Cohort profile: the potentially preventable burden of community-acquired pneumonia in South African adults in the era of widespread PCV13 immunisation and antiretroviral therapy roll-out, before and during the COVID-19 pandemic – the multicentre, multimethod PotPrev Study

Purpose
In the setting of an established childhood pneumococcal vaccination programme with immediate initiation and treatment of antiretroviral therapy (ART) for people living with HIV (PLWH), the risk of adult pneumococcal community-acquired pneumonia (CAP) is not recently described. We aimed to investigate CAP incidence, recurrence, mortality, risk factors and microbiology before and during the COVID-19 pandemic.

Participants
Adults aged ≥18 years were enrolled in three South African provinces from March 2019 to October 2021, with a brief halt during the initial COVID-19 lockdown. The first group, PdCAP, a surveillance cohort, had their data abstracted to estimate the population incidence of physician-diagnosed CAP by counting incident CAP patients presenting to emergency rooms (ER) and mapping them to catchment areas linked to census data. From those admitted to wards from ERs, a prospective cohort (HospCAP) was enrolled and followed up to 1 year after discharge. Microbiology testing was performed and data were abstracted and collected for economic assessments. A third group (StART) of PLWH without respiratory illness at enrolment, attending primary healthcare clinics to initiate or reinitiate ART, was prospectively enrolled and followed. HospCAP and StART participants (totalling 2950 participants) were followed for at least 1 year and assessed for CAP episodes, hospitalisations and mortality.

Findings to date
Surveillance identified 6546 patients attending ERs with physician-diagnosed CAP; 61/6546 (0.9%) died in the ER. We prospectively enrolled 2000 hospitalised patients with CAP of whom 1079/2000 (54.0%) were PLWH. Overall, 271/2000 (13.6%) hospitalised CAP patients died during their first admission and 298/2000 (14.9%) died during follow-up. Among StART cohort, 18/950 (1.9%) died during follow-up.

Future plans
Planned analyses include incidence estimates of pneumococcal serotype-specific adult CAP and its recurrence, using Urinary Antigen Detection assay results to model the burden of pneumococcal CAP better and health economics analyses.

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Clinical characteristics and diagnostic accuracy of preliminary diagnoses in adults with infections in Danish emergency departments: a multicentre combined cross-sectional and diagnostic study

Objective
Rapid and accurate infection diagnosis is a prerequisite for appropriate antibiotic prescriptions in an ED. Accurately diagnosing acute infections can be difficult due to nonspecific symptoms and limitations of diagnostic testing. The accuracy of preliminary diagnoses, established on the initial clinical assessment, depends on a physician’s skills and knowledge. It has been scarcely studied, and knowledge of how infected patients present at EDs today is needed to improve it. Based on expert reference diagnoses and a current ED population, this study aimed to characterise adults presenting at EDs with suspected infection to distinguish between infections and non-infections and to investigate the accuracy of the preliminary infection diagnoses.

Design
This study was multicentre with a design that combined a cross-sectional study and a diagnostic study with a prospective enrolment.

Setting
Multicenter study including EDs at three Danish hospitals.

Participants
Adults admitted with a preliminary diagnosis of an infectious disease.

Outcome measures
Data were collected from medical records and participant interviews. The primary outcome was the reference diagnosis made by two medical experts on chart review. Univariate logistic regression analysis was performed to identify factors associated with infectious diseases.

Results
We included 954 patients initially suspected of having an infection, with 81% later having an infectious disease confirmed by experts. Parameters correlating to infection were fever, feeling unwell, male sex, high C-reactive protein, symptoms onset within 3 days, high heart rate, low oxygen saturation and abnormal values of neutrophilocytes and leucocytes. The three main conditions were community-acquired pneumonia (CAP) (34%), urinary tract infection (UTI) with systemic symptoms (21%) and cellulitis (10%). The sensitivity of the physician’s preliminary infection diagnoses was 87% for CAP, 74% for UTI and 77% for other infections.

Conclusions
Four out of five patients with a preliminary infection diagnosis, established on initial clinical assessment, were ultimately confirmed to have an infectious disease. The main infections included CAP, UTI with systemic symptoms and cellulitis. Physicians’ preliminary infection diagnoses were moderately in accordance with the reference diagnoses.

Trial registration number
NCT04661085, NCT04681963, NCT04667195.

