Blocking RAGE expression after injury reduces inflammation in mouse model of acute lung injury.

BACKGROUND: Receptor for Advanced Glycated Endproducts (RAGE) plays a major role in the inflammatory response to infectious and toxin induced acute lung injury. We tested the hypothesis that a RAGE blocking antibody when administered after the onset of injury can reduce lung inflammation compared to control antibody. METHODS: Male and female C57BL/6 (WT) mice were used. Forty-six received lipopolysaccharide (LPS) and 26 PBS by nasal instillation on day one, repeated on day three. On day 2, 36 mice receiving LPS were divided into two groups of 18, one treated with 200 µg of non-immune isotype control IgG and the second group treated with 200 µg of anti-RAGE Ab, each dose divided between IV and IP. Ten of the 46 were not treated. On day 4, before euthanasia, mice were injected with fluorescein isothiocyanate (FITC) labelled albumen. BALF and serum samples were collected as well as lung tissue for immunohistochemistry (IHC). BALF was analyzed for cell (leukocyte) counts, for FITC BALF/serum ratios indicating pulmonary vascular leak, and for cytokines/chemokines using bead based multiplex assays. Quantitative IHC was performed for MPO and RAGE. RESULTS: Ten LPS mice showed minimal inflammation by all measures indicating poor delivery of LPS and were excluded from analysis leaving n = 11 in the LPS + IgG group and n = 12 in the LPS + anti-RAGE group. BALF cell counts were low in the PBS administered mice (4.9 ± 2.1 × 105/ml) and high in the LPS injured untreated mice (109 ± 34) and in the LPS + IgG mice (91 ± 54) while in comparison, LPS + anti-RAGE ab mice counts were significantly lower (51.3 ± 18 vs. LPS + IgG, P = 0.03). The BALF/serum FITC ratios were lower for the LPS + anti-RAGE mice than for the LPS + IgG mice indicating less capillary leakiness. Quantitative IHC RAGE staining was lower in the LPS + anti-RAGE ab mice than in the LPS + IgG treated mice (P = 0.02). CONCLUSIONS: These results describe a four-day LPS protocol to sustain lung injury and allow for treatment and suggests that treatment aimed at blocking RAGE when given after onset of injury can reduce lung inflammation.

Diagnostic performance characteristics of planar quantitative and semi-quantitative parameters of Tc99m pyrophosphate (PYP) imaging for diagnosis of transthyretin (ATTR) cardiac amyloidosis: the SCAN-MP study.

BACKGROUND: The optimal heart-to-contralateral chest (H/CL) ratio threshold for non-invasive diagnosis of transthyretin cardiac amyloidosis (ATTR-CA) using Tc99m pyrophosphate (PYP) imaging in a population with low pretest probability is not known. METHODS: Using myocardial PYP retention by SPECT as the reference standard, we evaluated the diagnostic performance of different semi-quantitative and quantitative (H/CL chest ratio) planar parameters obtained from 3-hour PYP imaging in a prospectively recruited cohort of minority older adults with heart failure and increased LV wall thickness. RESULTS: Of 229 patients, 14 were found to have ATTR-CA (6.1%). No PYP uptake (grade 0) was observed in 77% of scans, all grade 3 scans were ATTR-CA, and only 4 of 11 (36%) grade 2 scans were ATTR-CA. An H/CL threshold of ≥ 1.4 maximized specificity (99%) and positive predictive value (93%) but resulted in decreased sensitivity (93%), compared to the ≥ 1.3 threshold which had 100% sensitivity. CONCLUSION: Among patients with a low pretest likelihood of ATTR-CA, planar interpretation, while useful to exclude disease, must be interpreted with caution. H/CL ratio threshold of ≥ 1.3 resulted in clinically important misclassifications. These data suggest that quantitative planar imaging thresholds may not be appropriate to apply in low pretest likelihood populations being evaluated for ATTR-CA.

Prevalence and significance of extracardiac uptake on pyrophosphate imaging in the SCAN-MP study: the first 379 cases.

