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BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) is a major cause of morbidity and mortality in patients with type 2 diabetes (T2DM). Acute increases in circulating levels of ketone body 3-hydroxybutyrate have beneficial acute hemodynamic effects in patients without T2DM with chronic heart failure with reduced ejection fraction. However, the cardiovascular effects of prolonged oral ketone ester (KE) treatment in patients with T2DM and HFpEF remain unknown. METHODS: A total of 24 patients with T2DM and HFpEF completed a 6-week randomized, double-blind crossover study. All patients received 2 weeks of KE treatment (25 g D-ß-hydroxybutyrate-(R)-1,3-butanediol × 4 daily) and isocaloric and isovolumic placebo, separated by a 2-week washout period. At the end of each treatment period, patients underwent right heart catheterization, echocardiography, and blood samples at trough levels of intervention, and then during a 4-hour resting period after a single dose. A subsequent second dose was administered, followed by an exercise test. The primary end point was cardiac output during the 4-hour rest period. RESULTS: During the 4-hour resting period, circulating 3-hydroxybutyrate levels were 10-fold higher after KE treatment (1010±56 µmol/L; P<0.001) compared with placebo (91±55 µmol/L). Compared with placebo, KE treatment increased cardiac output by 0.2 L/min (95% CI, 0.1 to 0.3) during the 4-hour period and decreased pulmonary capillary wedge pressure at rest by 1 mm Hg (95% CI, -2 to 0) and at peak exercise by 5 mm Hg (95% CI, -9 to -1). KE treatment decreased the pressure-flow relationship (∆ pulmonary capillary wedge pressure/∆ cardiac output) significantly during exercise (P<0.001) and increased stroke volume by 10 mL (95% CI, 0 to 20) at peak exercise. KE right-shifted the left ventricular end-diastolic pressure-volume relationship, suggestive of reduced left ventricular stiffness and improved compliance. Favorable hemodynamic responses of KE treatment were also observed in patients treated with sodium-glucose transporter-2 inhibitors and glucagon-like peptide-1 analogs. CONCLUSIONS: In patients with T2DM and HFpEF, a 2-week oral KE treatment increased cardiac output and reduced cardiac filling pressures and ventricular stiffness. At peak exercise, KE treatment markedly decreased pulmonary capillary wedge pressure and improved pressure-flow relationship. Modulation of circulating ketone levels is a potential new treatment modality for patients with T2DM and HFpEF. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique Identifier: NCT05236335.

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BACKGROUND: Cardiogenic shock (CS) presents a medical challenge with limited treatment options. Positive end-expiratory pressure (PEEP) during mechanical ventilation has been linked with clinical benefits in patients with CS. We investigated if increasing PEEP levels could unload the left ventricle (LV) in CS in a large animal model of LV-CS. METHODS: LV-CS was induced in 26 female pigs (60 kg) by microsphere injections into the left main coronary artery. In one study protocol PEEP was increased (5, 10, and 15 cmH2O) and then reverted (15, 10, 5 cmH2O) in 3-minute intervals. In another protocol PEEP increments with higher granularity were conducted through 3-minute intervals (5, 8, 10, 13, and 15 cmH2O). Hemodynamic measurements were performed at all PEEP levels during the healthy state and LV-CS with LV pressure-volume loops. The primary endpoint was pressure-volume area (PVA). Secondary endpoints included other mechano-energetic parameters and estimates of LV preload and afterload. RESULTS: Cardiac output (CO) decreased significantly in LV-CS from 4.5±1.0 L/min to 3.1±0.9 L/min (P<0.001). Increasing PEEP resulted in lower PVA, demonstrating a 36±3% decrease in the healthy state (P<0.001) and 18±3% in LV-CS (P<0.001) at PEEP 15 cmH2O. These effects were highly reversible when PEEP was returned to 5 cmH2O. While mean arterial pressure declined with higher PEEP, CO remained preserved during LV-CS (P=0.339). Increasing PEEP caused reductions in key measures of LV preload and afterload during LV-CS. Right ventricular stroke work index was decreased with increased PEEP. Despite a minor increase in heart rate (HR) at PEEP levels of 15 cmH2O (71 bpm vs. 75 bpm, p<0.05), total mechanical power expenditure (PVA normalized to HR) decreased at higher PEEP. CONCLUSIONS: Applying higher PEEP levels reduced PVA, preserving CO while decreasing MAP. PEEP could be a viable LV unloading strategy if titrated optimally during LV-CS.

