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Background: Endomyocardial biopsy (EMB) is the gold standard method for surveillance of acute cardiac allograft rejection (ACAR) despite its invasive nature. Cardiovascular magnetic resonance (CMR)–based myocardial tissue characterization allows detection of myocarditis. The feasibility of CMR-based surveillance for ACAR-induced myocarditis in the first year after heart transplantation is currently undescribed. Methods: CMR-based multiparametric mapping was initially assessed in a prospective cross-sectional fashion to establish agreement between CMR- and EMB-based ACAR and to determine CMR cutoff values between rejection grades. A prospective randomized noninferiority pilot study was then undertaken in adult orthotopic heart transplant recipients who were randomized at 4 weeks after orthotopic heart transplantation to either CMR- or EMB-based rejection surveillance. Clinical end points were assessed at 52 weeks. Results: Four hundred one CMR studies and 354 EMB procedures were performed in 106 participants. Forty heart transplant recipients were randomized. CMR-based multiparametric assessment was highly reproducible and reliable at detecting ACAR (area under the curve, 0.92; sensitivity, 93%; specificity, 92%; negative predictive value, 99%) with greater specificity and negative predictive value than either T1 or T2 parametric CMR mapping alone. High-grade rejection occurred in similar numbers of patients in each randomized group (CMR, n=7; EMB, n=8; P =0.74). Despite similarities in immunosuppression requirements, kidney function, and mortality between groups, the rates of hospitalization (9 of 20 [45%] versus 18 of 20 [90%]; odds ratio, 0.091; P =0.006) and infection (7 of 20 [35%] versus 14 of 20 [70%]; odds ratio, 0.192; P =0,019) were lower in the CMR group. On 15 occasions (6%), patients who were randomized to the CMR arm underwent EMB for clarification or logistic reasons, representing a 94% reduction in the requirement for EMB-based surveillance. Conclusions: A noninvasive CMR-based surveillance strategy for ACAR in the first year after orthotopic heart transplantation is feasible compared with EMB-based surveillance. Registration: HREC/13/SVH/66 and HREC/17/SVH/80. Australian New Zealand Clinical Trials Registry: ACTRN12618000672257.

Background: \ud Spontaneous coronary artery dissection (SCAD) is an increasingly recognized cause of acute coronary syndromes (ACS) afflicting predominantly younger to middle-aged women. Observational studies have reported a high prevalence of extracoronary vascular anomalies, especially fibromuscular dysplasia (FMD) and a low prevalence of coincidental cases of atherosclerosis. PHACTR1/EDN1 is a genetic risk locus for several vascular diseases, including FMD and coronary artery disease, with the putative causal noncoding variant at the rs9349379 locus acting as a potential enhancer for the endothelin-1 (EDN1) gene.\ud \ud Objectives: \ud This study sought to test the association between the rs9349379 genotype and SCAD.\ud \ud Methods: \ud Results from case control studies from France, United Kingdom, United States, and Australia were analyzed to test the association with SCAD risk, including age at first event, pregnancy-associated SCAD (P-SCAD), and recurrent SCAD.\ud \ud Results: \ud The previously reported risk allele for FMD (rs9349379-A) was associated with a higher risk of SCAD in all studies. In a meta-analysis of 1,055 SCAD patients and 7,190 controls, the odds ratio (OR) was 1.67 (95% confidence interval [CI]: 1.50 to 1.86) per copy of rs9349379-A. In a subset of 491 SCAD patients, the OR estimate was found to be higher for the association with SCAD in patients without FMD (OR: 1.89; 95% CI: 1.53 to 2.33) than in SCAD cases with FMD (OR: 1.60; 95% CI: 1.28 to 1.99). There was no effect of genotype on age at first event, P-SCAD, or recurrence.\ud \ud Conclusions: \ud The first genetic risk factor for SCAD was identified in the largest study conducted to date for this condition. This genetic link may contribute to the clinical overlap between SCAD and FMD.

