ORCID Profile
0000-0002-3995-7040
Current Organisations
Royal College of Physicians
,
Royal Australasian College of Physicians
,
Princess Alexandra Hospital
Does something not look right? The information on this page has been harvested from data sources that may not be up to date. We continue to work with information providers to improve coverage and quality. To report an issue, use the Feedback Form.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 28-09-2018
DOI: 10.2215/CJN.06560518
Publisher: Wiley
Date: 08-2017
DOI: 10.5694/MJA17.00161
Abstract: Increased early and incidental detection, improved surgical techniques and technological advancement mean that the management of renal mass lesions is constantly evolving. The treatment of choice for renal mass lesions has historically been radical nephrectomy. Partial nephrectomy is now recommended for localised renal masses, owing to favourable renal functional outcomes. Ablative renal surgery confers a significant risk of chronic kidney disease. There are few studies assessing long term outcomes of nephrectomy on renal outcomes, and virtually no studies assessing long term outcomes for less invasive therapies such as ablation. Unless a renal mass is clearly benign on imaging, management decisions will be made with an assumption of malignancy. The content of this review applies to both benign and malignant renal mass lesions. We advocate for improved strategies for kidney function assessment and risk stratification, early targeted referral, and regular screening for chronic kidney disease for all patients after surgery.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 18-05-2011
DOI: 10.1126/SCITRANSLMED.3002099
Abstract: A clinically approved agent can generate ex vivo graft-reactive, functional mouse and human regulatory T cells.
Publisher: Wiley
Date: 06-06-2018
DOI: 10.1111/TME.12542
Publisher: Wiley
Date: 28-01-2016
DOI: 10.1111/NEP.12580
Abstract: In the last decade, chronic kidney disease (CKD), defined as reduced renal function (glomerular filtration rate (GFR) < 60 mL/min per 1.73 m(2) ) and/or evidence of kidney damage (typically manifested as albuminuria) for at least 3 months, has become one of the fastest-growing public health concerns worldwide. CKD is characterized by reduced clearance and increased serum accumulation of metabolic waste products (uremic retention solutes). At least 152 uremic retention solutes have been reported. This review focuses on indoxyl sulphate (IS), a protein-bound, tryptophan-derived metabolite that is generated by intestinal micro-organisms (microbiota). Animal studies have demonstrated an association between IS accumulation and increased fibrosis, and oxidative stress. This has been mirrored by in vitro studies, many of which report cytotoxic effects in kidney proximal tubular cells following IS exposure. Clinical studies have associated IS accumulation with deleterious effects, such as kidney functional decline and adverse cardiovascular events, although causality has not been conclusively established. The aims of this review are to: (i) establish factors associated with increased serum accumulation of IS (ii) report effects of IS accumulation in clinical studies (iii) critique the reported effects of IS in the kidney, when administered both in vivo and in vitro and (iv) summarize both established and hypothetical therapeutic options for reducing serum IS or antagonizing its reported downstream effects in the kidney.
Publisher: InTech
Date: 10-02-2012
DOI: 10.5772/29075
Publisher: SAGE Publications
Date: 22-04-2018
Abstract: Indoxyl sulfate (IS) is a protein-bound uremic toxin that accumulates in patients with declining kidney function. Although generally thought of as a consequence of declining kidney function, emerging evidence demonstrates direct cytotoxic role of IS on endothelial cells and cardiomyocytes, largely through the expression of pro-inflammatory and pro-fibrotic factors. The direct toxicity of IS on human kidney proximal tubular epithelial cells (PTECs) remains a matter of debate. The current study explored the effect of IS on primary cultures of human PTECs and HK-2, an immortalized human PTEC line. Pathologically relevant concentrations of IS induced apoptosis and increased the expression of the proapoptotic molecule Bax in both cell types. IS impaired mitochondrial metabolic activity and induced cellular hypertrophy. Furthermore, statistically significant upregulation of pro-fibrotic (transforming growth factor-β, fibronectin) and pro-inflammatory molecules (interleukin-6, interleukin-8, and tumor necrosis factor-α) in response to IS was observed. Albumin had no influence on the toxicity of IS. The results of this study suggest that IS directly induced a pro-inflammatory and pro-fibrotic phenotype in proximal tubular cells. In light of the associated apoptosis, hypertrophy, and metabolic dysfunction, this study demonstrates that IS may play a role in the progression of chronic kidney disease.
