Publications by authors named "James Warwick"

49 Publications

Biomarkers to predict FDG PET/CT activity after the standard duration of treatment for spinal tuberculosis: An exploratory study.

Tuberculosis (Edinb) 2021 Jul 8;129:102107. Epub 2021 Jul 8.

DST/NRF Centre of Excellence for Biomedical TB Research and SAMRC Centre for TB Research, Division of Molecular Biology and Human Genetics, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Stellenbosch University, Francie van Zijl Drive, Tygerberg, 7505, Cape Town, South Africa. Electronic address:

Objectives: 18F-Fluorodeoxyglucose (FDG) Positron Emission Tomography- Computed Tomography (PET/CT) scans can be used to assess healing following treatment for spinal tuberculosis (TB) but have limited accessibility and high cost. This study investigated the association between immune biomarkers and FDG-PET/CT activity after ≥9 months of treatment for spinal TB.

Methods: Patients who had completed ≥9 months of treatment for spinal TB were recruited from a major hospital in the Western Cape, South Africa. Participants underwent a FDG-PET/CT scan and FDG- PET/CT activity was quantified for all spinal and extra-spinal sites. Participants also provided a blood sample, which was evaluated for 19 cytokines along with erythrocyte sedimentation rate (ESR). Correlations and multiple regression analyses were used to investigate the association between biomarkers and PET/CT measures.

Results: Twenty-eight patients were recruited, of whom 24 (86%) had spinal and/or extra-spinal FDG-PET/CT activity. In the strongest multiple regression model, CXCL10/IP-10, VEGFA, IFN-γ, CRP and Factor D/Adipsin explained 52% of the variation in overall maximal FDG uptake. Conventional monitoring marker ESR showed no significant association with PET/CT measures.

Conclusions: The current findings offered encouragement that biomarkers to predict FDG-PET/CT activity may show some promise and identified candidate biomarkers for further investigation in this regard.
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http://dx.doi.org/10.1016/j.tube.2021.102107DOI Listing
July 2021

Is Progressive Accumulation of Radiolabelled White Cells a Valid Positive Criterion in Suspected Vascular Graft/ Endograft Infections?

Eur J Vasc Endovasc Surg 2021 03 24;61(3):529-530. Epub 2020 Oct 24.

NuMeRI Node for Infection Imaging, Central Analytical Facilities, Stellenbosch University, Cape Town, South Africa.

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http://dx.doi.org/10.1016/j.ejvs.2020.09.012DOI Listing
March 2021

Association of Prehospital Step 1 Vital Sign Criteria and Vital Sign Decline with Increased Emergency Department and Hospital Death.

J Am Coll Surg 2021 Apr 19;232(4):572-579. Epub 2020 Dec 19.

University of Kentucky and the Division of Acute Care Surgery, Trauma, and Critical Care, Department of Surgery, University of Kentucky College of Medicine, Lexington, KY. Electronic address:

Background: This study analyzed data from the 2017 American College of Surgeons National Trauma Data Bank to examine the effects of pre-hospital Field Triage Decision Scheme Step 1 vital sign criteria (S1C) and vital sign decline on subsequent emergency department (ED) and hospital death in emergency medical services (EMS) transported trauma victims.

Study Design: Patient and injury characteristics, transport time, and ED and hospital disposition were collected. S1C (respiratory rate [RR]<10, RR>29 breaths/min, systolic blood pressure [SBP]<90 mmHg, Glasgow Coma Scale [GCS]<14) were recorded at the injury scene and hospital arrival. Decline was defined as a change ≥ 1 standard deviation (SD) into or within an S1C range. S1C and decline were analyzed relative to ED and hospital death using logistic regression.

Results: Of 333,213 included patients, 54,849 (16.5%) met Step 1 criteria at the scene, and 21,566 (6.9%) declined en route. The ED death rate was 0.4% (n = 1,188), and the hospital death/hospice rate was 4.0% (11,624 of 287,675). Patients who met S1C at the scene or who declined were more likely to require longer hospital lengths of stay, ICU admission, and surgical intervention. S1C and decline patients had higher odds of death in both the ED (S1C odds ratio [OR] 15.1, decline OR 2.4, p values < 0.001) and hospital (S1C OR 4.8, decline OR 2.0, p values < 0.001) after adjusting for patient demographics, transport time and mode, injury severity, and injury mechanism. Each S1C and decline measure was independently predictive of death.

Conclusions: This study quantifies the mortality risks associated with individual S1C and validates their use as an indicator for injury severity and pre-hospital triage tool.
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http://dx.doi.org/10.1016/j.jamcollsurg.2020.12.009DOI Listing
April 2021

Repeatability of glomerular filtration rate studies performed using 99mTc-DTPA in a population including cancer patients.

Nucl Med Commun 2021 Mar;42(3):261-266

Nuclear Medicine Division, Department of Medical Imaging and Clinical Oncology, Stellenbosch University.

Objective: Glomerular filtration rate (GFR) measurement remains an integral investigation in clinical practice and is particularly important in the prediction and follow-up of renal side-effects of nephrotoxic chemotherapy in cancer patients. Knowing the coefficient of variation (CV) of a test is vital for the correct interpretation of serial studies. Recent difficulties with 51Cr-EDTA availability have renewed interest in 99mTc-DTPA, but there is a paucity of data on the test-retest variability of this radiopharmaceutical. Furthermore, the authors are unaware of published repeatability data in cancer patients. The aim of this study was to determine the CV of repeat 99mTc-DTPA GFR measurements in a clinical patient population that included cancer patients.

Methods: Patients who had undergone ≥2 GFR studies at our department between January 2009 and December 2019 were retrospectively identified. Patients with chronic kidney disease and those who had received chemotherapy, radiotherapy or surgery between measurements were excluded. The CV for each patient was calculated and the mean CVs of cancer and prospective renal donor groups were calculated and compared.