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OBJECTIVE: Despite high COVID-19 vaccination rates in many populations, concerns persist about potential adverse events, including concerns about involuntary movements. While case studies have shown occurrences of involuntary movements following COVID-19 vaccination, no systematic studies have explored this association. Our study aims to investigate the relationship between COVID-19 vaccination and involuntary movements. METHODS: This study employs a longitudinal panel design. The study population consists of 165,834 responses from a total of 97,537 unique individuals sourced from the BiCoVac cohort, which is a randomly sampled cohort of Danish individuals aged 16 to 65. Data were collected through a combination of questionnaires and national registers, and analyses were conducted using mixed effects logistic regression. RESULTS: Vaccinated individuals had lower odds of reporting involuntary movements compared to non-vaccinated individuals. Although adjustments attenuated the results, a consistent pattern of lower odds was observed among the vaccinated individuals. The strongest association for the first dose was observed in individuals who received the vaccine within the last 4 weeks before reporting symptoms (OR = 0.72 (0.60; 0.85)). For the second dose, the strongest association was found in individuals who received the second vaccine dose more than 4 weeks before reporting symptoms (OR = 0.77 (0.65; 0.91)). CONCLUSION: The results of the study do not indicate involuntary movements as an adverse reaction to the COVID-19 vaccine. These findings support the safety profile of the COVID-19 vaccine concerning involuntary movements and contribute to enhancing public trust in vaccination programs.

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BACKGROUND: The ketone body 3-hydroxybutyrate (3-OHB) increases cardiac output (CO) by 35% to 40% in healthy people and people with heart failure. The mechanisms underlying the effects of 3-OHB on myocardial contractility and loading conditions as well as the cardiovascular effects of its enantiomeric forms, D-3-OHB and L-3-OHB, remain undetermined. METHODS AND RESULTS: Three groups of 8 pigs each underwent a randomized, crossover study. The groups received 3-hour infusions of either D/L-3-OHB (racemic mixture), 100% L-3-OHB, 100% D-3-OHB, versus an isovolumic control. The animals were monitored with pulmonary artery catheter, left ventricle pressure-volume catheter, and arterial and coronary sinus blood samples. Myocardial biopsies were evaluated with high-resolution respirometry, coronary arteries with isometric myography, and myocardial kinetics with D-[11C]3-OHB and L-[11C]3-OHB positron emission tomography. All three 3-OHB infusions increased 3-OHB levels (P<0.001). D/L-3-OHB and L-3-OHB increased CO by 2.7 L/min (P<0.003). D-3-OHB increased CO nonsignificantly (P=0.2). Circulating 3-OHB levels correlated with CO for both enantiomers (P<0.001). The CO increase was mediated through arterial elastance (afterload) reduction, whereas contractility and preload were unchanged. Ex vivo, D- and L-3-OHB dilated coronary arteries equally. The mitochondrial respiratory capacity remained unaffected. The myocardial 3-OHB extraction increased only during the D- and D/L-3-OHB infusions. D-[11C]3-OHB showed rapid cardiac uptake and metabolism, whereas L-[11C]3-OHB demonstrated much slower pharmacokinetics. CONCLUSIONS: 3-OHB increased CO by reducing afterload. L-3-OHB exerted a stronger hemodynamic response than D-3-OHB due to higher circulating 3-OHB levels. There was a dissocitation between the myocardial metabolism and hemodynamic effects of the enantiomers, highlighting L-3-OHB as a potent cardiovascular agent with strong hemodynamic effects.

