Generative Pre-trained Transformer 4 analysis of cardiovascular magnetic resonance reports in suspected myocarditis: A multicenter study.

BACKGROUND: Diagnosing myocarditis relies on multimodal data, including cardiovascular magnetic resonance (CMR), clinical symptoms, and blood values. The correct interpretation and integration of CMR findings require radiological expertise and knowledge. We aimed to investigate the performance of Generative Pre-trained Transformer 4 (GPT-4), a large language model, for report-based medical decision-making in the context of cardiac MRI for suspected myocarditis. METHODS: This retrospective study includes CMR reports from 396 patients with suspected myocarditis and eight centers, respectively. CMR reports and patient data including blood values, age, and further clinical information were provided to GPT-4 and radiologists with 1 (resident 1), 2 (resident 2), and 4 years (resident 3) of experience in CMR and knowledge of the 2018 Lake Louise Criteria. The final impression of the report regarding the radiological assessment of whether myocarditis is present or not was not provided. The performance of Generative pre-trained transformer 4 (GPT-4) and the human readers were compared to a consensus reading (two board-certified radiologists with 8 and 10 years of experience in CMR). Sensitivity, specificity, and accuracy were calculated. RESULTS: GPT-4 yielded an accuracy of 83%, sensitivity of 90%, and specificity of 78%, which was comparable to the physician with 1 year of experience (R1: 86%, 90%, 84%, p = 0.14) and lower than that of more experienced physicians (R2: 89%, 86%, 91%, p = 0.007 and R3: 91%, 85%, 96%, p < 0.001). GPT-4 and human readers showed a higher diagnostic performance when results from T1- and T2-mapping sequences were part of the reports, for residents 1 and 3 with statistical significance (p = 0.004 and p = 0.02, respectively). CONCLUSION: GPT-4 yielded good accuracy for diagnosing myocarditis based on CMR reports in a large dataset from multiple centers and therefore holds the potential to serve as a diagnostic decision-supporting tool in this capacity, particularly for less experienced physicians. Further studies are required to explore the full potential and elucidate educational aspects of the integration of large language models in medical decision-making.

Potential of GPT-4 for Detecting Errors in Radiology Reports: Implications for Reporting Accuracy.

Background Errors in radiology reports may occur because of resident-to-attending discrepancies, speech recognition inaccuracies, and large workload. Large language models, such as GPT-4 (ChatGPT; OpenAI), may assist in generating reports. Purpose To assess effectiveness of GPT-4 in identifying common errors in radiology reports, focusing on performance, time, and cost-efficiency. Materials and Methods In this retrospective study, 200 radiology reports (radiography and cross-sectional imaging [CT and MRI]) were compiled between June 2023 and December 2023 at one institution. There were 150 errors from five common error categories (omission, insertion, spelling, side confusion, and other) intentionally inserted into 100 of the reports and used as the reference standard. Six radiologists (two senior radiologists, two attending physicians, and two residents) and GPT-4 were tasked with detecting these errors. Overall error detection performance, error detection in the five error categories, and reading time were assessed using Wald χ2 tests and paired-sample t tests. Results GPT-4 (detection rate, 82.7%;124 of 150; 95% CI: 75.8, 87.9) matched the average detection performance of radiologists independent of their experience (senior radiologists, 89.3% [134 of 150; 95% CI: 83.4, 93.3]; attending physicians, 80.0% [120 of 150; 95% CI: 72.9, 85.6]; residents, 80.0% [120 of 150; 95% CI: 72.9, 85.6]; P value range, .522-.99). One senior radiologist outperformed GPT-4 (detection rate, 94.7%; 142 of 150; 95% CI: 89.8, 97.3; P = .006). GPT-4 required less processing time per radiology report than the fastest human reader in the study (mean reading time, 3.5 seconds ± 0.5 [SD] vs 25.1 seconds ± 20.1, respectively; P < .001; Cohen d = -1.08). The use of GPT-4 resulted in lower mean correction cost per report than the most cost-efficient radiologist ($0.03 ± 0.01 vs $0.42 ± 0.41; P < .001; Cohen d = -1.12). Conclusion The radiology report error detection rate of GPT-4 was comparable with that of radiologists, potentially reducing work hours and cost. © RSNA, 2024 See also the editorial by Forman in this issue.

Critical care management of acute intoxications, dynamics and changes over time: a cohort study.