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Australian Particle Therapy Clinical Quality Registry (ASPIRE) protocol (TROG 21.12): a multicentre prospective study on patients with rare tumours, treated with radiation therapy

Introduction
In 2020, the Australian Medical Services Advisory Committee (MSAC) recommended new proton beam therapy (PBT) item numbers be added to the Medicare Benefits Schedule. During the MSAC 1638 application process, MSAC recognised the uncertainties inherent in the cost-utility modelling of PBT. To address these uncertainties, MSAC proposed the establishment of a national registry with the intention to gather evidence to validate the claim of PBT’s superior toxicity outcomes and cost-effectiveness compared with conventional photon radiation therapy.

Methods and analysis
The Australian Particle Therapy Clinical Quality Registry is a prospective, observational, longitudinal registry collecting national data on paediatric, adolescent young adult and adult patients with rare tumours receiving any form of radiation therapy for a defined group of diseases, specified by the MSAC 1638 Public Summary Document. Eligible patients undergoing radiation therapy at participating institutions will be provided with information about the registry, including the opt-out procedure. The registry has no enrolment cap and will persist either indefinitely or until the conclusion of the study.
The study design was informed by the Australian Metadata Online Repository and contains a core set of minimum data elements. Representing baseline participant demographics, assessment, diagnosis and treatment; incorporating radiation and systemic therapies, with a specific focus on long-term follow-up, treatment toxicities and specific organ-at-risk testing.

Ethics and dissemination
There will be no identifying data used in any reports or presentations of data. Additionally, all identifiable data will be safeguarded according to standard practices and available only to the host institution submitting the data to the registry. Aggregated data for the purposes of research will be stripped of identifiers. The registry has been approved under the National Mutual Agreement by the Central Adelaide Local Health Network Human Research Ethics Committee—HREC: 2021/HRE00394.

Trial registration number
Australian and New Zealand Clinical Trials Registry (ANZCTR): ACTRN12622000026729p.

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Abstract 4139404: Post-Translational Regulation of Larp6 by IGF-1 Modulates Collagen Synthesis in Smooth Muscle Cells

Circulation, Volume 150, Issue Suppl_1, Page A4139404-A4139404, November 12, 2024. Introduction:Vascular smooth muscle cells (SMCs) play a crucial role in atherosclerosis, contributing to plaque stability by forming the main cellular component of the fibrous cap and synthesizing extracellular matrix. We previously showed that insulin-like growth factor-1 (IGF-1) increases expression of the collagen mRNA binding protein La ribonucleoprotein domain family member 6 (Larp6) and of collagen in atherosclerotic plaques. However, molecular mechanisms remain unclear.Hypothesis:We hypothesized that IGF-1 increases collagen synthesis via a post-translational regulation mechanism of Larp6.Methods:An SMC-specific Larp6 overexpression mouse model (SMC-Larp6) was generated using the Myh11 promoter. Entire aortas and aortic roots were isolated for plaque analysis. IGF-1 was injected in WT mice at a dosage of 1.5 mg/kg. For in vitro assays, human aortic SMCs were transduced with an adenoviral vector to overexpress Larp6 and treated with 50 ng/mL IGF-1 for 18 h.Results:SMC-Larp6 mice had no significant change in plaque collagen content. Additionally, IGF-1 increased Larp6 protein but not mRNA levels suggesting that IGF-1 likely regulated Larp6 via a post-transcriptional mechanism. Western blotting identified two major Larp6 bands at 67 kDa and 70 kDa. We observed a clear band shift from the lower to the upper band after IGF-1 treatment, with a concomitant increase in Procollagen I, suggesting that IGF-1 enhances Larp6’s role in promoting collagen through post-translational modification. Mass spectrometry analysis revealed multiple phosphorylation sites on the LaM and LSA domains of Larp6, including S451, which is phosphorylated by the IGF-1/PI3K/AKT axis. We also observed this protein modification pattern in mouse aortic tissue lysates following IGF-1 injection.Conclusions:IGF-1 regulates Larp6 phosphorylation in SMC, thereby likely playing an important role in IGF-1 induced collagen synthesis. This study provides insight into molecular mechanisms underlying collagen production in SMCs and could inform therapeutic strategies for plaque stabilization.

