Utilising pyrophosphate uptake imaging to establish the timing of acute myocardial infarction: An often-forgotten art.

INTRODUCTION: While pyrophosphate uptake imaging with Technetium-99 m pyrophosphate (Tc-99 m PYP) is frequently used for cardiac ATTR amyloid imaging, its role in determining the timing of acute myocardial infarction (AMI) is near forgotten. We present a case that demonstrates the clinical benefit of pyrophosphate uptake imaging in differentiating recent from remote infarction as a reminder of the continued utility of pyrophosphate uptake imaging for this indication. CASE AND OUTCOMES: A 68-year-old male was referred for surgical replacement of his bicuspid aortic valve with severe aortic regurgitation. He was clinically well, but an elective pre-operative electrocardiogram suggested an anteroseptal wall infarct of possibly recent onset. Troponin-I was elevated at 430 ng/L (N < 26 ng/L) but did not change significantly over several days. Coronary angiography confirmed an occluded left anterior descending artery. Tc-99 m PYP uptake imaging was then utilised to determine the age of infarct and demonstrated mild regional tracer uptake in the left ventricular apex, consistent with a recent infarction. As the infarct was recent, elective surgery was postponed. DISCUSSION: In this case, the age of the patient's AMI had an important bearing on the timing of his elective surgical aortic valve replacement. Given the recommendation to delay elective cardiac surgery in patients with recent myocardial infarction to reduce peri­operative morbidity and mortality, this now rare use of pyrophosphate uptake imaging was critical in helping determine when cardiac surgery could be performed safely. CONCLUSION: This case demonstrates the clinical utility of pyrophosphate uptake imaging in establishing the temporal profile of myocardial infarction to help guide appropriate clinical management.

Characterising polymyalgia rheumatica on whole-body 18F-FDG PET/CT: an atlas.

The impact of modern imaging in uncovering the underlying pathology of PMR cannot be understated. Long dismissed as an inflammatory syndrome with links to the large vessel vasculitis giant cell arteritis (GCA), a pathognomonic pattern of musculotendinous inflammation is now attributed to PMR and may be used to confirm its diagnosis. Among the available modalities, 18F-fluorodeoxyglucose (18F-FDG) PET/CT is increasingly recognized for its high sensitivity and specificity, as well as added ability to detect concomitant large vessel GCA and exclude other relevant differentials like infection and malignancy. This atlas provides a contemporary depiction of PMR's pathology and outlines how this knowledge translates into a pattern of findings on whole body 18F-FDG PET/CT that can reliably confirm its diagnosis.

FDG-PET/CT for investigation of pyrexia of unknown origin: a cost of illness analysis.

BACKGROUND: Our study aims to explore the current utilisation of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) in the diagnostic pathway of pyrexia of unknown origin (PUO) and associated cost of illness in a large tertiary teaching hospital in Australia. METHOD: 1257 febrile patients between June 2016 and September 2022 were retrospectively reviewed. There were 57 patients who met the inclusion criteria of "classical PUO", of which FDG-PET/CT was performed in 31 inpatients, 15 outpatients and 11 inpatients did not have an FDG-PET/CT scan. The patient demographics, clinical characteristics and inpatient cost were analysed, together with the diagnostic performance of FDG-PET/CT and impact on clinical management. RESULT: The mean age, length of stay and total cost of admission were higher for inpatients who received FDG-PET/CT versus those who did not. The median cost per patient-bed-day did not differ between the two groups. Inpatients who received earlier FDG-PET/CTs (≤ 7 days from admission) had shorter length of stays and lower total cost compared to those who received a later scan. A negative FDG-PET/CT scan, demonstrating no serious or life-threatening abnormalities resulted in subsequent discharge from hospital or outpatient clinic in 7/10 (70%) patients. There were 11/40 (28%) scans where ancillary abnormalities were identified, requiring further evaluation. CONCLUSION: FDG-PET/CT showed high diagnostic accuracy and significant impact on patient management in patients with PUO. FDG-PET/CT performed earlier in admission for PUO was associated with shorter length of stay and lower total cost.

Acute leg pain and weakness in pregnancy: A new diagnosis of myotonic dystrophy.

We present a unique case of a 44-year-old woman who presented at 29 weeks' gestation with proximal limb pain and elevated creatine kinase. This occurred in the background of premature cataracts, atrial fibrillation and abnormal liver function. Clinical, pathological and neurodiagnostic findings supported a diagnosis of myotonic dystrophy, confirmed by genetic testing which revealed dystrophia myotonica protein kinase gene expansion. Muscle biopsy found both recent necrotising and chronic myopathic processes. Following delivery, the mother's myalgia resolved and creatine kinase quickly declined. The fetus was diagnosed with congenital myotonic dystrophy. We review the impact of myotonic dystrophy on pregnancy and discuss potential explanations for this patient's clinical course. This case emphasises the importance of considering myotonic dystrophy as a differential diagnosis in the right clinical context and the need for pre-pregnancy assessment and genetic counselling in women with known myotonic dystrophy.

