Displaying publications 1 - 20 of 27 in total

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  1. Maggo SD, Chua EW, Chin P, Cree S, Pearson J, Doogue M, et al.
    N Z Med J, 2017 Dec 01;130(1466):62-69.
    PMID: 29197902
    A multitude of factors can affect drug response in individuals. It is now well established that variations in genes, especially those coding for drug metabolising enzymes, can alter the pharmacokinetic and/or pharmacodynamic profile of a drug, impacting on efficacy and often resulting in drug-induced toxicity. The UDRUGS study is an initiative from the Carney Centre for Pharmacogenomics to biobank DNA and store associated clinical data from patients who have suffered rare and/or serious adverse drug reactions (ADRs). The aim is to provide a genetic explanation of drug-induced ADRs using methods ranging from Sanger sequencing to whole exome and whole genome sequencing. Participants for the UDRUGS study are recruited from various sources, mainly via referral through clinicians working in Canterbury District Health Board, but also from district health boards across New Zealand. Participants have also self-referred to us from word-of-mouth communication between participants. We have recruited various ADRs across most drug classes. Where possible, we have conducted genetic analyses in single or a cohort of cases to identify known and novel genetic association(s) to offer an explanation to why the ADR occurred. Any genetic results relevant to the ADR are communicated back to the referring clinician and/or participant. In conclusion, we have developed a programme for studying the genetic basis of severe, rare or unusual ADR cases resulting from pharmacological treatment. Genomic analyses could eventually identify most genetic variants that predispose to ADRs, enabling a priori detection of such variants with high throughput DNA tests.
  2. Konopacka A, Qiu J, Yao ST, Greenwood MP, Greenwood M, Lancaster T, et al.
    J Neurosci, 2015 Apr 01;35(13):5144-55.
    PMID: 25834041 DOI: 10.1523/JNEUROSCI.4121-14.2015
    The Na-K-2Cl cotransporter 2 (NKCC2) was thought to be kidney specific. Here we show expression in the brain hypothalamo-neurohypophyseal system (HNS), wherein upregulation follows osmotic stress. The HNS controls osmotic stability through the synthesis and release of the neuropeptide hormone, arginine vasopressin (AVP). AVP travels through the bloodstream to the kidney, where it promotes water conservation. Knockdown of HNS NKCC2 elicited profound effects on fluid balance following ingestion of a high-salt solution-rats produced significantly more urine, concomitant with increases in fluid intake and plasma osmolality. Since NKCC2 is the molecular target of the loop diuretics bumetanide and furosemide, we asked about their effects on HNS function following disturbed water balance. Dehydration-evoked GABA-mediated excitation of AVP neurons was reversed by bumetanide, and furosemide blocked AVP release, both in vivo and in hypothalamic explants. Thus, NKCC2-dependent brain mechanisms that regulate osmotic stability are disrupted by loop diuretics in rats.
  3. Yahya N, Ebert MA, Bulsara M, House MJ, Kennedy A, Joseph DJ, et al.
    Radiother Oncol, 2015 Nov;117(2):277-82.
    PMID: 26476560 DOI: 10.1016/j.radonc.2015.10.003
    This study aimed to compare urinary dose-symptom correlates after external beam radiotherapy of the prostate using commonly utilised peak-symptom models to multiple-event and event-count models which account for repeated events.
  4. Yahya N, Ebert MA, Bulsara M, Haworth A, Kennedy A, Joseph DJ, et al.
    Radiother Oncol, 2015 Jul;116(1):112-8.
    PMID: 26163088 DOI: 10.1016/j.radonc.2015.06.011
    To identify dosimetry, clinical factors and medication intake impacting urinary symptoms after prostate radiotherapy.
  5. Yahya N, Ebert MA, Bulsara M, Kennedy A, Joseph DJ, Denham JW
    Radiother Oncol, 2016 08;120(2):339-45.
    PMID: 27370204 DOI: 10.1016/j.radonc.2016.05.010
    BACKGROUND AND PURPOSE: Most predictive models are not sufficiently validated for prospective use. We performed independent external validation of published predictive models for urinary dysfunctions following radiotherapy of the prostate.