Acute intoxications and poisonings are a relevant cause for ICU admission of critically ill patients. This study aimed to determine the characteristics of intoxicated patients in a tertiary center medical ICU in Austria over time and to investigate parameters associated with ICU mortality. This study was a retrospective data analysis including adult ICU patients from the years 2007 to 2021. In addition to ICU documentation, pre-hospital, and emergency department documents as well as autopsy reports were utilized. In an exploratory subanalysis, we compared these findings to a historical dataset from our facility from 1992 to 1996. We identified 581 cases admitted to the medical ICU because of acute poisoning (2007-2021), of which 45% were female and 46.6% were mixed intoxications. Suicidal intent was the primary cause of intoxication (48.2%) and ICU length of stay was median 1.2 days. The majority of deceased patients received pre-hospital mechanical CPR. Primary and secondary poison/toxin removal modalities were used in 29.9% and 11.7% of cases, whereas antidotes were administered in 54.4%. Comparing the data with a historical cohort (n = 168), we found a shift in primary detoxification away from gastric lavage and an increase in alternative secondary poison/toxin removal techniques. The ICU mortality was 4.1% and 4.2% in the present and historic cohort, respectively. Pre-existing psychiatric illnesses increased from 49% in the historic to 69% in the present cohort. Psychiatric illness predisposes patients to severe intoxications necessitating ICU care, thus increasing prevention measures seems warranted. Females did present with a different spectrum of intoxications compared to males. ICU mortality remained low over time and most deceased patients had a grim prognosis already on ICU arrival.

Compressed SENSE accelerated 3D single-breath-hold late gadolinium enhancement cardiovascular magnetic resonance with isotropic resolution: clinical evaluation.

Aim: The purpose of this study was to investigate the clinical application of Compressed SENSE accelerated single-breath-hold LGE with 3D isotropic resolution compared to conventional LGE imaging acquired in multiple breath-holds. Material & Methods: This was a retrospective, single-center study including 105 examinations of 101 patients (48.2 ± 16.8 years, 47 females). All patients underwent conventional breath-hold and 3D single-breath-hold (0.96 × 0.96 × 1.1 mm3 reconstructed voxel size, Compressed SENSE factor 6.5) LGE sequences at 1.5 T in clinical routine for the evaluation of ischemic or non-ischemic cardiomyopathies. Two radiologists independently evaluated the left ventricle (LV) for the presence of hyperenhancing lesions in each sequence, including localization and transmural extent, while assessing their scar edge sharpness (SES). Confidence of LGE assessment, image quality (IQ), and artifacts were also rated. The impact of LV ejection fraction (LVEF), heart rate, body mass index (BMI), and gender as possible confounders on IQ, artifacts, and confidence of LGE assessment was evaluated employing ordinal logistic regression analysis. Results: Using 3D single-breath-hold LGE readers detected more hyperenhancing lesions compared to conventional breath-hold LGE (n = 246 vs. n = 216 of 1,785 analyzed segments, 13.8% vs. 12.1%; p < 0.0001), pronounced at subendocardial, midmyocardial, and subepicardial localizations and for 1%-50% of transmural extent. SES was rated superior in 3D single-breath-hold LGE (4.1 ± 0.8 vs. 3.3 ± 0.8; p < 0.001). 3D single-breath-hold LGE yielded more artifacts (3.8 ± 1.0 vs. 4.0 ± 3.8; p = 0.002) whereas IQ (4.1 ± 1.0 vs. 4.2 ± 0.9; p = 0.122) and confidence of LGE assessment (4.3 ± 0.9 vs. 4.3 ± 0.8; p = 0.374) were comparable between both techniques. Female gender negatively influenced artifacts in 3D single-breath-hold LGE (p = 0.0028) while increased heart rate led to decreased IQ in conventional breath-hold LGE (p = 0.0029). Conclusions: In clinical routine, Compressed SENSE accelerated 3D single-breath-hold LGE yields image quality and confidence of LGE assessment comparable to conventional breath-hold LGE while providing improved delineation of smaller LGE lesions with superior scar edge sharpness. Given the fast acquisition of 3D single-breath-hold LGE, the technique holds potential to drastically reduce the examination time of CMR.

Dual-layer dual-energy CT-derived pulmonary perfusion for the differentiation of acute pulmonary embolism and chronic thromboembolic pulmonary hypertension.