Results: Fifty-four patients were included in the final analysis. The mean CV in the cancer group (38 patients) was 8.5% [95% confidence interval (CI) 6.9-10.2%] and in the renal donor group (16 patients) 7.1% (95% CI 4.2-10.1%). These figures did not differ significantly (P = 0.37). The groups were combined to calculate the final overall mean CV of 8.1% (95% CI 6.7-9.6%).

Conclusion: In both non-cancer and cancer patients the CV of GFR studies performed with 99mTc-DTPA was comparable with mostly 51Cr-EDTA figures presented in literature.
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http://dx.doi.org/10.1097/MNM.0000000000001326DOI Listing
March 2021

Validation of ICD-10-CM surveillance codes for traumatic brain injury inpatient hospitalizations.

Brain Inj 2020 12 6;34(13-14):1763-1770. Epub 2020 Dec 6.

Kentucky Injury Prevention and Research Center, University of Kentucky , Lexington, USA.

: Using inpatient data from a 1,160-bed health system, we assessed the positive predictive value (PPV) of ICD-10-CM (International Classification of Diseases, Tenth Revision, Clinical Modification) codes included in a traumatic brain injury (TBI) surveillance definition proposed by the Centers for Disease Control and Prevention (CDC) in 2016. : A random sample of 196 records with ICD-10-CM TBI codes was reviewed. The PPVs for the ICD-10-CM codes' ability to capture true TBI cases were calculated as the percentage of records with confirmed clinical provider-documented TBI and reported with 95% confidence intervals [95%CIs]. : The estimated overall PPV was 74% [67.9%, 80.1%] when the codes were listed in any diagnostic field, but 91.5% [86.2%, 96.8%] when listed as the principal diagnosis. S06 codes (intracranial injury) had an overall PPV of 80.2% [74.3%, 86.1%] and 96.9% [93.3%, 100%] when listed as the principal diagnosis. S02.0-.1 codes (vault/base skull fractures) in any position without co-existing S06 codes had a PPV of 15.8% [0%, 33.2%]. : Intracranial injury codes (S06) in any diagnostic position had a very high estimated PPV. Further research is needed to determine the utility of other codes included in the CDC proposed definition for TBI surveillance.
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http://dx.doi.org/10.1080/02699052.2020.1849801DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7808251PMC
December 2020

Estimated glomerular filtration rate in children: adapting existing equations for a specific population.

Pediatr Nephrol 2021 03 29;36(3):669-683. Epub 2020 Sep 29.

Nuclear Medicine Division, Department of Medical Imaging and Clinical Oncology, Stellenbosch University and Tygerberg Hospital, Cape Town, South Africa.

Background: Creatinine-based glomerular filtration rate (GFR)-estimating equations frequently do not perform well in populations that differ from the development populations in terms of mean GFR, age, pathology, ethnicity, and diet. After first evaluating the performance of existing equations, the aim of this study was to demonstrate the utility of an in-house modification of the equations to better fit a specific population.

Methods: Estimated GFR using 8 creatinine-based equations was first compared to 2-sample Cr-ethylenediaminetetra-acetic acid plasma clearance in non-cancer and cancer groups independently. The groups were then divided into development and validation sets. Using the development set data, the Microsoft® Excel SOLVER add-in was used to modify the parameters of 7 equations to better fit the data. Using the validation set data, the performance of the original and modified equations was compared.

Results: Two hundred fifty-six GFR measurements were performed in 160 children. GFR was overestimated in both groups (non-cancer 4.3-22.6 ml/min/1.73 m, cancer 17.2-46.6 ml/min/1.73 m). The root mean square error (RMSE) was 19.1-21.8 ml/min/1.73 m (non-cancer) and 18.6-20.8 ml/min/1.73 m (cancer). The P values were 49.1-73.0% (non-cancer) and 19.6-66.0% (cancer). Modifying the parameters of seven equations resulted in significant improvements in the P values in the non-cancer (65.0-85.0%) and cancer (79.6-87.8%) groups.

Conclusions: Modifying the parameters of pediatric GFR estimating-equations using a simple Excel-based tool significantly improved their accuracy in both non-cancer and cancer populations. Graphical abstract.
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http://dx.doi.org/10.1007/s00467-020-04770-6DOI Listing
March 2021

Combined versus subtraction-only technique in parathyroid scintigraphy: effect on scan interpretation.

Nucl Med Commun 2020 Sep;41(9):883-887

Node for Infection Imaging, Central Analytical Facilities, Stellenbosch University, Cape Town, South Africa.

Introduction: Parathyroidectomy is the choice of treatment for patients with primary and tertiary hyperparathyroidism. Scintigraphic, preoperative localization of hyperfunctioning parathyroid tissue depends on either a delayed washout technique, a subtraction technique, or a combination of the two. The rationale for adopting a combination approach is its presumed superior sensitivity, but there is limited evidence to support this strategy at the cost of patient inconvenience and impact on departmental workflows.

Objective: To determine whether a combined technique detects any additional lesions during scan interpretation compared to using subtraction-only technique in patients undergoing parathyroid scintigraphy before surgery.

Methods: A retrospective analysis was performed of parathyroid scans at Tygerberg Hospital between January 2012 and April 2018. Scans were reinterpreted by consensus by three readers, blinded to the original interpretation. A McNemar discordant pairs analysis was then performed.

Results: A total of 97 participant scans were reviewed (female: 71; mean age: 50.8 years). The number of patients with primary, secondary, and tertiary hyperparathyroidism were 63, 21, and 13, respectively. A total of 192 lesions were identified in this study. While both combined and subtraction-only approaches identified hyperfunctioning parathyroid lesions, only four lesions were identified using the combined technique that were missed by the subtraction technique. This result was not statistically significant (P = 0.125).

