healthy levels of PA for at-risk youth. Results will be disseminated with the goal of promoting equitable access to PA for youth.
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http://dx.doi.org/10.1123/jpah.2017-0327DOI Listing
August 2018

Lifetime risk of end-stage kidney disease in living donors for paediatric kidney transplant recipients in Australia and New Zealand - a retrospective study.

Transpl Int 2018 10 20;31(10):1144-1152. Epub 2018 Jun 20.

University of Melbourne, Parkville, Vic., Australia.

Living kidney donors (LKD) for paediatric kidney transplant recipients (KTR) have a heightened motivation to donate for emotional reasons and the clear health benefits to the KTR. We hypothesized that the cohort of LKD for paediatric KTR (LKD-P) includes motivated young parents with a higher lifetime end-stage kidney disease (ESKD) risk compared to adult KTR (LKD-A). Data from the Australia and New Zealand Dialysis and Transplant LKD Registry (2004-2015) was analysed to compare baseline characteristics and predonation ESKD risk in LKD-P (n = 315) versus LKD-A (n = 3448). LKD-P were younger (median age 42 vs. 50 years; P < 0.001) and had a marginally higher lifetime ESKD risk (median 0.44% vs. 0.40%; P < 0.01), with a similar proportion of LKD exceeding 1% risk threshold (5.4% vs. 5.6%; P = NS). Compared to grandparents as LKD-P, parents (median age 41 vs. 59 years; P < 0.001) had a higher lifetime ESKD (0.44% vs. 0.25%; P < 0.001). Although unique benefits to paediatric KTR justify the minor increase in lifetime ESKD risk in young parents, carefully selected grandparents are an alternative LKD-P option, allowing parents to donate for subsequent transplants.
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http://dx.doi.org/10.1111/tri.13284DOI Listing
October 2018