OBJECTIVES: To evaluate dual-layer dual-energy computed tomography (dlDECT)-derived pulmonary perfusion maps for differentiation between acute pulmonary embolism (PE) and chronic thromboembolic pulmonary hypertension (CTEPH). METHODS: This retrospective study included 131 patients (57 patients with acute PE, 52 CTEPH, 22 controls), who underwent CT pulmonary angiography on a dlDECT. Normal and malperfused areas of lung parenchyma were semiautomatically contoured using iodine density overlay (IDO) maps. First-order histogram features of normal and malperfused lung tissue were extracted. Iodine density (ID) was normalized to the mean pulmonary artery (MPA) and the left atrium (LA). Furthermore, morphological imaging features for both acute and chronic PE, as well as the combination of histogram and morphological imaging features, were evaluated. RESULTS: In acute PE, normal perfused lung areas showed a higher mean and peak iodine uptake normalized to the MPA than in CTEPH (both p < 0.001). After normalizing mean ID in perfusion defects to the LA, patients with acute PE had a reduced average perfusion (IDmean,LA) compared to both CTEPH patients and controls (p < 0.001 for both). IDmean,LA allowed for a differentiation between acute PE and CTEPH with moderate accuracy (AUC: 0.72, sensitivity 74%, specificity 64%), resulting in a PPV and NPV for CTEPH of 64% and 70%. Combining IDmean,LA in the malperfused areas with the diameter of the MPA (MPAdia) significantly increased its ability to differentiate between acute PE and CTEPH (sole MPAdia: AUC: 0.76, 95%-CI: 0.68-0.85 vs. MPAdia + 256.3 * IDmean,LA - 40.0: AUC: 0.82, 95%-CI: 0.74-0.90, p = 0.04). CONCLUSION: dlDECT enables quantification and characterization of pulmonary perfusion patterns in acute PE and CTEPH. Although these lack precision when used as a standalone criterion, when combined with morphological CT parameters, they hold potential to enhance differentiation between the two diseases. CLINICAL RELEVANCE STATEMENT: Differentiating between acute PE and CTEPH based on morphological CT parameters is challenging, often leading to a delay in CTEPH diagnosis. By revealing distinct pulmonary perfusion patterns in both entities, dlDECT may facilitate timely diagnosis of CTEPH, ultimately improving clinical management. KEY POINTS: • Morphological imaging parameters derived from CT pulmonary angiography to distinguish between acute pulmonary embolism and chronic thromboembolic pulmonary hypertension lack diagnostic accuracy. • Dual-layer dual-energy CT reveals different pulmonary perfusion patterns between acute pulmonary embolism and chronic thromboembolic pulmonary hypertension. • The identified parameters yield potential to enable more timely identification of patients with chronic thromboembolic pulmonary hypertension.

Initiation of SGLT2 inhibitors and GLP-1 receptor agonists according to level of frailty in people with type 2 diabetes and cardiovascular disease in Denmark: a cross-sectional, nationwide study.

BACKGROUND: Whether frailty influences the initiation of two cardioprotective diabetes drug therapies (ie, SGLT2 inhibitors and GLP-1 receptor agonists) in people with type 2 diabetes and cardiovascular disease is unknown. We aimed to assess rates of initiation of SGLT2 inhibitors and GLP-1 receptor agonists according to frailty in people with type 2 diabetes and cardiovascular disease. METHODS: For this cross-sectional, nationwide study, all people with type 2 diabetes and cardiovascular disease in Denmark between Jan 1, 2015, and Dec 31, 2021, from six Danish health-data registers were identified. People younger than 40 years, with end-stage renal disease, with registered contraindications to SGLT2 inhibitors or GLP-1 receptor agonists, or with previous use of either drug therapy were excluded. The Hospital Frailty Risk Score was used to categorise people as either non-frail, moderately frail, or severely frail. Cox proportional hazards models were used to analyse the association between frailty and initiation of an SGLT2 inhibitor or a GLP-1 receptor agonist. FINDINGS: Of 119 390 people with type 2 diabetes and cardiovascular disease, 103 790 were included. Median follow-up time was 4·5 years (IQR 2·7-6·1) and median age across the three frailty groups was 71 years (64-79). 65 959 (63·6%) of 103 790 people were male and 37 831 (36·5%) were female. At index date, 66 910 (64·5%) people were non-frail, 29 250 (28·2%) were moderately frail, and 7630 (7·4%) were severely frail. Frailty was associated with a significantly lower probability of initiating therapy with an SGLT2 inhibitor or a GLP-1 receptor agonist than in people who were non-frail (moderately frail hazard ratio 0·91, 95% CI 0·88-0·94, p<0·0001; severely frail 0·75, 0·70-0·80, p<0·0001). This association persisted after adjustment for age, sex, socioeconomic status, year of inclusion, duration of type 2 diabetes, duration of cardiovascular disease, polypharmacy, and comorbidity. INTERPRETATION: In people with type 2 diabetes and cardiovascular disease in Denmark, frailty was associated with a significantly lower probability of SGLT2-inhibitor or GLP-1 receptor-agonist initiation, despite their benefits. Formulating clear and updated guidelines on the use of SGLT2 inhibitors and GLP-1 receptor agonists in people who are frail with type 2 diabetes and cardiovascular disease should be a priority. FUNDING: Department of Cardiology, Herlev and Gentofte University Hospital. TRANSLATION: For the Danish translation of the abstract see Supplementary Materials section.