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BACKGROUND: Lactate is traditionally recognized as a by-product of anaerobic metabolism. However, lactate is a preferred oxidative substrate for stressed myocardium. Exogenous lactate infusion increases cardiac output (CO). The exact mechanism underlying this mechanism has yet to be elucidated. The aim of this study was to investigate the cardiovascular mechanisms underlying the acute haemodynamic effects of exogenous lactate infusion in an experimental model of human-sized pigs. METHODS: In this randomised, blinded crossover study in eight 60-kg-pigs, the pigs received infusions with one molar sodium lactate and a control infusion of tonicity matched hypertonic saline in random order. We measured CO and pulmonary pressures using a pulmonary artery catheter. A pressure-volume admittance catheter in the left ventricle was used to measure contractility, afterload, preload and work-related parameters. RESULTS: Lactate infusion increased circulating lactate levels by 9.9 mmol/L (95% confidence interval (CI) 9.1 to 11.0) and CO by 2.0 L/min (95% CI 1.2 to 2.7). Afterload decreased as arterial elastance fell by  -1.0 mmHg/ml (95% CI  -2.0 to  -0.1) and systemic vascular resistance decreased by  -548 dynes/s/cm5 (95% CI  -261 to  -835). Mixed venous saturation increased by 11 percentage points (95% CI 6 to 16), whereas ejection fraction increased by 16.0 percentage points (95% CI 1.1 to 32.0) and heart rate by 21 bpm (95% CI 8 to 33). No significant changes in contractility nor preload were observed. CONCLUSION: Lactate infusion increased cardiac output by increasing heart rate and lowering afterload. No differences were observed in left ventricular contractility or preload. Lactate holds potential as a treatment in situations with lowered CO and should be investigated in future clinical studies.

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BACKGROUND: Heart failure triggers a shift in myocardial metabolic substrate utilization, favoring the ketone body 3-hydroxybutyrate as energy source. We hypothesized that 14-day treatment with ketone ester (KE) would improve resting and exercise hemodynamics and exercise capacity in patients with heart failure with reduced ejection fraction. METHODS: In a randomized, double-blind cross-over study, nondiabetic patients with heart failure with reduced ejection fraction received 14-day KE and 14-day isocaloric non-KE comparator regimens of 4 daily doses separated by a 14-day washout period. After each treatment period, participants underwent right heart catheterization, echocardiography, and blood sampling at plasma trough levels and after dosing. Participants underwent an exercise hemodynamic assessment after a second dosing. The primary end point was resting cardiac output (CO). Secondary end points included resting and exercise pulmonary capillary wedge pressure and peak exercise CO and metabolic equivalents. RESULTS: We included 24 patients with heart failure with reduced ejection fraction (17 men; 65±9 years of age; all White). Resting CO at trough levels was higher after KE compared with isocaloric comparator (5.2±1.1 L/min versus 5.0±1.1 L/min; difference, 0.3 L/min [95% CI, 0.1-0.5), and pulmonary capillary wedge pressure was lower (8±3 mm Hg versus 11±3 mm Hg; difference, -2 mm Hg [95% CI, -4 to -1]). These changes were amplified after KE dosing. Across all exercise intensities, KE treatment was associated with lower mean exercise pulmonary capillary wedge pressure (-3 mm Hg [95% CI, -5 to -1] ) and higher mean CO (0.5 L/min [95% CI, 0.1-0.8]), significantly different at low to moderate steady-state exercise but not at peak. Metabolic equivalents remained similar between treatments. In exploratory analyses, KE treatment was associated with 18% lower NT-proBNP (N-terminal pro-B-type natriuretic peptide; difference, -98 ng/L [95% CI, -185 to -23]), higher left ventricular ejection fraction (37±5 versus 34±5%; P=0.01), and lower left atrial and ventricular volumes. CONCLUSIONS: KE treatment for 14 days was associated with higher CO at rest and lower filling pressures, cardiac volumes, and NT-proBNP levels compared with isocaloric comparator. These changes persisted during exercise and were achieved on top of optimal medical therapy. Sustained modulation of circulating ketone bodies is a potential treatment principle in patients with heart failure with reduced ejection fraction. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT05161650.