    MATERIALS/METHODS: Multivariable models developed to predict atomised and generalised urinary symptoms, both acute and late, were considered for validation using a dataset representing 754 participants from the TROG 03.04-RADAR trial. Endpoints and features were harmonised to match the predictive models. The overall performance, calibration and discrimination were assessed.

    RESULTS: 14 models from four publications were validated. The discrimination of the predictive models in an independent external validation cohort, measured using the area under the receiver operating characteristic (ROC) curve, ranged from 0.473 to 0.695, generally lower than in internal validation. 4 models had ROC >0.6. Shrinkage was required for all predictive models' coefficients ranging from -0.309 (prediction probability was inverse to observed proportion) to 0.823. Predictive models which include baseline symptoms as a feature produced the highest discrimination. Two models produced a predicted probability of 0 and 1 for all patients.

    CONCLUSIONS: Predictive models vary in performance and transferability illustrating the need for improvements in model development and reporting. Several models showed reasonable potential but efforts should be increased to improve performance. Baseline symptoms should always be considered as potential features for predictive models.

  6. Yahya N, Ebert MA, Bulsara M, Haworth A, Kearvell R, Foo K, et al.
    Radiat Oncol, 2014;9:282.
    PMID: 25498565 DOI: 10.1186/s13014-014-0282-7
    To assess the impact of incremental modifications of treatment planning and delivery technique, as well as patient anatomical factors, on late gastrointestinal toxicity using data from the TROG 03.04 RADAR prostate radiotherapy trial.
  7. Lozić M, Tasić T, Martin A, Greenwood M, Šarenac O, Hindmarch C, et al.
    Pharmacol Res, 2016 12;114:185-195.
    PMID: 27810519 DOI: 10.1016/j.phrs.2016.10.024
    The hypothalamic paraventricular nucleus (PVN) is a key integrative site for the neuroendocrine control of the circulation and of the stress response. It is also a major source of the neuropeptide hormone vasopressin (VP), and co-expresses V1a receptors (V1aR). We thus sought to investigate the role of V1aR in PVN in cardiovascular control in response to stress. Experiments were performed in male Wistar rats equipped with radiotelemetric device. The right PVN was transfected with adenoviral vectors (Ads) engineered to over-express V1aR along with an enhanced green fluorescent protein (eGFP) tag. Control groups were PVN transfected with Ads expressing eGFP alone, or wild-type rats (Wt). Rats were recorded with and without selective blockade of V1aR (V1aRX) in PVN under both baseline and stressed conditions. Blood pressure (BP), heart rate (HR), their short-term variabilities, and baroreflex sensitivity (BRS) were evaluated using spectral analysis and the sequence method, respectively. Under baseline physiological conditions,V1aR rats exhibited reduced BRS and a marked increase of BP and HR variability during exposure to stress. These effects were all prevented by V1aRX pretreatment. In Wt rats, V1aRX did not modify cardiovascular parameters under baseline conditions, and prevented BP variability increase by stress. However, V1aRX pretreatment did not modify baroreflex desensitization by stress in either rat strain. It follows that increased expression of V1aR in PVN influences autonomic cardiovascular regulation and demarcates vulnerability to stress. We thus suggest a possible role of hypothalamic V1aR in cardiovascular pathology.
  8. Eriksson K, Strimling P, Gelfand M, Wu J, Abernathy J, Akotia CS, et al.
    Nat Commun, 2021 Apr 26;12(1):2483.
    PMID: 33903599 DOI: 10.1038/s41467-021-22955-x
  9. Eriksson K, Strimling P, Gelfand M, Wu J, Abernathy J, Akotia CS, et al.
    Nat Commun, 2021 03 05;12(1):1481.
    PMID: 33674587 DOI: 10.1038/s41467-021-21602-9