INTRODUCTION: Technetium-labeled bone-avid radiotracers can be used to diagnose transthyretin cardiac amyloidosis (ATTR-CA). Extracardiac uptake of technetium pyrophosphate (Tc-99m PYP) in this context has not been extensively explored and its significance is not well characterized. We assessed extracardiac Tc-99m PYP uptake in individuals undergoing nuclear scintigraphy and the extent of clinically actionable findings. METHODS: The Screening for Cardiac Amyloidosis with Nuclear Imaging in Minority Populations (SCAN-MP) study utilizes Tc-99m PYP imaging to identify ATTR-CA in self-identified Black and Caribbean Hispanic participants ≥ 60 years old with heart failure. We characterized the distribution of extracardiac uptake, including stratification of findings by timing of scan (1 hour vs 3 hours after Tc-99m PYP administration) and noted any additional testing in these subjects. RESULTS: Of 379 participants, 195 (51%) were male, 306 (81%) Black race, and 120 (32%) Hispanic ethnicity; mean age was 73 years. Extracardiac Tc-99m PYP uptake was found in 42 subjects (11.1%): 21 with renal uptake only, 14 with bone uptake only, 4 with both renal and bone uptake, 2 with breast uptake, and 1 with thyroid uptake. Extracardiac uptake was more common in subjects with Tc-99m PYP scans at 1 hour (23.8%) than at 3 hours (6.2%). Overall, four individuals (1.1%) had clinically actionable findings. CONCLUSION: Extracardiac Tc-99m PYP uptake manifested in about 1 in 9 SCAN-MP subjects but was clinically actionable in only 1.1% of cases.

Blocking RAGE improves wound healing in diabetic pigs.

Receptor for Advanced Glycated End-products (RAGE) is highly expressed in diabetes and impairs wound healing. We proposed that administering an antibody that blocks RAGE will hasten the healing of dorsal wounds in diabetic pigs compared with a non-immune IgG. Two purpose-bred diabetic (D) Yucatan minipigs (Sinclair, Auxvasse MO) each underwent 12 2 × 2 cm full thickness dorsal wounds: four wounds received decellularized porcine skin patches (Xylyx Bio, Bklyn NY): four anti-RAGE Ab (CR-3) infused patches, four saline infused patches and four wounds were left open. One pig received anti-RAGE Ab (CR-3) 1 mg/kg IM q 10 days and other received non-immune IgG. Wounds were measured at 2 and 4 weeks followed by euthanasia and wound harvesting. At 2 weeks few of the patches appeared to be incorporated into the wound. By 4 weeks all patches in pigs treated systemically with CR-3 were detached and the wounds almost healed. For all 24 wounds for both pigs regardless of presence of patch or type of patch, the average IgG treated pig wound size at 4 weeks was 69.2 ± 14.6% of initial size and the average CR-3 treated pig wound size was 40.9 ± 11.3% of initial size (P = 0.0002). Quantitative immunohistology showed greater staining for collagen in the CR-3 treated wounds compared with IgG treated. Staining was positive for RAGE, Mac, and IL-6 in the IgG treated wounds and negative in the CR-3 treated wounds. From these pilot experiments, we conclude that a RAGE blocking antibody given parenterally improved wound healing in a diabetic pig while patches were not effective.

Single-photon emission computed tomography/computed tomography imaging of RAGE in smoking-induced lung injury.

BACKGROUND: Expression of the Receptor for Advanced Glycation Endproducts (RAGE) initiates pro-inflammatory pathways resulting in lung destruction. We hypothesized that RAGE directed imaging demonstrates increased lung uptake in smoke-exposure. METHODS: After exposure to room air or to cigarette smoke for 4-weeks or 16-weeks, rabbits were injected with 99mTc-anti-RAGE F(ab')2 and underwent Single-Photon Emission Computed Tomography/Computed Tomography (SPECT/CT) imaging. Lung radiotracer uptake was calculated as percent injected dose (%ID). Lungs were dissected for gamma well counting and histological analysis. RESULTS: 99mTc-anti-RAGE F(ab')2 SPECT/CT imaging demonstrated increased lung expression of RAGE with smoke exposure compared to room air control at 4-weeks: Room air right (R) 0.75 ± 0.38%ID, left (L) 0.62 ± 0.32%ID vs. Smoke exposed R 0.17 ± 0.03, L 0.17 ± 0.02%ID (p = 0.02 and 0.028, respectively). By 16-weeks of smoke exposure, the uptake decreased to 0.19 ± 0.05%ID R and 0.17 ± 0.05%ID L, significantly lower than 4-week imaging (p = 0.0076 and 0.0129 respectively). Staining for RAGE confirmed SPECT results, with the RAGE ligand HMGB1 upregulated in the macrophages of 4-week smoke-exposed rabbits. CONCLUSIONS: RAGE-directed imaging identified pulmonary RAGE expression acutely in vivo in an animal model of emphysema early after smoke exposure, with diminution over time. These studies document the extent and time course of RAGE expression under smoke exposure conditions and could be utilized for disease monitoring and examining response to future RAGE-targeted therapies.