Conclusion: Based on our findings, the combined parathyroid scintigraphic technique does not improve lesion detection and may be dispensed with. Doing so will enhance patient convenience and comfort and improve departmental workflows without compromising lesion detection.
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http://dx.doi.org/10.1097/MNM.0000000000001239DOI Listing
September 2020

Quantitative 18F-FDG PET-CT scan characteristics correlate with tuberculosis treatment response.

EJNMMI Res 2020 Feb 10;10(1). Epub 2020 Feb 10.

Department of Science and Technology/National Research Foundation, Centre of Excellence for Biomedical Tuberculosis Research and South African Medical Research Council Centre for Tuberculosis Research, Cape Town, South Africa.

Background: There is a growing interest in the use of F-18 FDG PET-CT to monitor tuberculosis (TB) treatment response. Tuberculosis lung lesions are often complex and diffuse, with dynamic changes during treatment and persisting metabolic activity after apparent clinical cure. This poses a challenge in quantifying scan-based markers of burden of disease and disease activity. We used semi-automated, whole lung quantification of lung lesions to analyse serial FDG PET-CT scans from the Catalysis TB Treatment Response Cohort to identify characteristics that best correlated with clinical and microbiological outcomes.

Results: Quantified scan metrics were already associated with clinical outcomes at diagnosis and 1 month after treatment, with further improved accuracy to differentiate clinical outcomes after standard treatment duration (month 6). A high cavity volume showed the strongest association with a risk of treatment failure (AUC 0.81 to predict failure at diagnosis), while a suboptimal reduction of the total glycolytic activity in lung lesions during treatment had the strongest association with recurrent disease (AUC 0.8 to predict pooled unfavourable outcomes). During the first year after TB treatment lesion burden reduced; but for many patients, there were continued dynamic changes of individual lesions.

Conclusions: Quantification of FDG PET-CT images better characterised TB treatment outcomes than qualitative scan patterns and robustly measured the burden of disease. In future, validated metrics may be used to stratify patients and help evaluate the effectiveness of TB treatment modalities.
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http://dx.doi.org/10.1186/s13550-020-0591-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7010890PMC
February 2020

HIV status does not have an impact on positron emission tomography-computed tomography (PET-CT) findings or radiotherapy treatment recommendations in patients with locally advanced cervical cancer.

Int J Gynecol Cancer 2019 10 13;29(8):1252-1257. Epub 2019 Aug 13.

Epidemiology, Columbia University Mailman School of Public Health, New York, New York, USA.

Introduction: Positron emission tomography-computed tomography (PET-CT) imaging is commonly used to identify nodal involvement in locally advanced cervical carcinoma, but its appropriateness for that purpose among HIV-positive patients has rarely been studied. We analyzed PET-CT findings and subsequent treatment prescribed in patients with locally advanced cervical carcinoma in Cape Town, South Africa.

Methods: We identified a cohort of consecutive cervical carcinoma patients International Federation of Gynecology and Obstetrics (FIGO) stage IIB to IIIB at our cancer center who underwent a planning 18-fluorodeoxyglucose (FDG) PET-CT scan from January 2015 through December 2018. Demographics, PET-CT findings, and subsequent treatment prescribed were recorded. Patients were selected for PET-CT only if they had no signs of distant disease on staging chest X-ray or abdominal ultrasound; were deemed suitable for radical chemoradiation by the multi-disciplinary team; and had normal renal function. HIV-positive patients ideally had to have been established on continuous antiviral therapy for more than 3 months and to have a CD4 cell count above 150 cells/μL. Small cell and neuroendocrine carcinoma cases were excluded from the study. Differences in demographic and clinical measures between HIV-positive and HIV-negative patients were evaluated by means of t-tests for continuous variables and χ tests for categorical variables.

Results: Over a 4 year period, 278 patients-192 HIV-negative (69.1%) and 86 HIV-positive (30.9%)-met the inclusion criteria. HIV-positive patients had a median CD4 count of 475 cells/µL (IQR 307-612 cells/µL). More than 80% of patients had pelvic nodal involvement, and more than 40% had uptake in common iliac and/or para-aortic nodes. Nodal involvement was not associated with HIV status. Fifty-four patients (19.4%) had at least one site of distant metastatic disease. Overall, 235 patients (84.5%) were upstaged following PET-CT staging scan. Upstaging was not associated with HIV status (HIV-negative 83.9% vs HIV-positive 87.2%; p=0.47). Ten patients who did not return for radiotherapy were excluded from the analysis. Following their PET-CT scan, treatment intent changed for 124 patients (46.3%): 53.6% of HIV-positive patients and 42.9% of HIV-negative patients (p=0.11).

Conclusion: We found no differences between HIV-positive or HIV-negative patients in nodal involvement or occult metastases, and PET-CT imaging did not lead to, or justify, treatment differences between the two groups. Future studies will evaluate survival and correlation of upstaging with outcome.
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http://dx.doi.org/10.1136/ijgc-2019-000641DOI Listing
October 2019

Validation of Glomerular Filtration Rate Measurement with Blood Sampling from the Injection Site.

J Nucl Med Technol 2019 Dec 10;47(4):305-308. Epub 2019 Jun 10.

Nuclear Medicine Division, Department of Medical Imaging and Clinical Oncology, Stellenbosch University, Cape Town, South Africa.