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Lactate may inhibit lipolysis and thus enhance insulin sensitivity, but there is a lack of metabolic human studies. This study aimed to determine how hyperlactatemia affects lipolysis, glucose- and protein metabolism, and insulin sensitivity in healthy men. In a single-blind, randomized, crossover design, eight healthy men were studied after an overnight fast on two occasions: 1) during a sodium-lactate infusion (LAC) and 2) during a sodium-matched NaCl infusion (CTR). Both days consisted of a 3-h postabsorptive period followed by a 3-h hyperinsulinemic-euglycemic clamp (HEC). Lipolysis rate, endogenous glucose production (EGP), and delta glucose rate of disappearance (ΔRdglu) were evaluated using [9,10-3H]palmitate and [3-3H]glucose tracers. In addition, whole body- and forearm protein metabolism was assessed using [15N]phenylalanine, [2H4]tyrosine, [15N]tyrosine, and [13C]urea tracers. In the postabsorptive period, plasma lactate increased to 2.7 ± 0.5 mmol/L during LAC vs. 0.6 ± 0.3 mmol/L during CTR (P < 0.001). In the postabsorptive period, palmitate flux was 30% lower during LAC compared with CTR (84 ± 32 µmol/min vs. 120 ± 35 µmol/min, P = 0.003). During the HEC, palmitate flux was suppressed similarly during both interventions (P = 0.7). EGP, ΔRdglu, and M value were similar during LAC and CTR. During HEC, LAC increased whole body phenylalanine flux (P = 0.02) and protein synthesis (P = 0.03) compared with CTR; LAC did not affect forearm protein metabolism compared with CTR. Lactate infusion inhibited lipolysis by 30% under postabsorptive conditions but did not affect glucose metabolism or improve insulin sensitivity. In addition, whole body phenylalanine flux was increased. Clinical trial registrations: NCT04710875.NEW & NOTEWORTHY Lactate is a decisive intermediary metabolite, serving as an energy substrate and a signaling molecule. The present study examines the effects of lactate on substrate metabolism and insulin sensitivity in healthy males. Hyperlactatemia reduces lipolysis by 30% without affecting insulin sensitivity and glucose metabolism. In addition, hyperlactatemia increases whole body amino acid turnover rate.

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Evaluating right ventricular (RV) function remains a challenge. Recently, novel echocardiographic assessment of RV myocardial work (RVMW) by non-invasive pressure-strain loops was proposed. This enables evaluation of right ventriculoarterial coupling and quantifies RV dyssynchrony and post-systolic shortening. We aimed to assess RVMW in patients with different etiologies of RV dysfunction and healthy controls. We investigated healthy controls (n=17), patients with severe functional tricuspid regurgitation (FTR; n=22), and patients with precapillary pulmonary hypertension (PCPH; n=20). Echocardiography and right heart catheterization were performed to assess 1) RV global constructive work (RVGCW; work needed for systolic myocardial shortening and isovolumic relaxation), 2) RV global wasted work (RVGWW; myocardial shortening following pulmonic valve closure), and 3) RV global work efficiency (RVGWE; describes the relation between RV constructive and wasted work). RVGCW correlated with invasive RV stroke work index (r=0.66, P<0.001) and increased in tandem with higher afterload, i.e., was low in healthy controls (454±73 mmHg%), moderate in patients with FTR (687±203 mmHg%), and highest among patients with PCPH (881±255 mmHg%). RVGWE was lower and RVGWW was higher in patients with FTR (86±8% and 91 mmHg% [53-140]) or PCPH (86±10% and 110 mmHg% [66-159]) as compared with healthy controls (96±3% and 10 mmHg%). RVMW by echocardiography provides a promising index of RV function to discriminate between patients with RV volume or pressure overload. The prognostic value of this measure needs to be settled in future studies.

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PURPOSE: To evaluate the diagnostic capabilities of a supplementary color ramped iodine density map compared to virtual monoenergetic images (VMIs) at 74 keV in the diagnosis of acute bowel ischemia (ABI). METHODS: Data for this study were prospectively gathered and retrospectively evaluated. Patients referred to the Department of Diagnostic Radiology between October 2020 and August 2022 on the suspicion of ABI and underwent surgery < 12 h following fast kV-switching venous phase abdominal dual-energy CT (DECT) were consecutively included. Images were evaluated by two board-certified radiologists and two radiology residents. First round included only 74 keV VMIs resembling conventional 120 kVp images, and the second round included a supplementary iodine density map. Readers were asked to register presence of ABI as well as their confidence in their diagnosis based on a 5-point Likert scale. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated for each observer with the surgical findings as the gold-standard. McNemar's and Wilcoxon signed-rank test were used to compare registrations and diagnostic confidence across assessment rounds. RESULTS: A total of 29 patients resulting in 31 DECT scans were included. Fourteen cases of ischemic/necrotic bowel were reported following surgery. Sensitivity and NPV were decreased with the use of supplementary iodine map images compared to 120 kVp-like images without supplementary iodine map images for three of four observers (round 1 range: 71.4-92.9% and 78.0-94.8%; round 2 range: 57.1-78.6% and 70.1-83.3%, respectively), while specificity and PPV were increased for three of four observers (round 1 range: 64.7-94.1% and 67.4-93.1%; round 2 range: 88.2-94.1% and 73.8-91.1%, respectively). However, no significant difference in ABI diagnosis or diagnostic confidence was found (p-value range: 0.07-1.00 and 0.23-0.58, respectively). CONCLUSION: No significant difference for the diagnosis of ABI was found using supplementary iodine mapping. Our study may suggest a trend of increased specificity and decreased sensitivity, hence, the use of supplementary iodine mapping should be carefully considered.