Temporal Trends in Noncardiovascular Morbidity and Mortality Following Acute Myocardial Infarction.

BACKGROUND: Due to improved management, diagnosis, and care of myocardial infarction (MI), patients may now survive long enough to increasingly develop serious noncardiovascular conditions. OBJECTIVES: This study aimed to test this hypothesis by investigating the temporal trends in noncardiovascular morbidity and mortality following MI. METHODS: We conducted a registry-based nationwide cohort study of all Danish patients with MI during 2000 to 2017. Outcomes were cardiovascular and noncardiovascular mortality, incident cancer, incident renal disease, and severe infectious disease. RESULTS: From 2000 to 2017, 136,293 consecutive patients were identified (63.2% men, median age 69 years). The 1-year risk of cardiovascular mortality between 2000 to 2002 and 2015 to 2017 decreased from 18.4% to 7.6%, whereas noncardiovascular mortality decreased from 5.8% to 5.0%. This corresponded to an increase in the proportion of total 1-year mortality attributed to noncardiovascular causes from 24.1% to 39.5%. Furthermore, increases in 1-year risk of incident cancer (1.9%-2.4%), incident renal disease (1.0%-1.6%), and infectious disease (5.5%-9.1%) were observed (all P trend <0.01). In analyses standardized for changes in patient characteristics, the increased risk of cancer in 2015 to 2017 compared with 2000 to 2002 was no longer significant (standardized risk ratios for cancer: 0.99 [95% CI: 0.91-1.07]; renal disease: 1.28 [95% CI: 1.15-1.41]; infectious disease: 1.28 [95% CI: 1.23-1.34]). CONCLUSIONS: Although cardiovascular mortality following MI improved substantially during 2000 to 2017, the risk of noncardiovascular morbidity increased. Moreover, noncardiovascular causes constitute an increasing proportion of post-MI mortality. These findings suggest that further attention on noncardiovascular outcomes is warranted in guidelines and clinical practice and should be considered in the design of future clinical trials.

Coronary stent imaging in photon counting computed Tomography: Optimization of reconstruction kernels in a phantom.

PURPOSE: Imaging stents and in-stent stenosis remains a challenge in coronary computed tomography angiography (CCTA). In comparison to conventional Computed Tomography, Photon Counting CT (PCCT) provides decisive clinical advantages, among other things by providing low dose ultra-high resolution imaging of coronary arteries. This work investigates the image quality in CCTA using clinically established kernels and those optimized for the imaging of cardiac stents in PCCT, both for in-vitro stent imaging in 400 µm standard resolution mode (SRM) and 200 µm Ultra High Resolution Mode (UHR). METHODS: Based on experimental scans, vascular reconstruction kernels (Bv56, Bv64, Bv72) were optimized. In an established phantom, 10 different coronary stents with 3 mm diameter were scanned in the first clinically available PCCT. Scans were reconstructed with clinically established and optimized kernels. Four readers measured visible stent lumen, performed ROI-based density measurements and rated image quality. RESULTS: Regarding the visible stent lumen, UHR is significantly superior to SRM (p < 0.001). In all levels, the optimized kernels are superior to the clinically established kernels (p < 0.001). One optimized kernel showed a significant reduction of noise compared to the clinically established kernels. Overall image quality is improved with optimized kernels. CONCLUSIONS: In a phantom study PCCT UHR with optimized kernels for stent imaging significantly improves the ability to assess the in-stent lumen of small cardiac stents. We recommend using UHR with an optimized sharp vascular reconstruction kernel (Bv72uo) for imaging of cardiac stent.

Multimodal analysis of granulocytes, monocytes, and platelets in patients with cystic fibrosis before and after Elexacaftor-Tezacaftor-Ivacaftor treatment.