Publisher: Oxford University Press (OUP)
Date: 05-07-2018
DOI: 10.1093/CID/CIY549
Abstract: Opportunistic infections including cytomegalovirus (CMV) are a major cause of morbidity and mortality in solid organ transplant (SOT) recipients. The recurrent and protracted use of antiviral drugs with eventual emergence of drug resistance represents a significant constraint to therapy. Although adoptive T-cell therapy has been successfully used in hematopoietic stem cell transplant recipients, its extension to the SOT setting poses a considerable challenge because of the inhibitory effects of immunosuppressive drugs on the virus-specific T-cell response in vivo and the perceived risk of graft rejection. In this prospective study, 22 SOT recipients (13 renal and 8 lung and 1 heart transplants) with recurrent or ganciclovir-resistant CMV infection were recruited, and 13 of them were treated with in vitro-expanded autologous CMV-specific T cells. These patients were monitored for safety, clinical symptoms, and immune reconstitution. Autologous CMV-specific T-cell manufacture was attempted for 21 patients, and was successful in 20. The use of this adoptive immunotherapy was associated with no therapy-related serious adverse events. Eleven (84%) of the 13 treated patients showed improvement in symptoms, including complete resolution or reduction in DNAemia and CMV-associated end-organ disease and/or the cessation or reduced use of antiviral drugs. Furthermore, four of these patients showed coincident increased frequency of CMV-specific T cells in peripheral blood after completion of T-cell therapy. The data presented here demonstrate for the first time the clinical safety of CMV-specific adoptive T-cell therapy and its potential therapeutic benefit for SOT recipients with recurrent and/or drug-resistant CMV infection or disease. ACTRN12613000981729.
Publisher: Therapeutic Guidelines Limited
Date: 02-2017
Publisher: American Society for Clinical Investigation
Date: 14-10-2019
DOI: 10.1172/JCI128323
Publisher: Oxford University Press
Date: 05-2010
Publisher: Wiley
Date: 17-01-2017
DOI: 10.1111/TID.12639
Abstract: The aim of this research paper was to determine the incidence, risk factors, and clinical outcome of solid organ transplant (SOT) recipients diagnosed and treated for cryptococcosis at our institution. Retrospective analysis of all patients with SOT diagnosed and treated for cryptococcal infection occurring between January 2001 and December 2015. Of 102 patients diagnosed with cryptococcal infection, 23 were SOT recipients. Renal transplant accounted for 22/23 cases, of which 13 had meningitis. The annual incidence of infection has risen significantly, and is now greater than 2/1000 prevalent renal transplant recipients. As expected, biochemical factors associated with meningitis include lower glucose on cerebrospinal fluid (CSF) analysis, median 2.4 vs 4.5 mmol/L (P=.02) CSF white blood cell median 50 vs 1/μL (P<.001) CSF protein, median 950 vs 335 mg/L (P=.04). Serum cryptococcal antigen titers were higher in the meningitis cohort, median 512 vs 32 (P=.03). Clinically, headache on admission (odds ratio: 9 [1.29-63.03], P=.03) and a prolonged length of stay (median of 36 vs 13 days) in the meningitis cohort (P=.02) were significant. Cryptococcal infection in SOT recipients remains rare however, there has been a marked increase in cases since 2014. This study reveals a need for increased vigilance for a potential emerging infectious disease. It furthermore highlights the need for ongoing research to further aid early diagnosis, prognostication, management, and screening cost-effectiveness.