Single-Photon Emission Computed Tomography/Computed Tomography Imaging in a Rabbit Model of Emphysema Reveals Ongoing Apoptosis In Vivo.

Evaluation of lung disease is limited by the inability to visualize ongoing pathological processes. Molecular imaging that targets cellular processes related to disease pathogenesis has the potential to assess disease activity over time to allow intervention before lung destruction. Because apoptosis is a critical component of lung damage in emphysema, a functional imaging approach was taken to determine if targeting apoptosis in a smoke exposure model would allow the quantification of early lung damage in vivo. Rabbits were exposed to cigarette smoke for 4 or 16 weeks and underwent single-photon emission computed tomography/computed tomography scanning using technetium-99m-rhAnnexin V-128. Imaging results were correlated with ex vivo tissue analysis to validate the presence of lung destruction and apoptosis. Lung computed tomography scans of long-term smoke-exposed rabbits exhibit anatomical similarities to human emphysema, with increased lung volumes compared with controls. Morphometry on lung tissue confirmed increased mean linear intercept and destructive index at 16 weeks of smoke exposure and compliance measurements documented physiological changes of emphysema. Tissue and lavage analysis displayed the hallmarks of smoke exposure, including increased tissue cellularity and protease activity. Technetium-99m-rhAnnexin V-128 single-photon emission computed tomography signal was increased after smoke exposure at 4 and 16 weeks, with confirmation of increased apoptosis through terminal deoxynucleotidyl transferase dUTP nick end labeling staining and increased tissue neutral sphingomyelinase activity in the tissue. These studies not only describe a novel emphysema model for use with future therapeutic applications, but, most importantly, also characterize a promising imaging modality that identifies ongoing destructive cellular processes within the lung.

Treatment effect with anti-RAGE F(ab')2 antibody improves hind limb angiogenesis and blood flow in Type 1 diabetic mice with left femoral artery ligation.

We investigated treatment with a receptor for advanced glycation endproduct (RAGE) blocking antibody on angiogenic response to hind limb ischemia in diabetic mice. Streptozotocin treated C57BL/6 mice received either murine monoclonal anti-RAGE F(ab')2 intraperitoneally (n=10) or saline (n=9) for 9 weeks. Diabetic plus 10 non-diabetic C57BL/6 mice underwent left femoral artery ligation and 5 days later angiogenesis imaging with (99m)Tc-Arg-Gly-Asp (RGD) nanoSPECT/CT. Twenty-four days later, hind limb blood flow was measured with ultrasound, the mice were euthanized, and tissue was taken for immunohistochemistry. The angiogenic imaging signal in ischemic limbs was higher in RAGE-ab treated versus saline treated mice at day 5 (3.1±1.4 vs 1.68±0.35, p=0.02) and blood flow was higher at day 24 (1.49±0.5 vs 0.61±0.39, p=0.04). Immunohistochemistry of ischemic muscles showed greater capillary density in the RAGE-ab treated group versus the vehicle-treated group (p<0.001) (NS from non-diabetic mice). In conclusion, treatment with anti-RAGE F(ab')2 in diabetic mice improves neovascularization in the ischemic leg.

Contrast-enhanced ultrasonography to evaluate changes in renal cortical microcirculation induced by noradrenaline: a pilot study.