Cystic fibrosis (CF) is a monogenetic disease caused by an impairment of the cystic fibrosis transmembrane conductance regulator (CFTR). CF affects multiple organs and is associated with acute and chronic inflammation. In 2020, Elexacaftor-Tezacaftor-Ivacaftor (ETI) was approved to enhance and restore the remaining CFTR functionality. This study investigates cellular innate immunity, with a focus on neutrophil activation and phenotype, comparing healthy volunteers with patients with CF before (T1, n = 13) and after six months (T2, n = 11) of ETI treatment. ETI treatment reduced sweat chloride (T1: 95 mmol/l (83|108) vs. T2: 32 mmol/l (25|62), p < 0.01, median, first|third quartile) and significantly improved pulmonal function (FEV1 T1: 2.66 l (1.92|3.04) vs. T2: 3.69 l (3.00|4.03), p < 0.01). Moreover, there was a significant decrease in the biomarker human epididymis protein 4 (T1: 6.2 ng/ml (4.6|6.3) vs. T2: 3.0 ng/ml (2.2|3.7), p < 0.01) and a small but significant decrease in matrix metallopeptidase 9 (T1: 45.5 ng/ml (32.5|140.1) vs. T2: 28.2 ng/ml (18.2|33.6), p < 0.05). Neutrophil phenotype (CD10, CD11b, CD62L, and CD66b) and function (radical oxygen species generation, chemotactic and phagocytic activity) remained largely unaffected by ETI treatment. Likewise, monocyte phenotype and markers of platelet activation were similar at T1 and T2. In summary, the present study confirmed a positive impact on patients with CF after ETI treatment. However, neither beneficial nor harmful effects of ETI treatment on cellular innate immunity could be detected, possibly due to the study population consisting of patients with well-controlled CF.

Complement and platelets: prothrombotic cell activation requires membrane attack complex-induced release of danger signals.

Complement activation in the diseases paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS) results in cytolysis and fatal thrombotic events, which are largely refractory to anticoagulation and/or antiplatelet therapy. Anticomplement therapy, however, efficiently prevents thrombotic events in PNH and aHUS, but the underlying mechanisms remain unresolved. We show that complement-mediated hemolysis in whole blood induces platelet activation similarly to activation by adenosine 5'-diphosphate (ADP). Blockage of C3 or C5 abolished platelet activation. We found that human platelets failed to respond functionally to the anaphylatoxins C3a and C5a. Instead, complement activation did lead to prothrombotic cell activation in the whole blood when membrane attack complex (MAC)-mediated cytolysis occurred. Consequently, we demonstrate that ADP receptor antagonists efficiently inhibited platelet activation, although full complement activation, which causes hemolysis, occurred. By using an established model of mismatched erythrocyte transfusions in rats, we crossvalidated these findings in vivo using the complement inhibitor OmCI and cobra venom factor. Consumptive complement activation in this animal model only led to a thrombotic phenotype when MAC-mediated cytolysis occurred. In conclusion, complement activation only induces substantial prothrombotic cell activation if terminal pathway activation culminates in MAC-mediated release of intracellular ADP. These results explain why anticomplement therapy efficiently prevents thromboembolisms without interfering negatively with hemostasis.

Characterization of the aerosol release from spray cleaning and disinfection products - Spray scenarios in a climate chamber.

Cleaning work using spray products has been associated with adverse respiratory effects but little is known of the exposure concentrations. The purpose of this study was to characterize aerosol generation at spray scenarios in a controlled climate chamber. Spraying on vertically and horizontally oriented surfaces, as well as spraying on a cloth, was investigated. Furthermore, the effect of nozzle geometry was tested. The average mass generation rates of six pressurized spray cans and 13 trigger sprays were about 1.7 g/s and did not differ significantly, but the average values of the individual sprays had large variations (0.5-3.1 g/s). The time required to halve the air concentration of aerosol particles, the half-life time, was determined for all spray products. The average half-life time of the total particle mass concentration (TPMC) of the pressurized spray cans was 0.5 h versus 0.25 h for trigger sprays. Gravimetrically determined airborne fractions of pressurized spray cans tended to be higher than those of trigger sprays. However, airborne fractions based on the measured peak TPMC were up to three orders of magnitude smaller. A comparison of different trigger spray nozzles when spraying the same product showed that the TPMC can be up to 18 times higher for the largest emitting nozzle. The distance of the nozzle to a cloth should be 1 cm to significantly reduce the concentration of the generated aerosols. ConsExpo modeling predicted the measured peak TPMC well but less well the decay.

Frailty, Treatments, and Outcomes in Older Patients With Myocardial Infarction: A Nationwide Registry-Based Study.