Association of good oncological response to therapy with the development of rheumatic immune-related adverse events following PD-1 inhibitor therapy.

AIM: To investigate whether any patient or treatment characteristics are associated with the development of rheumatic immune-related adverse events (irAEs) following programmed cell death protein 1 (PD-1) inhibitor therapy for cancer. METHOD: This was a retrospective chart review of all patients who were dispensed nivolumab or pembrolizumab at a single center before 1 January, 2017, with follow-up until 1 July, 2017. Patients with any diagnosis of a non-cutaneous irAE were identified, regardless of severity, and rheumatic irAEs were characterized. RESULTS: Of 244 episodes of therapy, a non-cutaneous irAE occurred in 72 (29.5%). Rheumatic irAEs were diagnosed in 19 episodes of therapy (7.8%), with 12 de novo diagnoses (5.1% of episodes without a pre-existing autoimmune rheumatic disease) and 7 exacerbations of existing disease. Review by a rheumatologist occurred in only 11 of these. Rheumatic irAEs were more common in patients with a good oncological response to therapy (relative risk [RR] 11.16), those being treated for melanoma (RR 2.94) and those who developed another non-cutaneous irAE (RR 2.64). CONCLUSION: Rheumatic irAEs are relatively common with PD-1 inhibitor therapy, and appear to be associated with a good oncological response to therapy. Many rheumatic irAEs were not referred to rheumatological services. Prospective systematic investigation would be of benefit to explore these characteristics.

Rheumatic immune-related adverse events secondary to anti-programmed death-1 antibodies and preliminary analysis on the impact of corticosteroids on anti-tumour response: A case series.

IMPORTANCE: Rheumatic immune-related adverse events (irAEs) occur in approximately 10-20% of anti-programmed death 1 (anti-PD1)-treated cancer patients. There are limited data on the natural history, optimal treatment and long-term oncological outcomes of patients with rheumatic irAEs. OBJECTIVE: The objective of the study was to describe the spectrum and natural history of rheumatic irAEs and the potential impact of rheumatic irAEs and immunomodulators on anti-PD1 tumour efficacy. METHODS: Cancer patients with pre-existing rheumatic disease before anti-PD1 therapy or de novo rheumatic irAEs on anti-PD1 therapy were retrospectively reviewed across three sites. Patient demographics, treatment history, anti-PD1 irAEs, and anti-PD1 responses were evaluated. Relationships between the development or pre-existence of rheumatic irAE, use of immunomodulatory agents and outcomes were evaluated. RESULTS: This multicenter case series describes 36 cancer patients who had rheumatic disease before anti-PD1 therapy (n = 12) or developed de novo rheumatic irAEs (n = 24). Thirty-four of the 36 patients sustained rheumatic irAEs (median time to rheumatic irAE: 14.5 weeks), including 24 de novo (18 inflammatory arthritis, three myositis, two polymyalgia rheumatica, one fasciitis) and 10 flares in 12 patients with pre-existing rheumatic disease. Corticosteroids were used in 30 of 36 patients (median duration: 10 months), and disease-modifying antirheumatic drugs were used in 14 of 36 patients (median duration: 5.5 months). The objective response rate to anti-PD1 therapy was 69% (n = 25/36) overall and 81% (n = 21/26) in the melanoma subgroup. CONCLUSIONS: Rheumatic irAEs are often chronic and require prolonged immunomodulatory therapy. Prospective studies are required to define optimal management of rheumatic irAEs that maintain long-term anticancer outcomes.

Non-medical needs of older patients in the emergency department.

AIM: To determine the non-medical needs of older patients in the emergency department (ED). METHODS: We undertook a cross-sectional survey of three age groups (50-64, 65-79, 80+ years) using a self-administered questionnaire with five response options (strongly agree-strongly disagree) for 31 items. RESULTS: There were 548 patients enrolled. Significantly fewer older patients knew how to call for assistance (P < 0.01), knew how the ED works (P < 0.01), felt frightened by their illness (P < 0.01) or felt that the ED lights were too bright (P < 0.03). A substantial proportion of all patients did not agree that their illness and/or treatment had been well explained. CONCLUSION: Older patients appear resilient but need to be told to call for assistance when needed, to know how to call for this assistance and how the ED works. Clear information regarding their illness and treatment should be provided, particularly to younger patients who may be anxious.

Variables associated with parent satisfaction with their child's pain management.