INTRODUCTION: We used contrast-enhanced ultrasound (CEUS) to estimate the effect of an increase in mean arterial pressure (MAP) induced by noradrenaline infusion on renal microvascular cortical perfusion in critically ill patients. METHODS: Twelve patients requiring a noradrenaline infusion to maintain a MAP more than 60 mmHg within 48 hours of intensive care unit admission were included in the study. Renal CEUS scans with destruction-replenishment sequences and Sonovue® (Bracco, Milano Italy) as a contrast agent, were performed at baseline (MAP 60 to 65 mmHg) and after a noradrenaline-induced increase in MAP to 80 to 85 mmHg. RESULTS: There was no adverse effect associated with ultrasound contrast agent administration or increase in noradrenaline infusion rate. Adequate images were obtained in all patients at all study times. To reach the higher MAP target, median noradrenaline infusion rate was increased from 10 to 14 µg/min. Noradrenaline-induced increases in MAP were not associated with a significant change in overall CEUS derived mean perfusion indices (median perfusion index 3056 (interquartile range: 2438 to 6771) arbitrary units (a.u.) at baseline versus 4101 (3067 to 5981) a.u. after MAP increase, P = 0.38). At individual level, however, we observed important heterogeneity in responses (range -51% to +97% changes from baseline). CONCLUSIONS: A noradrenaline-induced increase in MAP was not associated with an overall increase in renal cortical perfusion as estimated by CEUS. However, at individual level, such response was heterogeneous and unpredictable suggesting great variability in pressure responsiveness within a cohort with a similar clinical phenotype.

Prediction of presence and severity of metabolic syndrome using regional body volumes measured by a multisensor white-light 3D scanner and validation using a mobile technology.

Aims: To test whether an index based on the combination of demographics and body volumes obtained with a multisensor 3D body volume (3D-BV) scanner and biplane imaging using a mobile application (myBVI®) will reliably predict the severity and presence of metabolic syndrome (MS). Methods and results: We enrolled 1280 consecutive subjects who completed study protocol measurements, including 3D-BV and myBVI®. Body volumes and demographics were screened using the least absolute shrinkage and selection operator to select features associated with an MS severity score and prevalence. We randomly selected 80% of the subjects to train the models, and performance was assessed in 20% of the remaining observations and externally validated on 133 volunteers who prospectively underwent myBVI® measurements. The mean ± SD age was 43.7 ± 12.2 years, 63.7% were women, body mass index (BMI) was 28.2 ± 6.2 kg/m2, and 30.2% had MS and an MS severity z-score of -0.2 ± 0.9. Features ß coefficients equal to zero were removed from the model, and 14 were included in the final model and used to calculate the body volume index (BVI), demonstrating an area under the receiving operating curve (AUC) of 0.83 in the validation set. The myBVI® cohort had a mean age of 33 ± 10.3 years, 61% of whom were women, 10.5% MS, an average MS severity z-score of -0.8, and an AUC of 0.88. Conclusion: The described BVI model was associated with an increased severity and prevalence of MS compared with BMI and waist-to-hip ratio. Validation of the BVI had excellent performance when using myBVI®. This model could serve as a powerful screening tool for identifying MS.

Effect of Active Workstations on Neurocognitive Performance and Typing Skills: A Randomized Clinical Trial.

BACKGROUND: Extended sedentary behavior is a risk factor for chronic disease and mortality, even among those who exercise regularly. Given the time constraints of incorporating physical activity into daily schedules, and the high likelihood of sitting during office work, this environment may serve as a potentially feasible setting for interventions to reduce sedentary behavior. METHODS AND RESULTS: A randomized cross-over clinical trial was conducted at an employee wellness center. Four office settings were evaluated on 4 consecutive days: stationary or sitting station on day 1 (referent), and 3 subsequent active workstations (standing, walking, or stepper) in randomized order. Neurocognitive function (Selective Attention, Grammatical Reasoning, Odd One Out, Object Reasoning, Visuospatial Intelligence, Limited-Hold Memory, Paired Associates Learning, and Digit Span) and fine motor skills (typing speed and accuracy) were tested using validated tools. Average scores were compared among stations using linear regression with generalized estimating equations to adjust standard errors. Bonferroni method adjusted for multiple comparisons. Healthy subjects were enrolled (n=44), 28 (64%) women, mean±SD age 35±11 years, weight 75.5±17.1 kg, height 168.5±10.0 cm, and body mass index 26.5±5.2 kg/m2. When comparing active stations to sitting, neurocognitive test either improved or remained unchanged, while typing speed decreased without affecting typing errors. Overall results improved after day 1, suggesting habituation. We observed no major differences across active stations, except decrease in average typing speed 42.5 versus 39.7 words per minute with standing versus stepping (P=0.003). CONCLUSIONS: Active workstations improved cognitive performance, suggesting that these workstations can help decrease sedentary time without work performance impairment. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT06240286.

Contrast-enhanced ultrasound to evaluate changes in renal cortical perfusion around cardiac surgery: a pilot study.