    Norm enforcement may be important for resolving conflicts and promoting cooperation. However, little is known about how preferred responses to norm violations vary across cultures and across domains. In a preregistered study of 57 countries (using convenience samples of 22,863 students and non-students), we measured perceptions of the appropriateness of various responses to a violation of a cooperative norm and to atypical social behaviors. Our findings highlight both cultural universals and cultural variation. We find a universal negative relation between appropriateness ratings of norm violations and appropriateness ratings of responses in the form of confrontation, social ostracism and gossip. Moreover, we find the country variation in the appropriateness of sanctions to be consistent across different norm violations but not across different sanctions. Specifically, in those countries where use of physical confrontation and social ostracism is rated as less appropriate, gossip is rated as more appropriate.
  10. Chua EW, Maggo S, Kennedy MA
    Methods Mol Biol, 2017;1620:65-74.
    PMID: 28540699 DOI: 10.1007/978-1-4939-7060-5_3
    Polymerase chain reaction (PCR) is an oft-used preparatory technique in amplifying specific DNA regions for downstream analysis. The size of an amplicon was initially limited by errors in nucleotide polymerization and template deterioration during thermal cycling. A variant of PCR, designated long-range PCR, was devised to counter these drawbacks and enable the amplification of large fragments exceeding a few kb. In this chapter we describe a protocol for long-range PCR, which we have adopted to obtain products of 6.6, 7.2, 13, and 20 kb from human genomic DNA samples.
  11. Kee PS, Karunanathie H, Maggo SDS, Kennedy MA, Chua EW
    Methods Mol Biol, 2023;2967:181-192.
    PMID: 37608112 DOI: 10.1007/978-1-0716-3358-8_15
    Polymerase chain reaction (PCR) is a laboratory technique used to amplify a targeted region of DNA, demarcated by a set of oligonucleotide primers. Long-range PCR is a form of PCR optimized to facilitate the amplification of large fragments. Using the adapted long-range PCR protocol described in this chapter, we were able to generate PCR products of 6.6, 7.2, 13, and 20 kb from human genomic DNA samples. For some of the long PCRs, successful amplification was not possible without the use of PCR enhancers. Thus, we also evaluated the impact of some enhancers on long-range PCR and included the findings as part of this updated chapter.
  12. Yahya N, Ebert MA, Bulsara M, House MJ, Kennedy A, Joseph DJ, et al.
    Med Phys, 2016 May;43(5):2040.
    PMID: 27147316 DOI: 10.1118/1.4944738
    Given the paucity of available data concerning radiotherapy-induced urinary toxicity, it is important to ensure derivation of the most robust models with superior predictive performance. This work explores multiple statistical-learning strategies for prediction of urinary symptoms following external beam radiotherapy of the prostate.
  13. May IJ, Nowak AK, Francis RJ, Ebert MA, Dhaliwal SS
    J Med Imaging Radiat Oncol, 2024 Feb;68(1):57-66.
    PMID: 37898984 DOI: 10.1111/1754-9485.13592
    INTRODUCTION: Malignant pleural mesothelioma is difficult to prognosticate. F18-Fluorodeoxyglucose positron emission tomography (FDG PET) shows promise for response assessment but is confounded by talc pleurodesis. F18-Fluorothymidine (FLT) PET is an alternative tracer specific for proliferation. We compared the prognostic value of FDG and FLT PET and determined the influence of talc pleurodesis on these parameters.

    METHODS: Overall, 29 prospectively recruited patients had FLT PET, FDG PET and CT-scans performed prior to and post one chemotherapy cycle; 10 had prior talc pleurodesis. Patients were followed for overall survival. CT response was assessed using mRECIST. Radiomic features were extracted using the MiM software platform. Changes in maximum SUV (SUVmax), mean SUV (SUVmean), FDG total lesion glycolysis (TLG), FLT total lesion proliferation (TLP) and metabolic tumour volume (MTV) after one chemotherapy cycle.