Publisher: Public Library of Science (PLoS)
Date: 25-03-2021
DOI: 10.1371/JOURNAL.PONE.0249000
Abstract: The need for kidney transplantation drives efforts to expand organ donation. The decision to accept organs from donors with acute kidney injury (AKI) can result in a clinical dilemma in the context of conflicting reports from published literature. This observational study included all deceased donor kidney transplants performed in Australia and New Zealand between 1997 and 2017. The association of donor-AKI, defined according to KDIGO criteria, with all-cause graft failure was evaluated by multivariable Cox regression. Secondary outcomes included death-censored graft failure, death, delayed graft function (DGF) and acute rejection. The study included 10,101 recipients of kidneys from 5,774 deceased donors, of whom 1182 (12%) recipients received kidneys from 662 (11%) donors with AKI. There were 3,259 (32%) all-cause graft failures, which included 1,509 deaths with functioning graft. After adjustment for donor, recipient and transplant characteristics, donor AKI was not associated with all-cause graft failure (adjusted hazard ratio [HR] 1.11, 95% CI 0.99–1.26), death-censored graft failure (HR 1.09, 95% CI 0.92–1.28), death (HR 1.15, 95% CI 0.98–1.35) or graft failure when death was evaluated as a competing event (sub-distribution hazard ratio [sHR] 1.07, 95% CI 0.91–1.26). Donor AKI was not associated with acute rejection but was associated with DGF (adjusted odds ratio [OR] 2.27, 95% CI 1.92–2.68). Donor AKI stage was not associated with any kidney transplant outcome, except DGF. Use of kidneys with AKI for transplantation appears to be justified.
Publisher: Elsevier BV
Date: 2016
DOI: 10.1038/MTM.2016.58
Publisher: Springer Science and Business Media LLC
Date: 05-06-2018
DOI: 10.1007/S11255-018-1901-2
Abstract: The purpose of this study was to investigate whether preoperative dehydration and intraoperative hypotension were associated with postoperative acute kidney injury in patients managed surgically for kidney tumours. A retrospective analysis of 184 patients who underwent nephrectomy at a single centre was performed, investigating associations between acute kidney injury after nephrectomy, and both intraoperative hypotension and preoperative hydration/volume status. Intraoperative hypotension was defined as mean arterial pressure < 60 mmHg for ≥ 5 min. Urine conductivity was evaluated as a surrogate measure of preoperative hydration (euhydrated 20 mS/cm). Multivariable logistic regression was used to evaluate associations between exposures and the primary outcome, with adjustment made for potential confounders. Patients who were dehydrated and mildly dehydrated had an increased risk of acute kidney injury (adjusted odds ratio [aOR] 4.1, 95% CI 1.3-13.5 and aOR 2.4, 95% CI 1.1-5.3, respectively) compared with euhydrated patients (p = 0.009). Surgical approach appeared to modify this effect, where dehydrated patients undergoing laparoscopic surgery were most likely to develop acute kidney injury, compared with patients managed using an open approach. Intraoperative hypotension was not associated with acute kidney injury. Preoperative dehydration may be associated with postoperative acute kidney injury. Avoiding dehydration in the preoperative period may be advisable, and adherence to international evidence-based guidelines on preoperative fasting is recommended.
Publisher: Springer Science and Business Media LLC
Date: 15-02-2019
DOI: 10.1038/S41467-019-08800-2
Abstract: The original version of this Article contained an error in the spelling of the author Laurence Faivre, which was incorrectly given as Laurence Faive. This has now been corrected in both the PDF and HTML versions of the Article.
Publisher: Wiley
Date: 02-2017
DOI: 10.1111/NEP.12933
Abstract: Disorders in the regulation of the alternate complement pathway often result in complement-mediated damage to the microvascular endothelium and can be associated with both glomerulonephritis and atypical haemolytic uraemic syndrome. Inherited defects in complement regulatory genes or autoantibodies against complement regulatory proteins are predictive of the severity of the disease and the risk of recurrence post kidney transplantation. Heterozygous mutations in CD46, which codes for a transmembrane cofactor glycoprotein membrane cofactor protein, usually have a lower incidence of end-stage kidney disease and decreased risk of recurrent disease post transplant, as wild-type membrane cofactor protein is present in the transplanted kidney. However, some patients with CD46 mutations have a second variant in other complement regulatory genes increasing the severity of disease. The following case report illustrates the course of a young adult patient with end-stage kidney disease initially ascribed to seronegative systemic lupus erythematosus, who presented with biopsy-proven thrombotic microangiopathy following kidney transplantation. It highlights the complexity associated with disorders of complement regulation and the need for a high index of suspicion and genetic testing in patients who present with thrombotic microangiopathy post-transplant.