Measurement of glomerular filtration rate (GFR) from the plasma clearance of a radionuclide-labeled tracer is reliable and accurate. However, to avoid contamination of the blood samples with radioactivity remaining at the injection site, venepuncture at 2 or more sites is required: one for tracer administration and the others for blood sampling. This requirement is uncomfortable for patients, particularly when venous access is difficult. The objective of this study was to validate the use of a single site of venous access in combination with injection site imaging, for GFR measurement. Twenty-two adults (≥18 y) who were referred for GFR determination were included prospectively. GFR was measured from the plasma clearance of Tc-diethylenetriaminepentaacetic acid according to international guidelines. After administration of the tracer through an intravenous cannula, a 60-s static image of the injection site was acquired. A second intravenous cannula was inserted into the contralateral arm. Venous blood samples were collected at 2, 3, and 4 h after administration of the radiotracer from both the injection site (experimental) and the contralateral arm (conventional). GFR was calculated using slope-intercept and single-sample methods. The median conventional and experimental plasma counts (decay- and background-corrected) were compared for the 2-, 3-, and 4-h venous samples. Conventional and experimental GFRs were then compared, with a more than 10% difference between conventional and experimental GFRs being regarded as significant. Four individuals had visible residual activity at the injection site. The median 2-h counts differed significantly between the conventional and experimental sampling sites ( = 0.007), whereas no significant difference was found at 3 or 4 h. When there was a clear injection site image, the difference between the experimental and conventional GFRs was more than 10% in 1 case for single-sample GFR but less than 8% in all cases for slope-intercept GFR. In cases with clear injection site images, slope-intercept GFR calculated after injection site blood sampling showed no clinically significant difference from conventional contralateral-arm sampling.
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http://dx.doi.org/10.2967/jnmt.119.229153DOI Listing
December 2019

Simple Anatomical Calculations Possibly As Accurate As Three-Dimensional Lobar Quantification with SPECT-CT in Predicting Lung Function after Pulmonary Resection.

Respiration 2019;98(1):82-85. Epub 2019 May 2.

Division of Pulmonology, Department of Medicine, Tygerberg Academic Hospital, Stellenbosch University, Cape Town, South Africa,

The estimation of predicted postoperative (PPO) lung function is important in lung resection candidates. We utilized simple anatomical calculations and single-photon emission computed tomography combined with computed tomography (SPECT-CT) to calculate PPO in 24 consecutive patients with impaired pulmonary function who underwent lung resection. PPO values calculated by anatomical calculations and three-dimensional lobar SPECT-CT quantification both correlated well with the postoperative forced expiratory volume in 1 s, with r = 0.825, p < 0.001 and r = 0.796, p < 0.001, respectively. Both techniques fared well at predicting postoperative lung function, but our observations unexpectedly suggested that simple anatomical calculations might be equivalent to three-dimensional SPECT-CT lobar quantification.
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http://dx.doi.org/10.1159/000497462DOI Listing
September 2020

Propagation of measurement errors in glomerular filtration rate determination: a comparison of slope-intercept, single-sample and slope-only methods.

Nucl Med Commun 2019 Apr;40(4):333-342

Department of Medical Imaging and Clinical Oncology, Nuclear Medicine Division, Stellenbosch University.

Background: Measurement errors occurring during glomerular filtration rate (GFR) studies propagate to an error in the calculated GFR. Previous work has modelled measurement errors for slope-intercept (SI-GFR), single-sample (SS-GFR) and slope-only (SO-GFR) methods. In this study, we have extended these models. The primary aims were to (i) compare measurement errors in two-sample SI-GFR, three-sample SI-GFR, SS-GFR and SO-GFR, and (ii) determine the sensitivity of GFR to errors arising from different measurements.

Patients And Methods: This study expanded on previous models of GFR measurement error incorporating biological data from 786 patients and realistic measurement errors. GFR median absolute error and the coefficient of variation (CV) were calculated for each method. A sensitivity analysis was carried out for individual measurement errors.

Results: The median absolute error ranged between 1.2 and 2.3 ml/min/1.73 m, lowest for SS-GFR (4 h) and highest for SO-GFR. At higher rates of clearance, CV was less than 5% for all methods. CV increased rapidly when GFR decreased below a threshold ranging between 34 and 56 ml/min/1.73 m, lowest for three-point SI-GFR and highest for SO-GFR. SI-GFR and SS-GFR are most sensitive to injected activity quantification, but less sensitive to other measurement errors.

Conclusion: Measurement errors are probably insignificant relative to biological variation for GFR of more than 60 ml/min/1.73 m, but become significant irrespective of biological variation at lower GFR, particularly in serial studies when GFR less than 25 ml/min/1.73 m. Limits of precision recommended in the 2018 British Nuclear Medicine Society guideline are appropriate for once-off GFR measurement, whereas slightly more stringent limits are proposed for serial studies.
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http://dx.doi.org/10.1097/MNM.0000000000000977DOI Listing
April 2019

Methamphetamine dependence with and without psychotic symptoms: A multi-modal brain imaging study.

Neuroimage Clin 2018 22;20:1157-1162. Epub 2018 Oct 22.

Department of Psychiatry and MRC Unit on Risk & Resilience in Mental Disorders, University of Cape Town, Cape Town, South Africa. Electronic address:

Objective: Methamphetamine dependence can lead to psychotic symptoms which may be mediated by frontal, striatal, limbic, and thalamic regions. There are few neuroimaging data that allow comparison of individuals with methamphetamine dependence who do, and do not, have psychosis. Two complementary imaging techniques were employed to investigate neurocircuitry associated with methamphetamine dependence with and without psychotic symptoms.

Methods: Three groups of participants were recruited: methamphetamine dependent (MAA) (N = 11), methamphetamine dependent with psychotic symptoms (MAP) (N = 14), and controls (N = 14). Resting brain glucose metabolism was measured using [F]fluorodeoxyglucose (FDG) positron emission tomography (PET) and cerebral perfusion was assessed using arterial spin labelling (ASL) magnetic resonance imaging.

Results: Methamphetamine abusers (MAA and MAP groups) had decreased glucose metabolism compared to healthy controls in the left insula, left precentral gyrus, and the anterior cingulate cortex. Compared to MAA participants, MAP participants had 1) decreased glucose metabolism in the left precentral gyrus and the left inferior frontal gyrus and 2) increased glucose metabolism in the putamen and pallidum. MAP participants also had increased cerebral perfusion in the right putamen and right pallidum compared to MAA.