    RESULTS: Cox univariate analysis demonstrated FDG PET radiomics were confounded by talc pleurodesis, and that percentage change in FLT MTV was predictive of overall survival. Cox multivariate analysis showed a 10% increase in FLT tumour volume corresponded with 9.5% worsened odds for overall survival (P = 0.028, HR = 1.095, 95% CI [1.010, 1.187]). No other variables were significant on multivariate analysis.

    CONCLUSION: This is the first prospective study showing the statistical significance of FLT PET tumour volumes for measuring mesothelioma treatment response. FLT may be better than FDG for monitoring mesothelioma treatment response, which could help optimise mesothelioma treatment regimes.

  14. Atieno OM, Opanga S, Martin A, Kurdi A, Godman B
    J Med Econ, 2018 Sep;21(9):878-887.
    PMID: 29860920 DOI: 10.1080/13696998.2018.1484372
    BACKGROUND: Currently the majority of cancer deaths occur in low- and middle-income countries, where there are appreciable funding concerns. In Kenya, most patients currently pay out of pocket for treatment, and those who are insured are generally not covered for the full costs of treatment. This places a considerable burden on households if family members develop cancer. However, the actual cost of cancer treatment in Kenya is unknown. Such an analysis is essential to better allocate resources as Kenya strives towards universal healthcare.

    OBJECTIVES: To evaluate the economic burden of treating cancer patients.

    METHOD: Descriptive cross-sectional cost of illness study in the leading teaching and referral hospital in Kenya, with data collected from the hospital files of sampled adult patients for treatment during 2016.

    RESULTS: In total, 412 patient files were reviewed, of which 63.4% (n = 261) were female and 36.6% (n = 151) male. The cost of cancer care is highly dependent on the modality. Most reviewed patients had surgery, chemotherapy and palliative care. The cost of cancer therapy varied with the type of cancer. Patients on chemotherapy alone cost an average of KES 138,207 (USD 1364.3); while those treated with surgery cost an average of KES 128,207 (1265.6), and those on radiotherapy KES 119,036 (1175.1). Some patients had a combination of all three, costing, on average, KES 333,462 (3291.8) per patient during the year.

    CONCLUSION: The cost of cancer treatment in Kenya depends on the type of cancer, the modality, cost of medicines and the type of inpatient admission. The greatest contributors are currently the cost of medicines and inpatient admissions. This pilot study can inform future initiatives among the government as well as private and public insurance companies to increase available resources, and better allocate available resources, to more effectively treat patients with cancer in Kenya. The authors will be monitoring developments and conducting further research.

  15. Ferreira CWS, Atan IK, Martin A, Shek KL, Dietz HP
    Int Urogynecol J, 2017 Oct;28(10):1499-1505.
    PMID: 28285396 DOI: 10.1007/s00192-017-3297-4
    INTRODUCTION AND HYPOTHESIS: Female pelvic organ prolapse is highly prevalent and childbirth has been shown to be an important risk factor. The study was carried out to observe if pelvic organ support deteriorates over time following a first birth.

    METHODS: This is a retrospective review using archived data sets of women seen in the context of two prospective perinatal imaging studies. All subjects had undergone a standardised interview, a clinical examination and 4D translabial ultrasound, 3 months and 2-5 years post-partum. Main outcome measures were pelvic organ descent and hiatal area at maximum Valsalva manoeuvre. Means at the two time points were compared using paired Student's t test. Predictors of change over time in continuous variables were explored using linear modelling methods.

    RESULTS: A total of 300 women had at least two postnatal follow-ups. They were first seen on average 0.39 (SD 0.2, range 0.2-2.1) years and again 3.1 (SD 1.5, range 1.4-8) years after the index delivery, with a mean interval of 2.71 (SD 1.5, range 0.7-7.7) years, providing a total of 813 (300 × 2.71) woman-years of observation. On univariate analysis, there was a significant decrease in mobility over time of the bladder neck, bladder, and rectal ampulla (P = < 0.004) and hiatal area (P = 0.012). The degree of improvement was less marked in women with levator avulsion.