Publisher: Wiley
Date: 22-05-2018
DOI: 10.1002/JSO.25037
Abstract: New-onset chronic kidney disease (CKD) following surgical management of kidney tumors is common. This study evaluated risk factors for new-onset CKD after nephrectomy for T1a renal cell carcinoma (RCC) in an Australian population-based cohort. There were 551 RCC patients from the Australian states of Queensland and Victoria included in this study. The primary outcome was new-onset CKD (eGFR 20 mm, radical nephrectomy, lower hospital caseloads (<20 cases/year), and rural place of residence. The associations between rural place of residence and low center volume were a consequence of higher radical nephrectomy rates. Risk factors for CKD after nephrectomy generally relate to worse baseline health, or likelihood of undergoing radical nephrectomy. Surgeons in rural centres and hospitals with low caseloads may benefit from formalized integration with specialist centers for continued professional development and case-conferencing, to assist in management decisions.
Publisher: Hindawi Limited
Date: 2017
DOI: 10.1155/2017/9096435
Abstract: The immunosuppressant tacrolimus has a narrow therapeutic window, necessitating therapeutic drug monitoring to maintain efficacy and minimise toxicity. There are very few reports examining the impact of impaired biliary excretion on tacrolimus blood levels or toxicity. We report the case of a 26-year-old combined liver and kidney transplant recipient, who developed acute biliary obstruction leading to tacrolimus toxicity with very high blood tacrolimus levels. Despite a careful evaluation, no alternative cause was found for her acute kidney injury, and her kidney function returned to previous baseline within several days following treatment of the biliary obstruction and temporary withdrawal of tacrolimus.
Publisher: Wiley
Date: 17-01-2011
Publisher: Springer Science and Business Media LLC
Date: 21-01-2019
DOI: 10.1038/S41467-018-07863-X
Abstract: Cranial growth and development is a complex process which affects the closely related traits of head circumference (HC) and intracranial volume (ICV). The underlying genetic influences shaping these traits during the transition from childhood to adulthood are little understood, but might include both age-specific genetic factors and low-frequency genetic variation. Here, we model the developmental genetic architecture of HC, showing this is genetically stable and correlated with genetic determinants of ICV. Investigating up to 46,000 children and adults of European descent, we identify association with final HC and/or final ICV + HC at 9 novel common and low-frequency loci, illustrating that genetic variation from a wide allele frequency spectrum contributes to cranial growth. The largest effects are reported for low-frequency variants within TP53 , with 0.5 cm wider heads in increaser-allele carriers versus non-carriers during mid-childhood, suggesting a previously unrecognized role of TP53 transcripts in human cranial development.
Publisher: Wiley
Date: 09-2008
Publisher: ACM
Date: 30-04-2023
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-2017
Publisher: AME Publishing Company
Date: 10-2017
Publisher: Wiley
Date: 02-2017
DOI: 10.1111/NEP.12934
Abstract: Haemolytic uraemic syndrome is a rare condition with an overall incidence of one to two cases in a population of 100 000 and approximately 10% of these cases are classified as atypical. Atypical haemolytic uraemic syndrome (aHUS) is a thrombotic microangiopathy (TMA) characterized by microangiopathic haemolytic anaemia (MAHA), thrombocytopenia and acute kidney injury. aHUS can be genetic, acquired or idiopathic (negative genetic screening and no environmental triggers). We describe a case of aHUS triggered by monoclonal gammopathy of renal significance (MGRS) successfully treated with plasmapheresis and a bortezomib-based chemotherapy regimen, resulting in marked improvement in renal function and other markers of haemolysis. This patient has been in remission for more than 2 years currently.
Publisher: American Society for Microbiology
Date: 04-2017
DOI: 10.1128/CMR.00074-16
Abstract: BK polyomavirus (BKV) causes frequent infections during childhood and establishes persistent infections within renal tubular cells and the uroepithelium, with minimal clinical implications. However, reactivation of BKV in immunocompromised in iduals following renal or hematopoietic stem cell transplantation may cause serious complications, including BKV-associated nephropathy (BKVAN), ureteric stenosis, or hemorrhagic cystitis. Implementation of more potent immunosuppression and increased posttransplant surveillance has resulted in a higher incidence of BKVAN. Antiviral immunity plays a crucial role in controlling BKV replication, and our increasing knowledge about host-virus interactions has led to the development of improved diagnostic tools and clinical management strategies. Currently, there are no effective antiviral agents for BKV infection, and the mainstay of managing reactivation is reduction of immunosuppression. Development of immune-based therapies to combat BKV may provide new and exciting opportunities for the successful treatment of BKV-associated complications.