INTRODUCTION: Contrast-enhanced ultrasound (CEUS) is a new technique that might enable portable and non-invasive organ perfusion quantification at the bedside. However, it has not yet been tested in critically ill patients. We sought to establish CEUS's feasibility, safety, reproducibility and potential diagnostic value in the assessment of renal cortical perfusion in the peri-operative period in cardiac surgery patients. METHODS: We recruited twelve patients deemed at risk of acute kidney injury (AKI) planned for elective cardiac surgery. We performed renal CEUS with destruction-replenishment sequences before the operation, on ICU arrival and the day following the admission. Enhancement was obtained with Sonovue® (Bracco, Milano, Italy) at an infusion rate of 1 ml/min. We collected hemodynamic parameters before, during and after contrast agent infusion. At each study time, we obtained five video sequences, which were analysed using dedicated software by two independent radiologists blinded to patient and time. The main output was a perfusion index (PI), corresponding to the ratio of relative blood volume (RBV) over mean transit time (mTT). RESULTS: All 36 renal CEUS studies, including 24 in the immediate post-operative period could be performed and were well tolerated. Correlation between readers for PI was excellent (R2 = 0.96, P < 0.0001). Compared with baseline, there was no overall difference in median PI's on ICU admission. However, the day after surgery, median PI's had decreased by 50% (P < 0.01) (22% decrease in RBV (P = 0.09); 48% increase in mTT (P = 0.04), both suggestive of decreased perfusion). These differences persisted after correction for haemoglobin; vasopressors use and mean arterial pressure. Four patients developed AKI in the post-operative period. CONCLUSIONS: CEUS appears feasible and well-tolerated in patients undergoing cardiac surgery even immediately after ICU admission. CEUS derived-parameters suggest a decrease in renal perfusion occurring within 24 hours of surgery.

Practitioner perceptions of trauma video review.

PURPOSE: Multidisciplinary trauma team education through trauma video review (TVR) is a useful performance improvement tool, but video recording resuscitations may cause providers anxiety. We examined perceptions of educational value and anxiety associated with being reviewed in TVR. METHODS: Trauma team members were asked to complete an anonymous online survey. Educational scores (E scores) and anxiety scores (A score) were calculated from survey responses. Respondents were divided into groups by roles: trainees (T; medical students, residents, and fellows), attending surgeons (A), and nurses (N). Kruskal-Wallis test was used for statistical testing. FINDINGS: A total of 39 subjects completed the survey (T = 17, 43%; A = 8, 23%; N = 14, 35%). TVR scored high in educational value (median E score 90; IQR = 78-96) but provoked moderate anxiety (median A score 27; IQR = 20-36). No significant differences in E scores were seen between groups. A scores were not significantly different between groups N and T (20 vs 33; P = .11) or groups T and A (33 vs. 35; P = 1.0) but were significantly higher in group A than in group N (36 vs 20; P = .04). CONCLUSIONS: Despite perceptions of educational value, TVR is associated with anxiety among providers, which is different between groups. Continued assessment of perceptions regarding TVR may allow for modifications to maintain educational value while decreasing anxiety.

A comparison of the Woman-centred care: strategic directions for Australian maternity services (2019) national strategy with other international maternity plans.

BACKGROUND: In 2019 the Australian government released a guiding document for maternity care: Woman-centred care strategic directions for Australian maternity services (WCC Strategy), with mixed responses from providers and consumers. The aims of this paper were to: examine reasons behind reported dissatisfaction, and compare the WCC Strategy against similar international strategies/plans. The four guiding values in the WCC strategy: safety, respect, choice, and access were used to facilitate comparisons and provide recommendations to governments/health services enacting the plan. METHODS: Maternity plans published in English from comparable high-income countries were reviewed. FINDINGS: Eight maternity strategies/plans from 2011 to 2021 were included. There is an admirable focus in the WCC Strategy on respectful care, postnatal care, and culturally appropriate maternity models. Significant gaps in support for continuity of midwifery care and place of birth options were notable, despite robust evidence supporting both. In addition, clarity around women's right to make decisions about their care was lacking or contradictory in the majority of the strategies/plans. Addressing hierarchical, structure-based obstacles to regulation, policy, planning, service delivery models and funding mechanisms may be necessary to overcome concerns and barriers to implementation. We observed that countries where midwifery is more strongly embedded and autonomous, have guidelines recommending greater contributions from midwives. CONCLUSION: Maternity strategy/plans should be based on the best available evidence, with consistent and complementary recommendations. Within this framework, priority should be given to women's preferences and choices, rather than the interests of organisations and individuals.