Conclusion: Findings support the involvement of frontal, striatal, and limbic regions in methamphetamine dependence. Furthermore, they indicate that glucose metabolism and cerebral perfusion in these regions are disrupted in methamphetamine dependent individuals with psychotic symptoms.
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http://dx.doi.org/10.1016/j.nicl.2018.10.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6205927PMC
February 2019

Nuclear Neuroimaging in Social Anxiety Disorder: A Review.

J Nucl Med 2018 12 5;59(12):1794-1800. Epub 2018 Oct 5.

Division of Nuclear Medicine, Stellenbosch University, Cape Town, South Africa.

In psychiatric research, nuclear imaging complements MRI. A recent neuroimaging review of social anxiety disorder focused predominantly on MRI, omitting the contribution of nuclear imaging methods. Nuclear imaging investigations of neural activity are sparse but have generally yielded results consistent with studies performed using MRI. Evidence for disturbances in neurotransmitter systems in social anxiety disorder is limited but suggestive of both serotonergic and dopaminergic dysfunction. Research focusing on additional molecular targets using existing and novel tracers, combined with recent technologic innovations and trends in collaborative methodology, may shape future nuclear imaging endeavors in this field.
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http://dx.doi.org/10.2967/jnumed.118.212795DOI Listing
December 2018

Joint Fluid Proteome after Anterior Cruciate Ligament Rupture Reflects an Acute Posttraumatic Inflammatory and Chondrodegenerative State.

Cartilage 2020 07 22;11(3):329-337. Epub 2018 Jul 22.

Department of Orthopedic Surgery, University of Kentucky, Lexington, KY, USA.

Objective: The purpose of this study was to evaluate changes in the synovial fluid proteome following acute anterior cruciate ligament (ACL) injury.

Design: This study represents a secondary analysis of synovial fluid samples collected from the placebo group of a previous randomized trial. Arthrocentesis was performed twice on 6 patients with an isolated acute ACL tear at a mean of 6 and 14 days postinjury. Synovial fluid was analyzed by a highly multiplexed assay of 1129 proteins (SOMAscan version 3, SomaLogic, Inc., Boulder, CO). Pathway analysis using DAVID was performed; genes included met 3 criteria: significant change between the 2 study time points using a paired test, significant change between the 2 study time points using a Mann-Whitney nonparametric test, and significant Benjamini analysis.

Results: Fifteen analytes demonstrated significant increases between time points. Five of the 15 have been previously associated with the onset and/or severity of rheumatoid arthritis, including apoliopoprotein E and isoform E3, vascular cell adhesion protein 1, interleukin-34, and cell surface glycoprotein CD200 receptor 1. Chondrodegenerative enzymes and products of cartilage degeneration all increased over time following injury: MMP-1 ( = 0.08, standardized response mean [SRM] = 1.00), MMP-3 ( = 0.05, SRM = 0.90), ADAM12 ( = 0.03, SRM = 1.31), aggrecan ( = 0.08, SRM = 1.13), and CTX-II ( = 0.07, SRM = 0.56). Notable pathways that were differentially expressed following injury were the cytokine-cytokine receptor interaction and osteoclast differentiation pathways.

Conclusions: The proteomic results and pathway analysis demonstrated a pattern of cartilage degeneration, not only consistent with previous findings but also changes consistent with an inflammatory arthritogenic process post-ACL injury.
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http://dx.doi.org/10.1177/1947603518790009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7298591PMC
July 2020

A semi-automatic technique to quantify complex tuberculous lung lesions on F-fluorodeoxyglucose positron emission tomography/computerised tomography images.

EJNMMI Res 2018 Jun 25;8(1):55. Epub 2018 Jun 25.

Division of Nuclear Medicine, Department of Medical Imaging and Clinical Oncology, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.

Background: There is a growing interest in the use of F-FDG PET-CT to monitor tuberculosis (TB) treatment response. However, TB causes complex and widespread pathology, which is challenging to segment and quantify in a reproducible manner. To address this, we developed a technique to standardise uptake (Z-score), segment and quantify tuberculous lung lesions on PET and CT concurrently, in order to track changes over time. We used open source tools and created a MATLAB script. The technique was optimised on a training set of five pulmonary tuberculosis (PTB) cases after standard TB therapy and 15 control patients with lesion-free lungs.

Results: We compared the proposed method to a fixed threshold (SUV > 1) and manual segmentation by two readers and piloted the technique successfully on scans of five control patients and five PTB cases (four cured and one failed treatment case), at diagnosis and after 1 and 6 months of treatment. There was a better correlation between the Z-score-based segmentation and manual segmentation than SUV > 1 and manual segmentation in terms of overall spatial overlap (measured in Dice similarity coefficient) and specificity (1 minus false positive volume fraction). However, SUV > 1 segmentation appeared more sensitive. Both the Z-score and SUV > 1 showed very low variability when measuring change over time. In addition, total glycolytic activity, calculated using segmentation by Z-score and lesion-to-background ratio, correlated well with traditional total glycolytic activity calculations. The technique quantified various PET and CT parameters, including the total glycolytic activity index, metabolic lesion volume, lesion volumes at different CT densities and combined PET and CT parameters. The quantified metrics showed a marked decrease in the cured cases, with changes already apparent at month one, but remained largely unchanged in the failed treatment case.

Conclusions: Our technique is promising to segment and quantify the lung scans of pulmonary tuberculosis patients in a semi-automatic manner, appropriate for measuring treatment response. Further validation is required in larger cohorts.
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http://dx.doi.org/10.1186/s13550-018-0411-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6020088PMC
June 2018

Evaluating the Role of F-18 Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography Scanning in the Staging of Patients With Stage IIIB Cervical Carcinoma and the Impact on Treatment Decisions.