Publisher: Wiley
Date: 16-12-2019
DOI: 10.1111/NEP.13221
Abstract: Differences in early graft function between kidney transplant recipients previously managed with either haemodialysis (HD) or peritoneal dialysis are well described. However, only two single-centre studies have compared graft and patient outcomes between extended hour and conventional HD patients, with conflicting results. This study compared the outcomes of all extended hour (≥24 h/week) and conventional HD patients transplanted in Australia and New Zealand between 2000 and 2014. The primary outcome was delayed graft function (DGF), defined in an ordinal manner as either a spontaneous fall in serum creatinine of less than 10% within 24 h, or the need for dialysis within 72 h following transplantation. Secondary outcomes included the requirement for dialysis within 72 h post-transplant, acute rejection, estimated glomerular filtration rate at 12 months, death-censored graft failure, all-cause and cardiovascular mortality, and a composite of graft failure and mortality. A total of 4935 HD patients (378 extended hour HD, 4557 conventional HD) received a kidney transplant during the study period. Extended hour HD was associated with an increased likelihood of DGF compared with conventional HD (adjusted proportional odds ratio 1.33 95% confidence interval 1.06-1.67). There was no significant difference between extended hour and conventional HD in terms of any of the secondary outcomes. Compared to conventional HD, extended hour HD was associated with DGF, although long-term graft and patient outcomes were not different.
Publisher: Elsevier BV
Date: 07-2010
Publisher: Oxford University Press (OUP)
Date: 25-08-2007
DOI: 10.1093/NDT/GFM277
Publisher: Wiley
Date: 06-12-2018
Publisher: Elsevier BV
Date: 2019
DOI: 10.1016/J.PATHOL.2018.10.009
Abstract: This study evaluated the relationship between histological markers of chronic kidney damage in patients undergoing radical nephrectomy for kidney tumours and preoperative kidney function, degree of albuminuria, and changes in glomerular volume. A schema to grade chronic kidney damage could be used to identify patients at risk of developing CKD following nephrectomy. Non-neoplastic cortical tissue was sourced from 150 patients undergoing radical nephrectomy for suspected kidney cancer. This tissue was evaluated for indicators of chronic damage, specifically: glomerulosclerosis, arteriosclerosis, interstitial fibrosis, and tubular atrophy. Glomerular volume was determined using the Weibel and Gomez method. Associations between these parameters and both estimated glomerular filtration rate (eGFR) and albumin-creatinine ratio (ACR) were determined using either a Mann-Whitney U-test or a Kruskal-Wallis ANOVA. Associations between both eGFR and ACR and glomerular volume were assessed using linear regression. eGFR was inversely associated with the degree of glomerulosclerosis (p < 0.001), vascular narrowing (p = 0.002), tubular atrophy (p < 0.001), and interstitial fibrosis (p < 0.001). ACR was associated only with the degree of interstitial fibrosis (p = 0.02) and tubular atrophy (p = 0.02). Glomerular volume was greater for males, diabetics, hypertensive patients, and patients with a greater degree of interstitial fibrosis. Glomerular volume was positively associated with ACR. A schema to grade chronic damage was developed. The proposed schema is associated with baseline clinical indices of kidney function and damage. Longitudinal validation is necessary to determine the prognostic utility of this schema.