Background Guidelines recommend that patients with myocardial infarction (MI) receive equal care regardless of age. However, withholding treatment may be justified in elderly and frail patients. This study aimed to investigate trends in treatments and outcomes of older patients with MI according to frailty. Methods and Results All patients aged ≥75 years with first-time MI during 2002 to 2021 were identified through Danish nationwide registries. Frailty was categorized using the Hospital Frailty Risk Score. One-year risk and hazard ratios (HRs) for days 0 to 28 and 29 to 365 were calculated for all-cause death. A total of 51 022 patients with MI were included (median, 82 years; 50.2% women). Intermediate/high frailty increased from 26.7% in 2002 to 2006 to 37.1% in 2017 to 2021. Use of treatment increased substantially regardless of frailty: for example, 28.1% to 48.0% (statins), 21.8% to 33.7% (dual antiplatelet therapy), and 7.6% to 28.0% (percutaneous coronary intervention) for high frailty (all P-trend <0.001). One-year death decreased for low frailty (35.1%-17.9%), intermediate frailty (49.8%-31.0%), and high frailty (62.8%-45.6%), all P-trend <0.001. Age- and sex-adjusted 29- to 365-day HRs (2017-2021 versus 2002-2006) were 0.53 (0.48-0.59), 0.62 (0.55-0.70), and 0.62 (0.46-0.83) for low, intermediate, and high frailty, respectively (P-interaction=0.23). When additionally adjusted for treatment, HRs attenuated to 0.74 (0.67-0.83), 0.83 (0.74-0.94), and 0.78 (0.58-1.05), respectively, indicating that increased use of treatment may account partially for the observed improvements. Conclusions Use of guideline-based treatments and outcomes improved concomitantly in older patients with MI, irrespective of frailty. These results indicate that guideline-based management of MI may be reasonable in the elderly and frail.

GPT-4 for Automated Determination of Radiological Study and Protocol based on Radiology Request Forms: A Feasibility Study.

Published under a CC BY 4.0 license.

Metabolic Silencing via Methionine-Based Amino Acid Restriction in Head and Neck Cancer.

In recent years, various forms of caloric restriction (CR) and amino acid or protein restriction (AAR or PR) have shown not only success in preventing age-associated diseases, such as type II diabetes and cardiovascular diseases, but also potential for cancer therapy. These strategies not only reprogram metabolism to low-energy metabolism (LEM), which is disadvantageous for neoplastic cells, but also significantly inhibit proliferation. Head and neck squamous cell carcinoma (HNSCC) is one of the most common tumour types, with over 600,000 new cases diagnosed annually worldwide. With a 5-year survival rate of approximately 55%, the poor prognosis has not improved despite extensive research and new adjuvant therapies. Therefore, for the first time, we analysed the potential of methionine restriction (MetR) in selected HNSCC cell lines. We investigated the influence of MetR on cell proliferation and vitality, the compensation for MetR by homocysteine, the gene regulation of different amino acid transporters, and the influence of cisplatin on cell proliferation in different HNSCC cell lines.

Discontinuation and reinitiation of SGLT-2 inhibitors and GLP-1R agonists in patients with type 2 diabetes: a nationwide study from 2013 to 2021.

Background: Small observational studies have observed poor persistency to sodium-glucose cotransporter-2 inhibitors (SGLT2-i) and glucacon-like-peptide-1-receptor agonists (GLP1-RA), contrary to what has been reported in clinical trials. Therefore, we investigated the risk of discontinuing SGLT2-is and GLP1-RAs in patients with type 2 diabetes (T2D) in a nationwide population. Methods: From Danish nationwide registers, all first-time users of SGLT2-is and GLP1-RAs from 2013 to 2021 were identified. Adherence over the first year of therapy, the five-year risk of discontinuing therapy for the first time and the subsequent one-year probability of reinitiating therapy, was assessed. The Aalen-Johansen estimator was used to account for censoring and competing risks and multivariable Cox regression models were used to identify covariates associated with discontinuation. Findings: A total of 77,745 first-time users of SGLT2-is (64% male, median age 64 [interquartile range 56-72]) and 56,037 first-time users of GLP1-RAs (56% male, median age 61 [53-70]) were included. The absolute five-year risk of discontinuing therapy was 56% (95% CI: 55-57) and 45% (45-46) for SGLT2-i- and GLP1-RA users, respectively, with a significantly decreased risk over the period studied. The subsequent one-year probability of reinitiating therapy was 24% (95% CI: 24-25) for initial SGLT2-i users and 26% (25-27) for GLP1-RA users. Interpretation: Approximately half of the users of SGLT2-is and GLP1-RAs discontinued therapy within five years, respectively. However, a large proportion of these patients reinitiated therapy during the following year. Further insight into the reasons for discontinuation and initiatives to reduce the time to reinitiation in eligible patients are warranted. Funding: The work was funded by an unrestricted research grant from 'Department of Cardiology, Herlev and Gentofte University Hospital'.