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Long COVID (LC) is an emerging global health concern. The underlying mechanism and pathophysiology remain unclear. Presence of neutralizing autoantibodies against type 1 interferons (IFN) has been established as a predictor of critical COVID-19. We hypothesized that persistent autoimmune activity with autoantibodies against type 1 IFN may contribute to symptoms in patients with LC. Plasma samples and clinical information were obtained from a Danish LC cohort consisting of adult patients with confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Information on symptoms and quality of life was derived from an LC-specific questionnaire and the EQ-5D-5L questionnaire. Detection of type 1 IFN autoantibodies in plasma were performed by ELISA. Samples collected between June, 2020, and September, 2021, from 279 patients were analyzed and compared to a control group of 94 individuals with prior mild SARS-CoV-2 infection who did not develop LC symptoms. In total, five LC patients (1.8%) and 3 (3.2%) of the controls had detectable circulating type 1 IFN autoantibodies. Collectively, prevalence of autoantibodies against type 1 IFN subtypes in our LC cohort were primarily driven by men and did not exceed the prevalence in controls. Thus, in our cohort, anti-type I IFN autoantibodies are unlikely to drive LC symptoms.

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BACKGROUND: Cardiogenic shock (CS) is a life-threatening condition with sparse treatment options. The ketone body 3-hydroxybutyrate has favorable hemodynamic effects in patients with stable chronic heart failure. Yet, the hemodynamic effects of exogenous ketone ester (KE) in patients with CS remain unknown. OBJECTIVES: The authors aimed to assess the hemodynamic effects of single-dose enteral treatment with KE in patients with CS. METHODS: In a double-blind, crossover study, 12 patients with CS were randomized to an enteral bolus of KE and isocaloric, isovolumic placebo containing maltodextrin. Patients were assessed with pulmonary artery catheterization, arterial blood samples, echocardiography, and near-infrared spectroscopy for 3 hours following each intervention separated by a 3-hour washout period. RESULTS: KE increased circulating 3-hydroxybutyrate (2.9 ± 0.3 mmol/L vs 0.2 ± 0.3 mmol/L, P < 0.001) and was associated with augmented cardiac output (area under the curve of relative change: 61 ± 22 L vs 1 ± 18 L, P = 0.044). Also, KE increased cardiac power output (0.07 W [95% CI: 0.01-0.14]; P = 0.037), mixed venous saturation (3 percentage points [95% CI: 1-5 percentage points]; P = 0.010), and forearm perfusion (3 percentage points [95% CI: 0-6 percentage points]; P = 0.026). Right (P = 0.048) and left (P = 0.017) ventricular filling pressures were reduced whereas heart rate and mean arterial and pulmonary arterial pressures remained similar. Left ventricular ejection fraction improved by 4 percentage points (95% CI: 2-6 percentage points; P = 0.005). Glucose levels decreased by 2.6 mmol/L (95% CI: -5.2 to 0.0; P = 0.047) whereas insulin levels remained unaltered. CONCLUSIONS: Treatment with KE improved cardiac output, biventricular function, tissue oxygenation, and glycemic control in patients with CS (Treatment With the Ketone Body 3-hydroxybutyrate in Patients With Cardiogenic Shock [KETO-SHOCK1]; NCT04642768).