Safety and efficacy of mirikizumab versus secukinumab and placebo in the treatment of moderate-to-severe plaque psoriasis (OASIS-2): a phase 3, multicentre, randomised, double-blind study.

BACKGROUND: Risankizumab and guselkumab, inhibitors of the interleukin (IL)-23 p19 subunit, are approved for treatment of adult patients with moderate-to-severe plaque psoriasis, and both have shown superiority over placebo in randomised clinical trials. Both agents have also shown superiority to the IL-17 inhibitor secukinumab at different timepoints. We investigated the efficacy and safety of the IL-23 p19 inhibitor mirikizumab versus placebo and secukinumab for patients with moderate-to-severe plaque psoriasis. METHODS: OASIS-2 was a phase 3, multicentre, randomised, double-blind trial. We recruited participants aged at least 18 years who had a confirmed diagnosis of chronic plaque psoriasis for at least 6 months before baseline that involved at least 10% of body surface area (BSA), an absolute Psoriasis Area and Severity Index (PASI) score of at least 12, and a Static Physician's Global Assessment (sPGA) score of at least 3 at both the screening and baseline visits. We excluded patients who had an uncontrolled or unstable health condition at screening. We randomly assigned patients (4:4:4:1) to receive 250 mg mirikizumab every 4 weeks for 16 weeks (induction) then every 8 weeks from week 16 to week 52 (maintenance); 250 mg mirikizumab every 4 weeks for 16 weeks, then 125 mg mirikizumab every 8 weeks from week 16 to 52; 300 mg secukinumab once weekly up to week 4, then every 4 weeks thereafter; or placebo every 4 weeks for 16 weeks, followed by 250 mg mirikizumab every 4 weeks from week 16 to 32 and then every 8 weeks from week 32 to 52. The primary outcome was superiority of mirikizumab (250 mg induction dose) versus placebo at week 16, assessed as the proportion of patients with an sPGA score of 0 or 1 with an improvement from baseline of at least 2 points, and the proportion of patients with at least 90% improvement from baseline in PASI score (PASI 90), in the intention-to-treat-population. We assessed safety in all randomly assigned participants who received at least one dose of mirikizumab until week 16 (induction safety population) and all randomly assigned participants who received at least one dose of mirikizumab or secukinumab until week 52 (active treatment safety population). This trial is registered at ClinicalTrials.gov, NCT03535194, and is completed. FINDINGS: Between June 26, 2018, and April 2, 2019, we screened 1738 participants, of whom 1465 (84·3%) were enrolled. The mean age of participants was 46·0 years (SD 13·8), 1000 (68·3%) were men, 465 (31·7%) were women, and 1195 (81·6%) were White. Participants were randomly assigned to receive mirikizumab 250 mg for induction and maintenance (n=454 [31·0%]), mirikizumab 250 mg for induction and 125 mg for maintenance (n=451 [30·8%]), secukinumab 300 mg (n=448 [30·6%]), or placebo followed by mirikizumab (n=112 [7·6%]). Baseline characteristics were similar across treatment groups. At week 16, 721 (79·7% [95% CI 77·0-82·3]) of 905 participants in the mirikizumab 250 mg induction groups had an sPGA score of 0 or 1 versus seven (6·3% [1·8-10·7]) of 112 participants in the placebo group (p<0·0001 for superiority). At week 16, 673 (74·4% [71·5-77·2]) of 905 participants in the mirikizumab groups had PASI 90 compared with seven (6·3% [1.8-10.7]) in the placebo group (p<0·0001 for superiority). Treatment-emergent adverse events were reported with similar frequency across treatment groups during weeks 0-52. Four major adverse cardiovascular events were reported in the mirikizumab groups versus none in the placebo and secukinumab groups up to week 16, with one fatal acute myocardial infarction in a patient treated with mirikizumab, which the investigator considered to be related to the study drug. INTERPRETATION: This trial showed superiority of mirikizumab at a dose of 250 mg over placebo in patients with moderate-to-severe plaque psoriasis, with a safety profile consistent with that of the IL-23 class. The study sponsor is not pursuing licensing of mirikizumab in this patient population because of a reprioritised development strategy with a focus on gastrointestinal-related indications. FUNDING: Eli Lilly and Company.