AimsComorbid anxiety and mood disorders occur in 30% and 60% of individuals post-ABI (acquired brain injury), respectively (Juengst et al, 2014). The presence of psychiatric symptoms correlate to poorer outcomes in post-stroke rehabilitation, worsened quality of life (QoL), and deficits in memory, attention, and processing speed that persists years following the index event. Despite this, it is unclear whether to what degree anxiety impacts cognition. Furthermore, the literature on this topic is inconsistent when comparing subjective and clinician measurements. This study seeks to ameliorate this gap in literature by analyzing how clinicians’ measures of anxiety and cognitive performance correlate with subjective assessments of patient's own anxiety symptoms.MethodIndividuals with an ABI who were seen in a clinical neuropsychiatry outpatient clinic between 2019 and 2020 completed a GAD-7 (Generalized Anxiety Disorder-7) questionnaire (patient's self-report of the severity of anxiety symptoms) and an observer completed a Neuropsychiatric Inventory Questionnaire (NPIQ) including a subscale for anxiety (NPIQ-A). Participants also underwent a formal cognitive examination with the Montreal Cognitive Assessment (MoCA). A total of 24 ABI patients (depressed ABI and non-depressed ABI) were analyzed for variation, statistical agreement and correlation. Here, total anxiety scores (using GAD-7 scores), anxiety severity (correlating category based on total GAD-7 score) were compared against the objective measures for anxiety (NPI-QA) and cognition (MoCA). In order to standardize MoCA scores, z scores were used in the statistical analysis.ResultThe patient's subjective raw scores of anxiety were statistically significantly different from the corresponding scores from objective observers on Wilcoxon-Rank Sum tests (p < 0.01), however, there was a statistical correlation between GAD (categorized by severity level) and NPI-QA (p = 0.75). Spearman Rank Correlation did show positive, but, statistically insignificant correlation between dyads of these independent variables (including GAD7/NPIQ-A, GAD 7 categorised/NPIQ-A, GAD7/MoCA, GAD 7 categorised/MoCA).ConclusionThese findings indicate (1) self-reported measures of anxiety (GAD7) in ABI were inconsistent with objective measures of anxiety in this cohort, (2) anxiety measures did not demonstrate significant correlation when compared to objective measures for cognitive function, and (3) ABI patients did not display good insight into the severity of their anxiety symptoms as measured by the GAD7. Further research should focus on utilizing other subjective measurement tools for anxiety and/or clinician evaluation tools with NPIQ-A.

Interleukin-10 (IL-10) plays a key role in regulating proinflammatory immune responses to infection but can interfere with pathogen clearance. Although IL-10 is upregulated throughout HIV-1 infection in multiple cell subsets, whether this is a viral immune evasion strategy or an appropriate response to immune activation is unresolved. Analysis of IL-10 production at the single cell level in 51 chronically infected subjects (31 antiretroviral (ART) naïve and 20 ART treated) showed that a subset of CD8(+) T cells with a CD25(neg) FoxP3(neg) phenotype contributes substantially to IL-10 production in response to HIV-1 gag stimulation. The frequencies of gag-specific IL-10- and IFN-γ-producing T cells in ART-naïve subjects were strongly correlated and the majority of these IL-10(+) CD8(+) T cells co-produced IFN-γ; however, patients with a predominant IL-10(+) /IFN-γ(neg) profile showed better control of viraemia. Depletion of HIV-specific CD8(+) IL-10(+) cells from PBMCs led to upregulation of CD38 on CD14(+) monocytes together with increased IL-6 production, in response to gag stimulation. Increased CD38 expression was positively correlated with the frequency of the IL-10(+) population and was also induced by exposure of monocytes to HIV-1 in vitro. Production of IL-10 by HIV-specific CD8(+) T cells may represent an adaptive regulatory response to monocyte activation during chronic infection.