Publisher: Wiley
Date: 09-01-2020
DOI: 10.1002/CCR3.2595
Publisher: SAGE Publications
Date: 07-2017
Abstract: Few studies have examined the relationship between socio-economic position (SEP) and peritoneal dialysis (PD) outcomes, particularly at a country level. The aim of this study was to investigate the relationships between SEP, technique failure, and mortality in PD patients undertaking treatment in Australia. The study included all Australian non-indigenous incident PD patients between January 1, 1997, and December 31, 2014, using Australia and New Zealand Dialysis and Transplant (ANZDATA) Registry data. The SEP was assessed by quartiles of postcode-based Australian Socio-Economic Indexes for Areas (SEIFA), including Index of Relative Socio-economic Advantage and Disadvantage (IRSAD – primary index), Index of Relative Socio-economic Disadvantage (IRSD), Index of Economic Resources (IER), and Index of Education and Occupation (IEO). Technique and patient survival were evaluated by multivariable Cox proportional hazards survival analyses. The study included 9,766 patients (mean age 60.6 ± 15 years, 57% male, 38% diabetic). Using multivariable Cox regression, no significant association was observed between quartiles of IRSAD and technique failure (30-day definition p = 0.65, 180-day definition p = 0.68). Similar results were obtained using competing risks regression. However, higher SEP, defined by quartiles of IRSAD, was associated with better patient survival (Quartile 1 reference Quartile 2 adjusted hazards ratio [HR] 0.96, 95% confidence interval [CI] 0.86 – 1.06 Quartile 3 HR 0.87, 95% CI 0.77 – 0.99 Quartile 4 HR 0.86, 95% CI 0.76 – 0.97). Similar results were found when IRSD was analyzed, but results were no longer statistically significant for IER and IEO. In Australia, where there is universal free healthcare, SEP was not associated with PD technique failure in non-indigenous PD patients. Higher SEP was generally associated with improved patient survival.
Publisher: Elsevier BV
Date: 11-2019
DOI: 10.1016/J.EUF.2018.04.012
Abstract: Most practice decisions relevant to preserving kidney function in patients managed surgically for kidney tumours are driven by observational studies. A wide range of outcome measures are used in these studies, which reduces comparability and increases the risk of reporting bias. To comprehensively and succinctly describe the outcomes used to evaluate kidney function in studies evaluating surgical management of kidney tumours. Electronic search of the PubMed database was conducted to identify studies with at least one measure of kidney function in patients managed surgically for kidney tumours, published between January 2000 and September 2017. Abstracts were initially screened for eligibility. Full texts of articles were then evaluated in more detail for inclusion. A narrative synthesis of the evidence was conducted. A total of 312 studies, involving 127905 participants, were included in this review. Most were retrospective (n=274) studies and conducted in a single centre (n=264). Overall, 78 unique outcome measures were identified, which were grouped into six outcome categories. Absolute postoperative kidney function (n=187), relative kidney function (n=181), and postoperative chronic kidney disease (n=131) were most frequently reported. Kidney function was predominantly quantified using estimated glomerular filtration rate or creatinine clearance (n=255), most using the modification of diet in renal disease equation (n=182). Only 70 studies provided rationale for specific outcome measures used. There is significant variability in the reporting and quantification of kidney function in studies evaluating patients managed surgically for kidney tumours. A standardised approach to measuring and reporting kidney function will increase the effectiveness of outcomes reported and improve relevance of research findings within a clinical context. Although we know that the removal of a kidney can reduce kidney function, clinical significance of various approaches is a matter of debate. This article demonstrates significant variability in the way kidney function was reported across all studies of patients with kidney cancer undergoing surgery, indicating a need for standardisation.