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Background The ketone body 3-hydroxybutyrate (3-OHB) increases cardiac output (CO) in patients with heart failure through unknown mechanisms. 3-OHB activates the hydroxycarboxylic acid receptor 2 (HCA2), which increases prostaglandins and suppresses circulating free fatty acids. We investigated whether the cardiovascular effects of 3-OHB involved HCA2 activation and if the potent HCA2-stimulator niacin may increase CO. Methods and Results Twelve patients with heart failure with reduced ejection fraction were included in a randomized crossover study and examined by right heart catheterization, echocardiography, and blood sampling on 2 separate days. On study day 1, patients received aspirin to block the HCA2 downstream cyclooxygenase enzyme, followed by 3-OHB and placebo infusions in random order. We compared the results with those of a previous study in which patients received no aspirin. On study day 2, patients received niacin and placebo. The primary end point was CO. 3-OHB increased CO (2.3 L/min, P<0.01), stroke volume (19 mL, P<0.01), heart rate (10 bpm, P<0.01), and mixed venous saturation (5%, P<0.01) with preceding aspirin. 3-OHB did not change prostaglandin levels, neither in the ketone/placebo group receiving aspirin nor the previous study cohort. Aspirin did not block 3-OHB-induced changes in CO (P=0.43). 3-OHB decreased free fatty acids by 58% (P=0.01). Niacin increased prostaglandin D2 levels by 330% (P<0.02) and reduced free fatty acids by 75% (P<0.01) but did not affect CO. Conclusions The acute increase in CO during 3-OHB infusion was not modified by aspirin, and niacin had no hemodynamic effects. These findings show that HCA2 receptor-mediated effects were not involved in the hemodynamic response to 3-OHB. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT04703361.

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BACKGROUND: Phenylephrine increases systemic- and pulmonary resistances and therefore may increase blood pressures at the expense of blood flow. Cardio-pulmonary bypass alters vasoreactivity and many patients exhibit chronotropic insufficiency after cardiac surgery. We aimed to describe the haemodynamic effects of phenylephrine infusion after cardiac surgery. METHODS: Patients in steady state after low-risk cardiac surgery received incremental infusion rates of phenylephrine up to 1.0 µg/kg/min with the aim of increasing systemic mean arterial blood pressure 20 mmHg. Invasive haemodynamic parameters, including pulmonary wedge pressures, were captured along with echocardiographic measures of biventricular function before, during phenylephrine infusion at target systemic blood pressure, and 20 min after phenylephrine discontinuation. RESULTS: Thirty patients were included. Phenylephrine increased mean arterial pressure increased from 78 (±9) mmHg to 98 (±10) mmHg with phenylephrine infusion. Also, pulmonary blood pressure as well as systemic- and pulmonary resistances increased. The ratio between systemic- and pulmonary artery resistances did not change statistically significantly (p = .59). Median cardiac output was 4.35 (interquartile range [IQR] 3.6-5.4) L/min at baseline and increased significantly with phenylephrine infusion (median Δcardiac output was 0.25 [IQR 0.1-0.6] L/min) (p = .012). Pulmonary artery wedge pressure increased from 10.2 (±3.0) mmHg to 11.9 (±3.4) mmHg (p < .001). This was accompanied by significant increases in central venous pressure. Phenylephrine infusion increased left ventricular end-diastolic volume from 105 (±46) mL to 119 (±44) mL (p < .001). All results of phenylephrine infusion were reversed with discontinuation. CONCLUSION: In haemodynamically stable patients after cardiac surgery, phenylephrine increased PVR and SVR, but did not change the PVR/SVR ratio. Phenylephrine increased biventricular filling pressures and left ventricular end-diastolic area. Consequently, CO increased as ejection fraction was maintained. These findings do not discourage the use of phenylephrine after low-risk cardiac surgery. REGISTRATION: clinicaltrial.gov (identifier NCT04419662).