Int J Gynecol Cancer 2018 02;28(2):379-384

Objective: FIGO (International Federation of Gynaecology and Obstetrics) staging is currently the most widely used clinical staging system for cervical cancer; however, this staging system has many shortcomings. One of these shortcomings is that lymph nodal status, specifically the para-aortic lymph nodal status, does not get taken into account. It is known that metabolic changes occur before changes are seen on anatomical imaging, and it is therefore possible to detect metastases earlier with the help of fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT). We hypothesized that by including an FDG PET/CT study as part of the staging investigations in patients with invasive cervical cancer, pretreatment staging would improve and management would change in a significant proportion of patients.

Methods/materials: Patients diagnosed with FIGO stage IIIB cervical cancer from September 2010 to December 2015 received an FDG PET/CT study as part of their staging workup. A whole-body FDG PET/CT was performed before initiation of treatment, and the results were interpreted by experienced nuclear medicine physicians and radiologists. We determined the percentage of patients in whom PET/CT changed the stage and/or altered management of the patient.

Results: There were 95 patients diagnosed with stage IIIB cervix cancer during the study period who received an FDG PET/CT as part of their staging workup. Eighty-eight patients were included in the final sample. Positron emission tomography/CT affected the management of 40% of patients, with 19% requiring a change in the radiation field due to identification of para-aortic nodal involvement and 21% upstaged to stage IVB.

Conclusions: Fluorodeoxyglucose PET/CT is useful in assessing distant disease and evaluating nodal involvement in patients with invasive cervical cancer. Additional findings on the PET/CT that were missed by conventional imaging and clinical examination caused treatment change in a significant proportion of patients.
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http://dx.doi.org/10.1097/IGC.0000000000001174DOI Listing
February 2018

Resting regional brain metabolism in social anxiety disorder and the effect of moclobemide therapy.

Metab Brain Dis 2018 04 3;33(2):569-581. Epub 2017 Nov 3.

Division of Nuclear Medicine, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.

While there is mounting evidence of abnormal reactivity of several brain regions in social anxiety disorder, and disrupted functional connectivity between these regions at rest, relatively little is known regarding resting regional neural activity in these structures, or how such activity is affected by pharmacotherapy. Using 2-deoxy-2-(F-18)fluoro-D-glucose positron emission tomography, we compared resting regional brain metabolism between SAD and healthy control groups; and in SAD participants before and after moclobemide therapy. Voxel-based analyses were confined to a predefined search volume. A second, exploratory whole-brain analysis was conducted using a more liberal statistical threshold. Fifteen SAD participants and fifteen matched controls were included in the group comparison. A subgroup of SAD participants (n = 11) was included in the therapy effect comparison. No significant clusters were identified in the primary analysis. In the exploratory analysis, the SAD group exhibited increased metabolism in left fusiform gyrus and right temporal pole. After therapy, SAD participants exhibited reductions in regional metabolism in a medial dorsal prefrontal region and increases in right caudate, right insula and left postcentral gyrus. This study adds to the limited existing work on resting regional brain activity in SAD and the effects of therapy. The negative results of our primary analysis suggest that resting regional activity differences in the disorder, and moclobemide effects on regional metabolism, if present, are small. While the outcomes of our secondary analysis should be interpreted with caution, they may contribute to formulating future hypotheses or in pooled analyses.
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http://dx.doi.org/10.1007/s11011-017-0145-7DOI Listing
April 2018

Host blood RNA signatures predict the outcome of tuberculosis treatment.

Tuberculosis (Edinb) 2017 12 12;107:48-58. Epub 2017 Aug 12.

The Center for Infectious Disease Research, Seattle, WA, USA. Electronic address:

Biomarkers for tuberculosis treatment outcome will assist in guiding individualized treatment and evaluation of new therapies. To identify candidate biomarkers, RNA sequencing of whole blood from a well-characterized TB treatment cohort was performed. Application of a validated transcriptional correlate of risk for TB revealed symmetry in host gene expression during progression from latent TB infection to active TB disease and resolution of disease during treatment, including return to control levels after drug therapy. The symmetry was also seen in a TB disease signature, constructed from the TB treatment cohort, that also functioned as a strong correlate of risk. Both signatures identified patients at risk of treatment failure 1-4 weeks after start of therapy. Further mining of the transcriptomes revealed an association between treatment failure and suppressed expression of mitochondrial genes before treatment initiation, leading to development of a novel baseline (pre-treatment) signature of treatment failure. These novel host responses to TB treatment were integrated into a five-gene real-time PCR-based signature that captures the clinically relevant responses to TB treatment and provides a convenient platform for stratifying patients according to their risk of treatment failure. Furthermore, this 5-gene signature is shown to correlate with the pulmonary inflammatory state (as measured by PET-CT) and can complement sputum-based Gene Xpert for patient stratification, providing a rapid and accurate alternative to current methods.
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http://dx.doi.org/10.1016/j.tube.2017.08.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5658513PMC
December 2017

Resting-state fMRI and social cognition: An opportunity to connect.

Hum Psychopharmacol 2017 09 1;32(5). Epub 2017 Aug 1.

Division of Nuclear Medicine, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.

Many psychiatric disorders are characterized by altered social cognition. The importance of social cognition has previously been recognized by the National Institute of Mental Health Research Domain Criteria project, in which it features as a core domain. Social task-based functional magnetic resonance imaging (fMRI) currently offers the most direct insight into how the brain processes social information; however, resting-state fMRI may be just as important in understanding the biology and network nature of social processing. Resting-state fMRI allows researchers to investigate the functional relationships between brain regions in a neutral state: so-called resting functional connectivity (RFC). There is evidence that RFC is predictive of how the brain processes information during social tasks. This is important because it shifts the focus from possibly context-dependent aberrations to context-independent aberrations in functional network architecture. Rather than being analysed in isolation, the study of resting-state brain networks shows promise in linking results of task-based fMRI results, structural connectivity, molecular imaging findings, and performance measures of social cognition-which may prove crucial in furthering our understanding of the social brain.
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http://dx.doi.org/10.1002/hup.2627DOI Listing
September 2017

Persisting positron emission tomography lesion activity and Mycobacterium tuberculosis mRNA after tuberculosis cure.