An Exploratory Study Using Next-Generation Sequencing to Identify Prothrombotic Variants in Patients with Cerebral Vein Thrombosis.

Prothrombotic hereditary risk factors for cerebral vein thrombosis (CVT) are of clinical interest to better understand the underlying pathophysiology and stratify patients for the risk of recurrence. This study explores prothrombotic risk factors in CVT patients. An initial screening in patients of the outpatient clinic of the Department of Transfusion Medicine and Hemostaseology of the University Hospital Erlangen, Germany, revealed 183 patients with a history of CVT. An initial screening identified a number of common prothrombic risk factors, including Factor V Leiden (rs6025) and Prothrombin G20210A (rs1799963). All patients without relevant findings (58 individuals) were invited to participate in a subsequent genetic analysis of 55 relevant genes using next-generation sequencing (NGS). Three intron variants (ADAMTS13: rs28446901, FN1: rs56380797, rs35343655) were identified to occur with a significantly higher frequency in the CVT patient cohort compared to the general European population. Furthermore, the combined prevalence of at least two of four potentially prothrombic variants (FGA (rs6050), F13A1 (rs5985), ITGB3 (rs5918), and PROCR (rs867186)) was significantly higher in the CVT subjects. The possible impact of the identified variants on CVT is discussed.

Association between pouch morphology, cardiovascular risk factors and ischemic brain lesions in patients with left-sided septal pouches.

BACKGROUND: Left atrial outpouching structures such as left atrial diverticula (LADs) and left-sided septal pouches (LSSPs) might be a source of cryptogenic stroke. This imaging study evaluates the association between pouch morphology, patient comorbidities and ischemic brain lesions (IBLs). METHODS: This is a retrospective single-center analysis of 195 patients who received both a cardiac CT and a cerebral MRI. LADs, LSSPs, and IBLs were retrospectively identified. Size measurements included pouch width, length and volume for LADs and circumference, area and volume for LSSPs. The association between LADs/LSSPs, IBLs and cardiovascular comorbidities was determined by univariate and bivariate regression analyses. RESULTS: The prevalence and mean volume were 36.4% and 372 ± 569 mm3 for LSSPs, and 40.5% and 415 ± 541 mm3 for LADs. The IBL prevalence was 67.6% in the LSSP group and 48.1% in the LAD group. LSSPs had 2.9-fold increased hazards of IBLs (95%CI: 1.2-7.4, p = 0.024), and LADs showed no significant correlation with IBLs. Size measurements had no impact on IBLs. A co-existing LSSP was associated with an increased prevalence of IBLs in patients with coronary artery disease (HR: 1.5, 95%CI: 1.1-1.9, p = 0.048), heart failure (HR: 3.7, 95%CI: 1.1-14.6, p = 0.032), arterial hypertension (HR: 1.9, 95%CI: 1.1-3.3, p = 0.017), and hyperlipidemia (HR: 2.2, 95%CI: 1.1-4.4, p = 0.018). CONCLUSION: Co-existing LSSPs were associated with IBLs in patients with cardiovascular risk factors, however, pouch morphology did not correlate with the IBL rate. Upon confirmation by further studies, these findings might be considered in the treatment, risk stratification, and stroke prophylaxis of these patients.

An exploratory study investigating the effect of targeted hyperoxemia in a randomized controlled trial in a long-term resuscitated model of combined acute subdural hematoma and hemorrhagic shock in cardiovascular healthy pigs.

Severe physical injuries and associated traumatic brain injury and/or hemorrhagic shock (HS) remain leading causes of death worldwide, aggravated by accompanying extensive inflammation. Retrospective clinical data indicated an association between mild hyperoxemia and improved survival and outcome. However, corresponding prospective clinical data, including long-term resuscutation, are scarce. Therefore, the present study explored the effect of mild hyperoxemia for 24 hours in a prospective randomized controlled trial in a long-term resuscitated model of combined acute subdural hematoma (ASDH) and HS. ASDH was induced by injecting 0.1 ml × kg-1 autologous blood into the subdural space and HS was triggered by passive removal of blood. After 2 hours, the animals received full resuscitation, including retransfusion of the shed blood and vasopressor support. During the first 24 hours, the animals underwent targeted hyperoxemia (PaO2 = 200 - 250 mmHg) or normoxemia (PaO2 = 80 - 120 mmHg) with a total observation period of 55 hours after the initiation of ASDH and HS. Survival, cardiocirculatory stability, and demand for vasopressor support were comparable between both groups. Likewise, humoral markers of brain injury and systemic inflammation were similar. Multimodal brain monitoring, including microdialysis and partial pressure of O2 in brain tissue, did not show significant differences either, despite a significantly better outcome regarding the modified Glasgow Coma Scale 24 hours after shock that favors hyperoxemia. In summary, the present study reports no deleterious and few beneficial effects of mild targeted hyperoxemia in a clinically relevant model of ASDH and HS with long-term resuscitation in otherwise healthy pigs. Further beneficial effects on neurological function were probably missed due to the high mortality in both experimental groups. The present study remains exploratory due to the unavailability of an a priori power calculation resulting from the lack of necessary data.