    CONCLUSIONS: A significant reduction in pelvic organ descent and hiatal area was noted over a mean of 2.7 years after a first birth.

  16. Yahya N, Ebert MA, House MJ, Kennedy A, Matthews J, Joseph DJ, et al.
    Int J Radiat Oncol Biol Phys, 2017 02 01;97(2):420-426.
    PMID: 28068247 DOI: 10.1016/j.ijrobp.2016.10.024
    PURPOSE: We assessed the association of the spatial distribution of dose to the bladder surface, described using dose-surface maps, with the risk of urinary dysfunction.

    METHODS AND MATERIALS: The bladder dose-surface maps of 754 participants from the TROG 03.04-RADAR trial were generated from the volumetric data by virtually cutting the bladder at the sagittal slice, intersecting the bladder center-of-mass through to the bladder posterior and projecting the dose information on a 2-dimensional plane. Pixelwise dose comparisons were performed between patients with and without symptoms (dysuria, hematuria, incontinence, and an International Prostate Symptom Score increase of ≥10 [ΔIPSS10]). The results with and without permutation-based multiple-comparison adjustments are reported. The pixelwise multivariate analysis findings (peak-event model for dysuria, hematuria, and ΔIPSS10; event-count model for incontinence), with adjustments for clinical factors, are also reported.

    RESULTS: The associations of the spatially specific dose measures to urinary dysfunction were dependent on the presence of specific symptoms. The doses received by the anteroinferior and, to lesser extent, posterosuperior surface of the bladder had the strongest relationship with the incidence of dysuria, hematuria, and ΔIPSS10, both with and without adjustment for clinical factors. For the doses to the posteroinferior region corresponding to the area of the trigone, the only symptom with significance was incontinence.

    CONCLUSIONS: A spatially variable response of the bladder surface to the dose was found for symptoms of urinary dysfunction. Limiting the dose extending anteriorly might help reduce the risk of urinary dysfunction.