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Background Pulmonary arterial hypertension (PAH) or chronic thromboembolic pulmonary hypertension (CTEPH) are debilitating diseases with a high mortality. Despite emerging treatments, pulmonary vascular resistance frequently remains elevated. However, the ketone body 3-hydroxybutyrate (3-OHB) may reduce pulmonary vascular resistance in these patients. Hence, the aim was to assess the hemodynamic effects of 3-OHB in patients with PAH or CTEPH. Methods and Results We enrolled patients with PAH (n=10) or CTEPH (n=10) and residual pulmonary hypertension. They received 3-OHB infusion and placebo (saline) for 2 hours in a randomized crossover study. Invasive hemodynamic and echocardiography measurements were performed. Furthermore, we investigated the effects of 3-OHB on the right ventricle of isolated hearts and isolated pulmonary arteries from Sprague-Dawley rats. Ketone body infusion increased circulating 3-OHB levels from 0.5±0.5 to 3.4±0.7 mmol/L (P<0.001). Cardiac output improved by 1.2±0.1 L/min (27±3%, P<0.001), and right ventricular annular systolic velocity increased by 1.4±0.4 cm/s (13±4%, P=0.002). Pulmonary vascular resistance decreased by 1.3±0.3 Wood units (18%±4%, P<0.001) with no significant difference in response between patients with PAH and CTEPH. In the rat studies, 3-OHB administration was associated with decreased pulmonary arterial tension compared with saline administration (maximal relative tension difference: 12±2%, P<0.001) and had no effect on right ventricular systolic pressures (P=0.63), whereas pressures rose at a slower pace (dP/dtmax, P=0.02). Conclusions In patients with PAH or CTEPH, ketone body infusion improves cardiac output and decreases pulmonary vascular resistance. Experimental rat studies support that ketone bodies relax pulmonary arteries. Long-term studies are warranted to assess the clinical role of hyperketonemia. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT04615754.

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A chest X-ray report is a communicative tool and can be used as data for developing artificial intelligence-based decision support systems. For both, consistent understanding and labeling is important. Our aim was to investigate how readers would comprehend and annotate 200 chest X-ray reports. Reports written between 1 January 2015 and 11 March 2022 were selected based on search words. Annotators included three board-certified radiologists, two trained radiologists (physicians), two radiographers (radiological technicians), a non-radiological physician, and a medical student. Consensus labels by two or more of the experienced radiologists were considered "gold standard". Matthew's correlation coefficient (MCC) was calculated to assess annotation performance, and descriptive statistics were used to assess agreement between individual annotators and labels. The intermediate radiologist had the best correlation to "gold standard" (MCC 0.77). This was followed by the novice radiologist and medical student (MCC 0.71 for both), the novice radiographer (MCC 0.65), non-radiological physician (MCC 0.64), and experienced radiographer (MCC 0.57). Our findings showed that for developing an artificial intelligence-based support system, if trained radiologists are not available, annotations from non-radiological annotators with basic and general knowledge may be more aligned with radiologists compared to annotations from sub-specialized medical staff, if their sub-specialization is outside of diagnostic radiology.

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PURPOSE: To compare noise, contrast-to-noise ratio (CNR), signal-to-noise ratio (SNR) and image quality using deep-learning image reconstruction (DLIR) vs. adaptive statistical iterative reconstruction (ASIR-V) in 0.625 and 2.5 mm slice thickness gray scale 74 keV virtual monoenergetic (VM) abdominal dual-energy CT (DECT). METHODS: This retrospective study was approved by the institutional review board and regional ethics committee. We analysed 30 portal-venous phase abdominal fast kV-switching DECT (80/140kVp) scans. Data were reconstructed to ASIR-V 60% and DLIR-High at 74 keV in 0.625 and 2.5 mm slice thickness. Quantitative HU and noise assessment were measured within liver, aorta, adipose tissue and muscle. Two board-certified radiologists evaluated image noise, sharpness, texture and overall quality based on a five-point Likert scale. RESULTS: DLIR significantly reduced image noise and increased CNR as well as SNR compared to ASIR-V, when slice thickness was maintained (p < 0.001). Slightly higher noise of 5.5-16.2% was measured (p < 0.01) in liver, aorta and muscle tissue at 0.625 mm DLIR compared to 2.5 mm ASIR-V, while noise in adipose tissue was 4.3% lower with 0.625 mm DLIR compared to 2.5 mm ASIR-V (p = 0.08). Qualitative assessments demonstrated significantly improved image quality for DLIR particularly in 0.625 mm images. CONCLUSIONS: DLIR significantly reduced image noise, increased CNR and SNR and improved image quality in 0.625 mm slice images, when compared to ASIR-V. DLIR may facilitate thinner image slice reconstructions for routine contrast-enhanced abdominal DECT.