Frailty and Recurrent Hospitalization After Transcatheter Aortic Valve Replacement.

Background For frail patients with limited life expectancy, time in hospital following transcatheter aortic valve replacement is an important measure of quality of life; however, data remain scarce. Thus, we aimed to investigate frailty and its relation to time in hospital during the first year after transcatheter aortic valve replacement. Methods and Results From 2008 to 2020, all Danish patients who underwent transcatheter aortic valve replacement and were alive at discharge were included. Using the validated Hospital Frailty Risk Score, patients were categorized in the low, intermediate, and high frailty groups. Time in hospital and mortality up to 1 year are reported according to frailty groups. In total, 3437 (57.6%), 2277 (38.1%), and 257 (4.3%) were categorized in the low, intermediate, and high frailty groups, respectively. Median age was ≈81 years. Female sex and comorbidity burden were incrementally higher across frailty groups (low frailty: heart failure, 24.1%; stroke, 7.2%; and chronic kidney disease, 4.5%; versus high frailty: heart failure, 42.8%; stroke, 34.2%; and chronic kidney disease, 29.2%). In the low frailty group, 50.5% survived 1 year without a hospital admission, 10.8% were hospitalized >15 days, and 5.8% of patients died. By contrast, 26.1% of patients in the high frailty group survived 1 year without a hospital admission, 26.4% were hospitalized >15 days, and 15.6% died within 1 year. Differences persisted in models adjusted for sex, age, frailty, and comorbidity burden (excluding overlapping comorbidities). Conclusions Among patients undergoing transcatheter aortic valve replacement, frailty is strongly associated with time in hospital and mortality. Prevention strategies for frail patients to reduce hospitalization burden could be beneficial.

The effect of sodium thiosulfate on immune cell metabolism during porcine hemorrhage and resuscitation.

Introduction: Sodium thiosulfate (Na2S2O3), an H2S releasing agent, was shown to be organ-protective in experimental hemorrhage. Systemic inflammation activates immune cells, which in turn show cell type-specific metabolic plasticity with modifications of mitochondrial respiratory activity. Since H2S can dose-dependently stimulate or inhibit mitochondrial respiration, we investigated the effect of Na2S2O3 on immune cell metabolism in a blinded, randomized, controlled, long-term, porcine model of hemorrhage and resuscitation. For this purpose, we developed a Bayesian sampling-based model for 13C isotope metabolic flux analysis (MFA) utilizing 1,2-13C2-labeled glucose, 13C6-labeled glucose, and 13C5-labeled glutamine tracers. Methods: After 3 h of hemorrhage, anesthetized and surgically instrumented swine underwent resuscitation up to a maximum of 68 h. At 2 h of shock, animals randomly received vehicle or Na2S2O3 (25 mg/kg/h for 2 h, thereafter 100 mg/kg/h until 24 h after shock). At three time points (prior to shock, 24 h post shock and 64 h post shock) peripheral blood mononuclear cells (PBMCs) and granulocytes were isolated from whole blood, and cells were investigated regarding mitochondrial oxygen consumption (high resolution respirometry), reactive oxygen species production (electron spin resonance) and fluxes within the metabolic network (stable isotope-based MFA). Results: PBMCs showed significantly higher mitochondrial O2 uptake and lower O 2 • - production in comparison to granulocytes. We found that in response to Na2S2O3 administration, PBMCs but not granulocytes had an increased mitochondrial oxygen consumption combined with a transient reduction of the citrate synthase flux and an increase of acetyl-CoA channeled into other compartments, e.g., for lipid biogenesis. Conclusion: In a porcine model of hemorrhage and resuscitation, Na2S2O3 administration led to increased mitochondrial oxygen consumption combined with stimulation of lipid biogenesis in PBMCs. In contrast, granulocytes remained unaffected. Granulocytes, on the other hand, remained unaffected. O 2 • - concentration in whole blood remained constant during shock and resuscitation, indicating a sufficient anti-oxidative capacity. Overall, our MFA model seems to be is a promising approach for investigating immunometabolism; especially when combined with complementary methods.