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Abstract 4143104: Atherosclerotic features of plaque instability are transmitted via gut microbial transplantation

Circulation, Volume 150, Issue Suppl_1, Page A4143104-A4143104, November 12, 2024. Background:Gut microbiota have been suggested as a causative agent of atherosclerosis mainly by converting dietary and endogenous molecules into active metabolites like the trimethylamine N-oxide (TMAO). Nevertheless, the relationship between gut microbiota and plaque features has not been well documented. In this study, we tested the hypothesis that gut microbial transplantation can transmit atherosclerotic plaque characteristics.Methods and Results:In a fecal microbiota transplantation mouse model, the colonization of gut microbiota from patients with acute coronary syndrome (ACS, n=9), chronic coronary syndrome (CCS, n=11) and control subjects (CTRL, n=8) was evaluated and plaque features of stability were assessed. Transplantation was performed into ApoE KO mice fed a diet containing 1% choline or a standard diet. Initially, resident intestinal microbes were suppressed using antibiotics, followed by the administration of fecal oral gavages from human donors over a period of 12 weeks. Firstly, a significant positive correlation was detected between TMAO serum levels assessed by UPLC-MS/MS system and atherosclerotic lesion formation measured by Oil Red O staining of aortic root cross-sections; however, no correlations were identified with plaque instability. Plaque composition was analyzed using necrotic core area and fibrous cap thickness as primary readouts of plaque vulnerability. Interestingly, microbiota from ACS patients significantly decreased plaque stability as showed by increased necrotic core and fibrous cap thinning. Further, it decreased α-SMA+cell population and increased MMP2 staining, indicating intraplaque metalloprotease activity.Gut microbiota composition was evaluated using 16S rRNA sequencing of ApoE KO mice fecal samples. In ACS transplanted mice, 14 bacterial genera were positively associated with larger necrotic core and 6 bacterial genera with MMP2. In CCS transplanted mice, 6 bacterial genera showed negative correlations with necrotic core size and 2 bacterial genera positively correlated with α-SMA+cells.Conclusions:In conclusion, we identified bacteria significantly associated with the vulnerable plaque phenotype, which provides potential insights to modulate atherosclerotic plaque composition by influencing the gut microbiota.

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Abstract 4141328: Exercise right heart catheterization combined with echocardiography in evaluation of subclinical pulmonary hypertension and heart failure with preserved left ventricular ejection fraction

Circulation, Volume 150, Issue Suppl_1, Page A4141328-A4141328, November 12, 2024. Introduction:Diagnosis of exercise-induced pulmonary hypertension (EIPH) or exercise-induced heart failure with preserved left ventricular ejection fraction (E-HFpEF) is challenging due to a lack of consensus. The 2022 ESC/ERS guidelines define EIPH as mean (m) PAP/CO > 3 mmHg/L/min, and E-HFpEF as PCWP/CO > 2 mmHg/L/min, a revision of the previous criteria of mPAP ≥ 30 mmHg and PCWP ≥ 25 mmHg.Hypothesis:We investigated the role of exercise RHC in identifying EIPH and E-HFpEF in a group of patients with dyspnea and correlated the rest echo findings with the E-RHC results. We hypothesized that the resting echo parameters can help identify patients with EIPH and E-HFpEF using 2022 ESC/ERS definitions.Methods:A cohort of patients with dyspnea and normal LVEF with E-RHC data from 2016-2019 was included. Patients were categorized into Groups (g) A-E (Fig 1-T1) according to the 2018 WSPH definition of PH. Echo, hemodynamic, and clinical data were collected. The ESC/ERS 2022 guidelines were used to identify EIPH and E-HFpEF. Echo parameters were retrospectively analyzed by logistic regression analysis.Results:200 patients were included. The mPAP and PCWP, but not PVR, significantly increased post-exercise in all groups. Over 50% of patients in each group had evidence of at least grade I LV diastolic dysfunction on rest Echo (Fig 1). PVs/PVd was significantly lower (0.8±0.3) and E/e’ higher (15±7.9) in g-C (Post-Cap) compared to g-A (No-PH), B (Pre-Cap) and E (undifferentiated). In g-A and g-E, 46.8% and 73% demonstrated EIPH, with 87% and 100% showing a mPAP≥30 mmHg respectively. The prevalence of E-HFpEF in g-A, g-B, and g-E was 45%, 50%, and 63% respectively. Only 34%, 42%, and 56% of subjects in g-A, g-B and g-E demonstrated E-PCWP ≥ 25 mmHg. Echo parameters that predicted E-HFpEF included E and E/e’; E/e’ also predicted EIPH (Fig 1).Conclusions:In this study, Echo features of advanced LV diastolic dysfunction including decreased PVs/PVd and increased E/e’ were associated with post-capillary PH. Rest E/e’ and E (LV rapid inflow velocity) may predict E-HFpEF. Exercise RHC may have utility in the evaluation of patients with suspected subclinical PH and HFpEF, but larger prospective designs are warranted