Nat Med 2016 10 5;22(10):1094-1100. Epub 2016 Sep 5.

National Medical Center, Seoul, South Korea.

The absence of a gold standard to determine when antibiotics induce a sterilizing cure has confounded the development of new approaches to treat pulmonary tuberculosis (PTB). We detected positron emission tomography and computerized tomography (PET-CT) imaging response patterns consistent with active disease, along with the presence of Mycobacterium tuberculosis (MTB) mRNA in sputum and bronchoalveolar lavage samples, in a substantial proportion of adult, HIV-negative patients with PTB after a standard 6-month treatment plus 1 year follow-up, including patients with a durable cure and others who later developed recurrent disease. The presence of MTB mRNA in the context of nonresolving and intensifying lesions on PET-CT images might indicate ongoing transcription, suggesting that even apparently curative treatment for PTB may not eradicate all of the MTB bacteria in most patients. This suggests an important complementary role for the immune response in maintaining a disease-free state. Sterilizing drugs or host-directed therapies, and better treatment response markers, are probably needed for the successful development of improved and shortened PTB-treatment strategies.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5053881PMC
http://dx.doi.org/10.1038/nm.4177DOI Listing
October 2016

Characterization of progressive HIV-associated tuberculosis using 2-deoxy-2-[F]fluoro-D-glucose positron emission and computed tomography.

Nat Med 2016 10 5;22(10):1090-1093. Epub 2016 Sep 5.

Department of Medicine, Imperial College London, London, UK.

Tuberculosis is classically divided into states of latent infection and active disease. Using combined positron emission and computed tomography in 35 asymptomatic, antiretroviral-therapy-naive, HIV-1-infected adults with latent tuberculosis, we identified ten individuals with pulmonary abnormalities suggestive of subclinical, active disease who were substantially more likely to progress to clinical disease. Our findings challenge the conventional two-state paradigm and may aid future identification of biomarkers that are predictive of progression.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5055809PMC
http://dx.doi.org/10.1038/nm.4161DOI Listing
October 2016

Resting functional connectivity in social anxiety disorder and the effect of pharmacotherapy.

Psychiatry Res Neuroimaging 2016 May 16;251:34-44. Epub 2016 Apr 16.

Division of Nuclear Medicine, Faculty of Health Sciences, Stellenbosch University, Cape Town, South Africa.

Neuroimaging research has reported differences in resting-state functional connectivity (RFC) between social anxiety disorder (SAD) patients and healthy controls (HCs). Limited research has examined the effect of treatment on RFC in SAD. We performed a study to identify differences in RFC between SAD and HC groups, and to investigate the effect of pharmacotherapy on RFC in SAD. Seed-based RFC analysis was performed on technetium-99m hexamethylpropylene amine oxime (Tc-99m HMPAO) SPECT scans using a cross-subject approach in SPM-12. Seeds were chosen to represent regions in a recently published network model of SAD. A second-level regression analysis was performed to further characterize the underlying relationships identified in the group contrasts. Twenty-three SAD participants were included, of which 18 underwent follow-up measures after an 8-week course of citalopram or moclobemide. Fifteen healthy control (HC) scans were included. SAD participants at baseline demonstrated several significant connectivity disturbances consistent with the existing network model as well as one previously unreported finding (increased connectivity between cerebellum and posterior cingulate cortex). After therapy, the SAD group demonstrated significant increases in connectivity with dorsal anterior cingulate cortex which may explain therapy-induced modifications in how SAD sufferers interpret emotions in others and improvements in self-related and emotional processing.
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http://dx.doi.org/10.1016/j.pscychresns.2016.04.009DOI Listing
May 2016

Appropriate indications for positron emission tomography/computed tomography, 2015.

S Afr Med J 2015 Oct 16;106(1 Pt 2):105-22. Epub 2015 Oct 16.

Department of Nuclear Medicine, Steve Biko Academic Hospital and Faculty of Health Sciences, University of Pretoria, South Africa.

These recommendations are intended to serve an important and relevant role in advising referring physicians on the appropriate use of 18F-fluorodeoxyglucose (18F-FDG) and non-18F-FDG positron emission tomography/computed tomography (PET/CT), which can be a powerful tool in patient management in oncology, cardiology, neurology and infection/inflammation. PET is a non-invasive molecular imaging tool that provides tomographic images and quantitative parameters of perfusion, cell viability, proliferation and/or metabolic activity of tissues. These images result from the use of different substances of biological interest (sugars, amino acids, metabolic precursors, hormones) labelled with positron-emitting radionuclides (PET radiopharmaceuticals). Fusion of the aforementioned important functional information with the morphological detail provided by CT as PET/CT provides clinicians with a sensitive and accurate one-step whole-body diagnostic and prognostic tool, which directs and changes patient management. Hence PET/CT is currently the most widely used molecular imaging technology for a patient-tailored treatment approach. In these recommendations we outline which oncological and non-oncological indications are appropriate for PET/CT. Once each combination of pathology and clinical indication is defined, a recommendation is given as: 1. Recommended; 2. Recommended in select cases; 3. May be considered; or 4. Not recommended.
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http://dx.doi.org/10.7196/SAMJ.2016.v106i1.10181DOI Listing
October 2015

Appropriate indications for positron emission tomography/computed tomography: College of Nuclear Physicians of the Colleges of Medicine of South Africa.

S Afr Med J 2015 Nov;105(11):894-6

Department of Nuclear Medicine, Steve Biko Academic Hospital and Faculty of Health Sciences, University of Pretoria, South Africa.