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Background: Post COVID-19 condition (PCC) is defined as symptoms lasting more than 12 weeks after developing COVID-19. Evidence of mitochondrial dysfunction has been reported in peripheral blood mononuclear cells obtained from patients with COVID-19. We hypothesized that PCC is caused by prolonged mitochondrial dysfunction. Given that coenzyme Q10 (CoQ10) can improve mitochondrial function, we examined whether high-dose CoQ10 can reduce the number and/or severity of PCC-related symptoms. Methods: In this placebo-controlled, double-blind, 2 × 2 crossover interventional trial, participants were recruited from two centres at Aarhus University Hospital and Gødstrup Hospital, Denmark. They were randomly assigned to receive either oral capsules of CoQ10 in a dose of 500 mg/day or placebo for 6 weeks, with crossover treatment after a 4-week washout period. The ED-5Q and a PCC-symptom specific questionnaire were completed by the participants at 5 visits during the 20-week study period. The primary endpoint was the change in the number and/or severity of PCC-related symptoms after the 6-week intervention compared to placebo. Participants who completed the two-dosing period were included in the primary analysis, while all participants receiving one dose were included in safety assessment. Findings: From May 25th, 2021, to September 22nd, 2021, 121 participants underwent randomization, and 119 completed both dosing periods - 59 and 60 in group A and B, respectively. At baseline, the mean PCC-related symptom score was 43.06 (95% CI: 40.18; 45.94), and the mean EQ-5D health index was 0.66 (95% CI: 0.64; 0.68). The difference between CoQ10 and placebo was not significant with respect to either the change in EQ-5D health index (with a mean difference of 0.01; 95% CI: -0.02; 0.04; p = 0.45) or the change in PCC-related symptom score (with a mean difference of -1.18; 95% CI: -3.54; 1.17; p = 0.32). Interpretation: Based on self-reported data, CoQ10 treatment does not appear to significantly reduce the number or severity of PCC-related symptoms when compared to placebo. However, we observed a significant spontaneous improvement on both scores regardless of treatment during 20 weeks observation. Funding: Placebo and CoQ10 capsules were provided by Pharma Nord, and the trial was supported by grants from the Novo Nordisk Foundation (NNF21OC0066984). This trial is registered with EudraCT, 2020-005961-16 and ClinicalTrials.gov, NCT04960215. The trial is completed.

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BACKGROUND: Incidental findings are common in abdominal computed tomography (CT) and often warrant further investigations with economic implications as well as implications for patients. PURPOSE: To evaluate the potential of dual-energy CT (DECT) in the identification and/or characterization of abdominal incidental mass lesions compared to conventional contrast-enhanced CT. MATERIAL AND METHODS: This retrospective study from a major tertiary hospital included 96 patients, who underwent contrast-enhanced abdominal DECT. Incidental lesions in adrenals, kidneys, liver, and pancreas were evaluated by two board-certified abdominal radiologists. Observer 1 only had access to standard CT reconstructions, while observer 2 had access to standard CT as well as DECT reconstructions. Disagreements were resolved by consensus review and used as a reference for observers using McNemar's test. RESULTS: Observers 1 and 2 identified a total of 40 and 34 findings, respectively. Furthermore, observer 1 registered 13 lesions requiring follow-up, of which seven (two renal and five adrenal lesions) were resolved following consensus review using DECT (P = 0.008). The inter-observer agreement was near perfect (κ = 0.82). CONCLUSION: DECT has the potential to improve the immediate characterization of incidental findings when compared to conventional CT for abdominal imaging.

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Consistent annotation of data is a prerequisite for the successful training and testing of artificial intelligence-based decision support systems in radiology. This can be obtained by standardizing terminology when annotating diagnostic images. The purpose of this study was to evaluate the annotation consistency among radiologists when using a novel diagnostic labeling scheme for chest X-rays. Six radiologists with experience ranging from one to sixteen years, annotated a set of 100 fully anonymized chest X-rays. The blinded radiologists annotated on two separate occasions. Statistical analyses were done using Randolph's kappa and PABAK, and the proportions of specific agreements were calculated. Fair-to-excellent agreement was found for all labels among the annotators (Randolph's Kappa, 0.40-0.99). The PABAK ranged from 0.12 to 1 for the two-reader inter-rater agreement and 0.26 to 1 for the intra-rater agreement. Descriptive and broad labels achieved the highest proportion of positive agreement in both the inter- and intra-reader analyses. Annotating findings with specific, interpretive labels were found to be difficult for less experienced radiologists. Annotating images with descriptive labels may increase agreement between radiologists with different experience levels compared to annotation with interpretive labels.