Effect of bismuth breast shielding on radiation dose and image quality in coronary CT angiography.

BACKGROUND: Coronary computed tomographic angiography (CCTA) is associated with high radiation dose to the female breasts. Bismuth breast shielding offers the potential to significantly reduce dose to the breasts and nearby organs, but the magnitude of this reduction and its impact on image quality and radiation dose have not been evaluated. METHODS: Radiation doses from CCTA to critical organs were determined using metal-oxide-semiconductor field-effect transistors positioned in a customized anthropomorphic whole-body dosimetry verification phantom. Image noise and signal were measured in regions of interest (ROIs) including the coronary arteries. RESULTS: With bismuth shielding, breast radiation dose was reduced 46%-57% depending on breast size and scanning technique, with more moderate dose reduction to the heart, lungs, and esophagus. However, shielding significantly decreased image signal (by 14.6 HU) and contrast (by 28.4 HU), modestly but significantly increased image noise in ROIs in locations of coronary arteries, and decreased contrast-to-noise ratio by 20.9%. CONCLUSIONS: While bismuth breast shielding can significantly decrease radiation dose to critical organs, it is associated with an increase in image noise, decrease in contrast-to-noise, and changes tissue attenuation characteristics in the location of the coronary arteries.

Noninvasive Physiologic Assessment of Cardiac Allograft Vasculopathy Is Prognostic for Post-Transplant Events.

BACKGROUND: Cardiac allograft vasculopathy (CAV) causes impaired blood flow in both epicardial coronary arteries and the microvasculature. A leading cause of post-transplant mortality, CAV affects 50% of heart transplant recipients within 10 years of heart transplant. OBJECTIVES: This analysis examined the outcomes of heart transplant recipients with reduced myocardial blood flow reserve (MBFR) and microvascular CAV detected by 13N-ammonia positron emission tomography (PET) myocardial perfusion imaging. METHODS: A total of 181 heart transplant recipients who underwent PET to assess for CAV were included with a median follow-up of 4.7 years. Patients were classified into 2 groups according to the total MBFR: >2.0 and ≤2.0. Microvascular CAV was defined as no epicardial CAV detected by PET and/or coronary angiography, but with an MBFR ≤2.0 by PET. RESULTS: In total, 71 (39%) patients had an MBFR ≤2.0. Patients with an MBFR ≤2.0 experienced an increased risk for all outcomes: 7-fold increase in death or retransplantation (HR: 7.05; 95% CI: 3.2-15.6; P < 0.0001), 12-fold increase in cardiovascular death (HR: 12.0; 95% CI: 2.64-54.12; P = 0.001), and 10-fold increase in cardiovascular hospitalization (HR: 10.1; 95% CI: 3.43-29.9; P < 0.0001). The 5-year mean survival was 302 days less than those with an MBFR >2.0 (95% CI: 260.2-345.4 days; P < 0.0001). Microvascular CAV (adjusted HR: 3.86; 95% CI: 1.58-9.40; P = 0.003) was independently associated with an increased risk of death or retransplantation. CONCLUSIONS: Abnormal myocardial blood flow reserve, even in the absence of epicardial CAV, identifies patients at a high risk of death or retransplantation. Measures of myocardial blood flow provide prognostic information in addition to traditional CAV assessment.

Bench-to-bedside review: contrast enhanced ultrasonography--a promising technique to assess renal perfusion in the ICU.

Acute kidney injury (AKI) is common in critically ill patients and associated with important morbidity and mortality. Although alterations in renal perfusion are thought to play a causative role in the pathogenesis of AKI, there is, to date, no reliable technique that allows the assessment of renal perfusion that is applicable in the ICU. Contrast-enhanced ultrasound (CEUS) is an ultrasound imaging technique that makes use of microbubble-based contrast agents. These microbubbles, when injected into the bloodstream, allow visualization of vascular structures and, with contrast-specific imaging modes, detection of blood flow at the capillary level. Some recent CEUS-derived approaches allow quantification of blood flow in several organs, including the kidney. Current generation ultrasound contrast agents have strong stability and safety profiles. Along with post-marketing surveillance, numerous studies report safe administration of these agents, including in critically ill patients. This review presents information on the physical principles underlying CEUS, the methods allowing blood flow quantification and the potential applications of CEUS in critical care nephrology, currently as a research tool but perhaps in the future as a way of monitoring renal perfusion.