  17. Gan WY, Sulaiman N, Law LS, Zalbahar N, Ahmad Fuzi SF, Wilkes MA
    PMID: 31947907 DOI: 10.3390/ijerph17010348
    Access to food has been determined to be a factor that strongly influences the dietary intake and eating habit of indigenous people (Orang Asli, OA). This study explored food acquisition and the barriers in obtaining traditional and market foods among the Jahai subtribe (within the Negrito ethnic group) via a qualitative approach. Twenty-eight OA (14 males and 14 females) from Gerik, Perak, Malaysia participated in four focus group discussions (FGDs; two male-only and two female-only groups; seven informants in each FGD). Thematic analysis was adopted to analyse the gathered data. The results found that the Jahai applied both modern (buying and receiving food assistance) and traditional (gathering, farming, fishing, and hunting) methods in obtaining food. The barriers they faced in gathering sufficient food supply included low purchasing power, high demand for food, high transport costs, depletion of food supplies in their surroundings, threats from wild animals on the farm and during food searching activities, and food sharing. Food preparation methods practiced by the OA include roasting and grilling, frying, simmering (gulai), and boiling. In conclusion, this study enhances our understanding of the dietary behaviour of the Jahai subtribe and highlights restricted food access among the OA, which demands urgent attention.
  18. Chua EW, Cree SL, Ton KN, Lehnert K, Shepherd P, Helsby N, et al.
    Front Pharmacol, 2016;7:1.
    PMID: 26858644 DOI: 10.3389/fphar.2016.00001
    Whole-exome sequencing (WES) has been widely used for analysis of human genetic diseases, but its value for the pharmacogenomic profiling of individuals is not well studied. Initially, we performed an in-depth evaluation of the accuracy of WES variant calling in the pharmacogenes CYP2D6 and CYP2C19 by comparison with MiSeq(®) amplicon sequencing data (n = 36). This analysis revealed that the concordance rate between WES and MiSeq(®) was high, achieving 99.60% for variants that were called without exceeding the truth-sensitivity threshold (99%), defined during variant quality score recalibration (VQSR). Beyond this threshold, the proportion of discordant calls increased markedly. Subsequently, we expanded our findings beyond CYP2D6 and CYP2C19 to include more genes genotyped by the iPLEX(®) ADME PGx Panel in the subset of twelve samples. WES performed well, agreeing with the genotyping panel in approximately 99% of the selected pass-filter variant calls. Overall, our results have demonstrated WES to be a promising approach for pharmacogenomic profiling, with an estimated error rate of lower than 1%. Quality filters, particularly VQSR, are important for reducing the number of false variants. Future studies may benefit from examining the role of WES in the clinical setting for guiding drug therapy.
  19. Chua EW, Harger SP, Kennedy MA
    Front Pharmacol, 2019;10:931.
    PMID: 31507424 DOI: 10.3389/fphar.2019.00931
    We report two cases of metoclopramide-induced acute dystonia in pregnant women and consider the role of genetic variation in the pathogenesis of the adverse effect. By whole-gene sequencing, we found that both women were CYP2D6 poor metabolizers. We theorize that CYP2D6 governs the risk of metoclopramide-related acute dystonia through its role in the synthesis of serotonin, which inhibits the dopamine tone. The effect of CYP2D6 poor metabolism is exaggerated by rises in the estrogen levels during pregnancy, as the hormone augments dopamine sensitivity. Together, the two factors may create a hyper-dopaminergic state that is easily upset by metoclopramide, resulting in acute dystonia.
  20. Ow LL, Subramaniam N, Kamisan Atan I, Friedman T, Martin A, Dietz HP
    Female Pelvic Med Reconstr Surg, 2018 7 7;25(6):415-418.
    PMID: 29979358 DOI: 10.1097/SPV.0000000000000608
    OBJECTIVE: Genital hiatus (Gh) and perineal body (Pb) are part of the Pelvic Organ Prolapse Quantification assessment system, but it is unclear whether measurements should be taken at rest or on Valsalva. This study was designed to assess the predictive value of Gh and Pb measurements obtained at rest and on Valsalva for signs and symptoms of pelvic organ prolapse (POP).

    METHODS: This is a retrospective study involving 416 women who presented to a tertiary urogynecology unit with symptoms of pelvic floor dysfunction. Genital hiatus and Pb were measured at rest and on maximal Valsalva. The strength of association between binary markers of POP and measurements of Gh/Pb was estimated using logistic regression analysis. Receiver operator characteristic statistics were used to compare predictive values of Gh and Pb measurements obtained at rest and on Valsalva.

    RESULTS: A total of 451 women were seen during the study period. Thirty-five were excluded owing to missing data, leaving 416. Fifty-four percent (n = 223) complained of POP symptoms. On examination, 80% (n = 332) had significant POP (stage 2+ in anterior or posterior compartments or stage 1+ in the central compartment). On imaging, significant POP was diagnosed in 66% (n = 275). Mean hiatal area was 22 cm (SD, 7; range, 5-49 cm) at rest and 30 cm (SD, 10; range, 11-69 cm) on Valsalva. Genital hiatus and Pb measured on Valsalva were consistently stronger predictors of prolapse symptoms and objective prolapse (by clinician examination and by ultrasound) than at Gh and Pb measured at rest. The corresponding area under the curve values were significantly larger for Gh/Pb measures on Valsalva after adjusting for multiple confounders.

    CONCLUSIONS: Genital hiatus/Pb measured on maximal Valsalva is a superior predictor of symptoms and signs of POP compared with Gh/Pb at rest.

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