OBJECTIVE: The provision of 'adequate analgesia' (which reduces the pain score by ≥2 and to <4 [0-10 scale]) is significantly associated with high levels of satisfaction with pain management among adult patients. We aimed to determine the variables (including 'adequate analgesia') associated with parent satisfaction with their child's pain management. METHODS: We undertook an observational, pilot study in a mixed, metropolitan ED. Patients aged 4-16 years with a triage pain score of ≥4 were enrolled. Data included demographics, presenting complaint, pain scores every 30 min, analgesia administered, time to first analgesia, provision of nurse-initiated analgesia (NIA), and 'adequate analgesia', and parent satisfaction 48-h post-discharge (6 point scale: very unsatisfied - very satisfied). RESULTS: Complete data were collected on 185 patients: mean (SD) age 10.4 (3.6) years, weight 41.9 (17.8) kg; 93 (50.3%) were male. One hundred and ten (59.4%) parents were very satisfied with their child's pain management. Children of very satisfied parents had shorter times to analgesia than those who did not (median [interquartile range] 14 (33) vs 33 (46) min, respectively, P = 0.003). Parents whose children received NIA or 'adequate analgesia' were more often very satisfied than those whose children did not. However, the differences were not significant (difference in proportions: 13.2% [95% CI -1.9, 28.3], P = 0.07 and 10.2% [95% CI -5.02, 25.34], P = 0.16, respectively). CONCLUSION: Short times to analgesia are associated with parent satisfaction. There were non-significant trends towards high levels of satisfaction following the provision of NIA and 'adequate analgesia'. These findings will inform a well-powered study to confirm this association.

Antiphospholipid antibodies internalised by human syncytiotrophoblast cause aberrant cell death and the release of necrotic trophoblast debris.

Antiphospholipid antibodies (aPL) are the strongest maternal risk factor for pre-eclampsia, a hypertensive disease of human pregnancy. Pre-eclampsia is triggered by a toxic factor released from the placenta that activates the maternal endothelium. Antiphospholipid antibodies cause the release of necrotic trophoblast debris from the placental syncytiotrophoblast and this debris can activate endothelial cells. In this study, we investigated how aPL affects syncytiotrophoblast death and production of necrotic trophoblast debris by examining the interaction between aPL and human first trimester placental explants. Human polyclonal and murine monoclonal aPL, but not control antibodies, were rapidly internalised by the syncytiotrophoblast. Inhibitors of endocytosis or the low-density lipoprotein receptor (LDLR) family, but not toll-like receptors, decreased the internalisation of aPL and prevented the release of necrotic trophoblast debris from the syncytiotrophoblast. Once internalised, aPL increased inner mitochondrial membrane leak and Cytochrome c release while depressing oxidative flux through Complex IV of the electron transport system in syncytiotrophoblast mitochondria. These data suggest that the human syncytiotrophoblast internalises aPL by antigen-dependent endocytosis involving LDLR family members. Once internalised by the syncytiotrophoblast, aPL affects the death-regulating mitochondria, causing extrusion of necrotic trophoblast debris which can activate maternal endothelial cells thereby contributing to the pathogenesis of pre-eclampsia.

The role of autocrine TGFbeta1 in endothelial cell activation induced by phagocytosis of necrotic trophoblasts: a possible role in the pathogenesis of pre-eclampsia.

Pre-eclampsia is a disorder of pregnancy characterized by hypertension and endothelial cell dysfunction. The causes of pre-eclampsia are unclear but it is proposed that a factor released from the placenta triggers the maternal symptoms. One possible triggering factor is dead trophoblasts that are shed from the placenta, then deported to become trapped in the maternal pulmonary capillaries. It is hypothesized that trophoblasts die by apoptosis in normal pregnancy, but by necrosis in pre-eclampsia. Deported trophoblasts may be phagocytosed by the pulmonary endothelial cells and we have previously shown that phagocytosis of necrotic trophoblasts leads to the activation of endothelial cells, accompanied by the release of interleukin-6 from these cells. However, the mechanistic pathway linking phagocytosis of necrotic trophoblasts and endothelial cell activation is unknown. Here we show that, after phagocytosis of necrotic, but not apoptotic, trophoblasts, endothelial cells secrete TGFbeta1. Using recombinant endoglin to inhibit the function of TGFbeta1 we have shown that the TGFbeta1 does not directly activate endothelial cells but rather it induces endothelial IL-6 secretion. The IL-6 then induces endothelial cell activation. Inhibiting either TGFbeta1 or IL-6 prevented endothelial cell activation in response to phagocytosing necrotic trophoblasts, but inhibiting IL-6 did not prevent secretion of TGFbeta1, confirming the order of signalling. IL-6 also reduced endothelial cell-surface endoglin but increased the amount of soluble endoglin released from placental explants. These interactions between the IL-6 and TGFbeta1 pathways in both the endothelium and placenta may help to regulate the maternal response to deported trophoblasts in pregnancy.