This study sought to test the diagnostic performance of native T1 mapping in acute myocarditis compared with cardiac magnetic resonance (CMR) techniques such as dark-blood T2-weighted (T2W)-CMR, bright-blood T2W-CMR, and late gadolinium enhancement (LGE) imaging.The diagnosis of acute myocarditis on CMR often requires multiple techniques, including T2W, early gadolinium enhancement, and LGE imaging. Novel techniques such as T1 mapping and bright-blood T2W-CMR are also sensitive to changes in free water content. We hypothesized that these techniques can serve as new and potentially superior diagnostic criteria for myocarditis.We investigated 50 patients with suspected acute myocarditis (age 42 ± 16 years; 22% women) and 45 controls (age 42 ± 14 years; 22% women). CMR at 1.5-T (median 3 days from presentation) included: 1) dark-blood T2W-CMR (short-tau inversion recovery); 2) bright-blood T2W-CMR (acquisition for cardiac unified T2 edema); 3) native T1 mapping (shortened modified look-locker inversion recovery); and 4) LGE. Image analysis included: 1) global T2 signal intensity ratio of myocardium compared with skeletal muscle; 2) myocardial T1 relaxation times; and 3) areas of LGE.Compared with controls, patients had significantly higher global T2 signal intensity ratios by dark-blood T2W-CMR (1.73 ± 0.27 vs. 1.56 ± 0.15, p0.01), bright-blood T2W-CMR (2.02 ± 0.33 vs. 1.84 ± 0.17, p0.01), and mean myocardial T1 (1,010 ± 65 ms vs. 941 ± 18 ms, p0.01). Receiver-operating characteristic analysis showed clear differences in diagnostic performance. The areas under the curve for each method were: T1 mapping (0.95), LGE (0.96), dark-blood T2 (0.78), and bright-blood T2 (0.76). A T1 cutoff of 990 ms had a sensitivity, specificity, and diagnostic accuracy of 90%, 91%, and 91%, respectively.Native T1 mapping as a novel criterion for the detection of acute myocarditis showed excellent and superior diagnostic performance compared with T2W-CMR. It also has a higher sensitivity compared with T2W and LGE techniques, which may be especially useful in detecting subtle focal disease and when gadolinium contrast imaging is not feasible.

The physiological ketosis of starvation makes sound evolutionary sense, as ketone bodies have several thermodynamic advantages over other nutritional substrates, in addition to their actions to conserve protein and glucose stores. Utilising the body’s metabolic responses to ketosis by delivering a novel nutritional source of ketone bodies, the work in this thesis explored the metabolic effects of ketosis on physical performance in humans. First, the pharmacokinetics and dosing requirements for ketone containing drink preparations were characterised in a population of athletes and healthy controls (n = 45). Using endurance exercise as a model of physiologic stress, the functional impact of ketosis during sustained high intensity effort was investigated in high performance athletes (n = 22). It was shown that nutritional ketosis improved performance in 18/22 athletes, who set 14 new best performances during 30 min of rowing. Furthermore, when ketones and glucose were delivered together, cycling performance was improved by 2% (n = 8) following 1.5 hours of fatiguing effort, compared with optimal carbohydrate intake. Blood D-β-hydroxybutyrate reached 3-5 mM following ketone drinks, equivalent to several days of total fasting, but rapidly decreased during exercise. It was found that higher physical workloads correlated with larger decreases in plasma ketone concentration (n = 8), consistent with their oxidation as respiratory fuels. Nutritional ketosis significantly altered fuel metabolism during exercise in elite athletes (n = 10), decreasing peripheral lipolysis, skeletal muscle glycolytic intermediates, blood lactate, and branched chain amino acid release. In conclusion this work suggests a new hierarchy of substrate preference during physical stress, whereby mimicking the physiology of starvation, the energetic consequences of oxidising ketones may significantly enhance athletic performance. The extrapolation of these findings may have therapeutic implications for patient populations where energetic demands are high, and deleterious switches in substrate selection occur.