Publisher: Elsevier BV
Date: 11-2022
DOI: 10.1053/J.JRN.2022.02.006
Abstract: Modulating the large intestinal microbiome of kidney transplant recipients (KTRs) may reduce infectious complications. The aim of this study is to assess the feasibility of a randomized controlled trial of prebiotics in reducing infections and gastrointestinal symptoms in KTRs. Acute KTRs were recruited to a double-blind, placebo-controlled, randomized trial at a single kidney transplant center. Patients were provided with prebiotics or placebo for 7 weeks. The primary outcome was feasibility, defined as recruitment of ≥80% of eligible people within 6 months. Secondary outcomes included adherence and tolerability, participant retention in trial, proportions of participants providing serum and stool specimens, self-reported quality of life, gastrointestinal symptoms, and infection events. During the 7-week period, 72 patients met eligibility criteria, of whom 60 (83%) consented to participate (mean ± standard deviation age 53 ± 12 years 62% males). Fifty-six (78%) participants were randomized (27 interventions and 29 controls). Although participants receiving intervention experienced reduced gastrointestinal symptoms (-0.28 [interquartile range, IQR -0.67 to 0.08] vs. -0.07 [IQR -0.27 to 0], P = .03), both control and intervention groups were similar in adherence (67% vs. 72%, P = .36), tolerability (56% vs. 62%, P = .64), quality of life (-0.2 [IQR -0.6 to 0] vs. -0.2 [IQR -0.8 to 0], P = .82), and infection events (33% vs. 34%, P = .83). Blood and stool s les were collected from ≥90% of participants in both groups. It is feasible to recruit and retain acute KTRs in a randomized, placebo-controlled trial examining the effect of prebiotics on infections and gastrointestinal symptoms. This study also showed that prebiotics significantly reduced gastrointestinal symptoms.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 20-03-2020
Abstract: The cerebral cortex underlies our complex cognitive capabilities. Variations in human cortical surface area and thickness are associated with neurological, psychological, and behavioral traits and can be measured in vivo by magnetic resonance imaging (MRI). Studies in model organisms have identified genes that influence cortical structure, but little is known about common genetic variants that affect human cortical structure. To identify genetic variants associated with human cortical structure at both global and regional levels, we conducted a genome-wide association meta-analysis of brain MRI data from 51,665 in iduals across 60 cohorts. We analyzed the surface area and average thickness of the whole cortex and 34 cortical regions with known functional specializations. We identified 369 nominally genome-wide significant loci ( P 5 × 10 −8 ) associated with cortical structure in a discovery s le of 33,992 participants of European ancestry. Of the 360 loci for which replication data were available, 241 loci influencing surface area and 66 influencing thickness remained significant after replication, with 237 loci passing multiple testing correction ( P 8.3 × 10 −10 187 influencing surface area and 50 influencing thickness). Common genetic variants explained 34% (SE = 3%) of the variation in total surface area and 26% (SE = 2%) in average thickness surface area and thickness showed a negative genetic correlation ( r G = −0.32, SE = 0.05, P = 6.5 × 10 −12 ), which suggests that genetic influences have opposing effects on surface area and thickness. Bioinformatic analyses showed that total surface area is influenced by genetic variants that alter gene regulatory activity in neural progenitor cells during fetal development. By contrast, average thickness is influenced by active regulatory elements in adult brain s les, which may reflect processes that occur after mid-fetal development, such as myelination, branching, or pruning. When considered together, these results support the radial unit hypothesis that different developmental mechanisms promote surface area expansion and increases in thickness. To identify specific genetic influences on in idual cortical regions, we controlled for global measures (total surface area or average thickness) in the regional analyses. After multiple testing correction, we identified 175 loci that influence regional surface area and 46 that influence regional thickness. Loci that affect regional surface area cluster near genes involved in the Wnt signaling pathway, which is known to influence areal identity. We observed significant positive genetic correlations and evidence of bidirectional causation of total surface area with both general cognitive functioning and educational attainment. We found additional positive genetic correlations between total surface area and Parkinson’s disease but did not find evidence of causation. Negative genetic correlations were evident between total surface area and insomnia, attention deficit hyperactivity disorder, depressive symptoms, major depressive disorder, and neuroticism. This large-scale collaborative work enhances our understanding of the genetic architecture of the human cerebral cortex and its regional patterning. The highly polygenic architecture of the cortex suggests that distinct genes are involved in the development of specific cortical areas. Moreover, we find evidence that brain structure is a key phenotype along the causal pathway that leads from genetic variation to differences in general cognitive function. ( A ) Measurement of cortical surface area and thickness from MRI. ( B ) Genomic locations of common genetic variants that influence global and regional cortical structure. ( C ) Our results support the radial unit hypothesis that the expansion of cortical surface area is driven by proliferating neural progenitor cells. ( D ) Cortical surface area shows genetic correlation with psychiatric and cognitive traits. Error bars indicate SE. IMAGE CREDITS: (A) K. COURTNEY (C) M. R. GLASS
Publisher: Elsevier BV
Date: 06-2019
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-2016
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Ross Francis.