Individualised patient treatment approaches demand precise determination of initial disease extent combined with early, accurate assessment of response to treatment, which is made possible by positron emission tomography/computed tomography (PET/CT). PET is a non-invasive tool that provides tomographic images and quantitative parameters of perfusion, cell viability, and proliferation and/or metabolic activity of tissues. Fusion of the functional information with the morphological detail provided by CT as PET/CT can provide clinicians with a sensitive and accurate one-step whole-body diagnostic and prognostic tool, which directs and changes patient management. Three large-scale national studies published by the National Oncologic PET Registry in the USA have shown that imaging with PET changes the intended patient management strategy in 36.5% to 49% of cases, with consistent results across all cancer types. The proven clinical effectiveness and growing importance of PET/CT have prompted the College of Nuclear Physicians of South Africa, in collaboration with university hospitals, to develop a list of recommendations on the appropriate use of fluorine-18-fluorodeoxyglucose (18F-FDG) and non-18F-FDG PET/CT in oncology, cardiology, neurology and infection/inflammation. It is expected that other clinical situations will be added to these recommendations, provided that they are based upon solid clinical evidence. These recommendations are intended to offer advice regarding contemporary applications of PET/CT, as well as indicating novel developments and potential future indications. The CNP believes that these recommendations will serve an important and relevant role in advising referring physicians on the appropriate use of 18F-FDG and non-18F-FDG PET/CT. More promising clinical applications will be possible in the future, as newer PET tracers become more readily available.
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http://dx.doi.org/10.7196/SAMJ.2015.v105i11.10180DOI Listing
November 2015

Integrated positron emission tomography/computed tomography for evaluation of mediastinal lymph node staging of non-small-cell lung cancer in a tuberculosis-endemic area: A 5-year prospective observational study.

S Afr Med J 2015 Jan 9;105(2):145-50. Epub 2015 Jan 9.

Division of Pulmonology, Department of Medicine, Faculty of Medicine and Health Sciences, Stellenbosch University and Tygerberg Academic Hospital, Tygerberg, Cape Town, South Africa.

Background: Integrated positron emission tomography/computed tomography (PET-CT) is a well-validated modality for assessing mediastinal lymph node metastasis in non-small-cell lung cancer (NSCLC), which determines management and predicts survival. Tuberculosis (TB) is known to lead to false-positive PET-CT findings.

Objectives: To assess the diagnostic accuracy of PET-CT in identifying mediastinal lymph node involvement of NSCLC in a high TB-endemic area.

Methods: Patients who underwent both PET-CT and lymph node tissue sampling for the investigation of suspected NSCLC were prospectively included in this observational study. Results were analysed per patient and per lymph node stage. A post-hoc analysis was performed to test the validity of a maximum standardised uptake value (SUV-max) cut-off for lymph node positivity.

Results: PET-CT had a sensitivity of 92.6%, specificity of 48.6%, positive predictive value of 56.8% and negative predictive value (NPV) of 90.0% in the per-patient analysis. Diagnostic accuracy was 67.2%. Similar values were obtained in the per-lymph node stage analysis. TB was responsible for 21.1% of false-positive results. A SUVmax cut-off of 4.5 yielded an improvement in diagnostic accuracy from 64.0% to 84.7% compared with a cut-off of 2.5, but at the cost of decreasing the NPV from 90.6% to 83.5%.

Conclusion: In a high TB-endemic area, PET-CT remains a valuable method for excluding mediastinal lymph node involvement in NSCLC. Patients with a negative PET-CT may proceed to definitive management without further invasive procedures. However, PET-CT-positive lymph nodes require pathological confirmation, and the possibility of TB must be considered.
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http://dx.doi.org/10.7196/samj.8357DOI Listing
January 2015

Measuring GFR Using the Plasma Clearance of (99m)Tc-DTPA.

Am J Kidney Dis 2015 May;65(5):806

Tygerberg Hospital and Stellenbosch University, Cape Town, South Africa.

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http://dx.doi.org/10.1053/j.ajkd.2015.02.333DOI Listing
May 2015

Hybrid imaging using low-dose, localizing computed tomography enhances lesion localization in renal hyperparathyroidism.

Nucl Med Commun 2014 Aug;35(8):884-9

Divisions of aNuclear Medicine bRadiology cNephrology, Tygerberg Hospital, Stellenbosch University, Cape Town, South Africa.

Background: Preoperative localization of parathyroid lesions is potentially beneficial in renal patients with hyperparathyroidism. The aim of this study was to determine the localizing value of hybrid single-photon emission computed tomography combined with low-dose x-ray computed tomography (SPECT/LDCT) compared with SPECT alone and whether the LDCT improved reader confidence.

Patients And Methods: A retrospective study examined parathyroid scintigraphy results of patients previously referred with a diagnosis of renal hyperparathyroidism. All patients underwent planar scintigraphy using technetium-99m (Tc)-pertechnetate, which was immediately followed with Tc-sestamibi and SPECT/LDCT ∼60 min after sestamibi injection and a delayed static image to assess differential washout. Planar subtraction images were generated. Two nuclear physicians, assisted by a radiologist, reported on planar+SPECT images followed by planar+SPECT/LDCT images.

Results: Thirty-seven patients (males: 21; females: 16) were included (mean age 39 years, range: 23.9-55.5). Mean creatinine level was 878 μmol/l (109-1839), mean corrected calcium level was 2.42 mmol/l (1.77-3.64), and median parathyroid hormone level was 156.2 pmol/l (2.4 to >201). Twenty-three patients had positive planar and SPECT results (46 lesions), six had positive planar results only, and eight had negative scintigraphy results. In the patients with positive planar and SPECT results, 35 lesions were classified as eutopic and 11 as ectopic. After the addition of LDCT, localization of five eutopic lesions (on SPECT) was amended to ectopic locations (on SPECT/LDCT), principally by identifying posteriorly situated glands. The addition of LDCT led to increased confidence in localization in all cases.

Conclusion: Compared with SPECT alone, SPECT/LDCT is beneficial in preoperative localization of lesions in renal hyperparathyroidism.
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http://dx.doi.org/10.1097/MNM.0000000000000131DOI Listing
August 2014
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