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Abstract 4120821: Electrochemical Impedance Spectroscopy Unmasks High-Risk Atherosclerotic Features in Human Coronary Artery Disease

Circulation, Volume 150, Issue Suppl_1, Page A4120821-A4120821, November 12, 2024. Background:Coronary plaque rupture remains the prominent mechanism of myocardial infarction. Accurate identification of rupture-prone plaque may improve clinical management. This study assessed the discriminatory performance of electrochemical impedance spectroscopy (EIS) in human cardiac explants to detect high-risk atherosclerotic features that portend rupture risk.Methods:In this single-center, prospective study, n=26 cardiac explants were collected for EIS interrogation of the three major coronary arteries. Vessels in which advancement of the EIS catheter without iatrogenic plaque disruption was rendered impossible were not assessed. N=61 vessels underwent EIS measurement and histological analyses. Plaques were dichotomized according to previously established high rupture-risk parameter thresholds. Diagnostic performance was determined via receiver operating characteristic areas-under-the-curve (AUC).Results:Necrotic cores were identified in n=19 vessels (median area 1.53 mm2) with median fibrous cap thickness of 62 μm. Impedance was significantly greater in plaques with necrotic core area ≥1.75 mm2vs 65 μm (19.1±3.5 kΩ vs 6.5±0.9 kΩ,P=0.004), and ≥20 macrophages per 0.3 mm-diameter high-power field (HPF) vs

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Abstract 4142693: Deletion of Prekallikrein enhances atherosclerotic plaque stability and prevents plaque rupture by modulating macrophages and smooth muscle cells

Circulation, Volume 150, Issue Suppl_1, Page A4142693-A4142693, November 12, 2024. Background:Atherosclerosis plaque rupture is the pathological basis and chief culprit of most acute cardiovascular events and death. Emerging evidence suggests that prekallikrein plays an important role in the pathogenesis of atherosclerosis including control of coagulation, complement, and inflammation processes, and regulation of cholesterol levels. However, little is known about the modulation mechanisms of prekallikrein in atherosclerotic plaque stability.Method:We divided 120 ACS patients into those with and without plaque rupture (PR and non-PR, respectively) based on optical coherence tomography image analysis, and quantified the patients’ serum prekallikrein levels. Next, we engineered KLKB1 deficient mice (Klkb1-/-Apoe-/-) and a murine atherosclerosis model with vulnerable plaques was induced with high-cholesterol diet and perivascular carotid collar placement surgeries in Apoe-/-mice. Pathological staining was used to detect necrotic plaque cores, ratios of neutral lipids and cholesterol crystal, as well as collagen fiber contents in these mice to characterize plaque stability. Finally, we further investigated the role and mechanism of prekallikrein in smooth muscle cells and macrophages phenotype switching, proliferation and migration by in vitro experiments.Result:The serum prekallikrein levels of PR patients is significantly higher than that of non-PR patients, and significantly correlated with the thickness of the fibrous cap of the plaque and the length and arc of the lipids. which may be an effective predictor of PR. On a high-fat diet, Klkb1-/-Apoe-/-mice exhibit reduced necrotic plaque cores, as well as neutral lipid and cholesterol crystal ratios, with increased collagen fiber content. Additionally, macrophage apoptosis and phenotypic changes of smooth muscle cells are inhibited in the plaques of Klkb1-/-Apoe-/-mice. In vitro, Klkb1 deficiency inhibits ox-LDL-induced macrophage autophagy and the smooth muscle cells phenotype switching, proliferation and migration.Conclusion:In the present work, we uncover a crucial role for prekallikrein in atherosclerosis as an important regulator of macrophage apoptosis and macrophages phenotype switching and subsequently atherosclerotic plaque destabilization. Cumulatively, these results suggest that targeting prekallikrein may represent a new treatment strategy for the prevention and treatment of acute cardiovascular deaths caused by PR.

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