Treatment outcomes of complement protein C5 inhibition in 509 UK patients with paroxysmal nocturnal hemoglobinuria.

ABSTRACT: Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired clonal hematopoietic disorder that occurs on a background of bone marrow failure (BMF). In PNH, chronic intravascular hemolysis causes an increase in morbidity and mortality, mainly because of thromboses. Over the last 20 years, treatment of PNH has focused on the complement protein C5 to prevent intravascular hemolysis using the monoclonal antibody eculizumab and more recently ravulizumab. In the United Kingdom, all patients are under review at 1 of 2 reference centers. We report on all 509 UK patients with PNH treated with eculizumab and/or ravulizumab between May 2002 and July 2022. The survival of patients with eculizumab and ravulizumab was significantly lower than that of age- and sex-matched controls (P = .001). Only 4 patients died of thromboses. The survival of patients with PNH (n = 389), when those requiring treatment for BMF (clonal evolution to myelodysplastic syndrome or acute leukemia or had progressive unresponsive aplastic anemia) were excluded, was not significantly different from that of age- and sex-matched controls (P = .12). There were 11 cases of meningococcal sepsis (0.35 events per 100 patient-years). Extravascular hemolysis was evident in patients who received treatment, with 26.7% of patients requiring transfusions in the most recent 12 months on therapy. Eculizumab and ravulizumab are safe and effective therapies that reduce mortality and morbidity in PNH, but further work is needed to reduce mortality in those with concomitant BMF.

Coronary sinus reducer for the treatment of refractory angina (ORBITA-COSMIC): a randomised, placebo-controlled trial.

BACKGROUND: The coronary sinus reducer (CSR) is proposed to reduce angina in patients with stable coronary artery disease by improving myocardial perfusion. We aimed to measure its efficacy, compared with placebo, on myocardial ischaemia reduction and symptom improvement. METHODS: ORBITA-COSMIC was a double-blind, randomised, placebo-controlled trial conducted at six UK hospitals. Patients aged 18 years or older with angina, stable coronary artery disease, ischaemia, and no further options for treatment were eligible. All patients completed a quantitative adenosine-stress perfusion cardiac magnetic resonance scan, symptom and quality-of-life questionnaires, and a treadmill exercise test before entering a 2-week symptom assessment phase, in which patients reported their angina symptoms using a smartphone application (ORBITA-app). Patients were randomly assigned (1:1) to receive either CSR or placebo. Both participants and investigators were masked to study assignment. After the CSR implantation or placebo procedure, patients entered a 6-month blinded follow-up phase in which they reported their daily symptoms in the ORBITA-app. At 6 months, all assessments were repeated. The primary outcome was myocardial blood flow in segments designated ischaemic at enrolment during the adenosine-stress perfusion cardiac magnetic resonance scan. The primary symptom outcome was the number of daily angina episodes. Analysis was done by intention-to-treat and followed Bayesian methodology. The study is registered with ClinicalTrials.gov, NCT04892537, and completed. FINDINGS: Between May 26, 2021, and June 28, 2023, 61 patients were enrolled, of whom 51 (44 [86%] male; seven [14%] female) were randomly assigned to either the CSR group (n=25) or the placebo group (n=26). Of these, 50 patients were included in the intention-to-treat analysis (24 in the CSR group and 26 in the placebo group). 454 (57%) of 800 imaged cardiac segments were ischaemic at enrolment, with a median stress myocardial blood flow of 1·08 mL/min per g (IQR 0·77-1·41). Myocardial blood flow in ischaemic segments did not improve with CSR compared with placebo (difference 0·06 mL/min per g [95% CrI -0·09 to 0·20]; Pr(Benefit)=78·8%). The number of daily angina episodes was reduced with CSR compared with placebo (OR 1·40 [95% CrI 1·08 to 1·83]; Pr(Benefit)=99·4%). There were two CSR embolisation events in the CSR group, and no acute coronary syndrome events or deaths in either group. INTERPRETATION: ORBITA-COSMIC found no evidence that the CSR improved transmural myocardial perfusion, but the CSR did improve angina compared with placebo. These findings provide evidence for the use of CSR as a further antianginal option for patients with stable coronary artery disease. FUNDING: Medical Research Council, Imperial College Healthcare Charity, National Institute for Health and Care Research Imperial Biomedical Research Centre, St Mary's Coronary Flow Trust, British Heart Foundation.

EGFR/MEK inhibitor therapy induces a distinct inflammatory hair follicle response that includes a collapse of immune privilege.

AIMS: Inhibitors of epidermal growth factor receptor (EGFRi) or mitogen-activated protein kinase (MEKi) induce a folliculitis in 75-90% of patients, whose pathobiology remains insufficiently understood. OBJECTIVES: (1) Characterize changes in the skin immune status and global transcriptional profile of EGFRi-treated patients (2) Probe whether EGFRi affects the hair follicle's (HF) immune privilege (IP) (3) Identify early pro-inflammatory signals induced by EGFRi/MEKi in human scalp HFs ex vivo. METHODS: Scalp biopsies were taken from long-term EGFRi-treated patients exhibiting folliculitis (Chronic-EGFRi, n=9) vs normal scalp skin (n=9) and patients prior to commencing EGFRi therapy and after two weeks of EGFRi therapy (Acute-EGFRi, n=5). Healthy organ-cultured scalp HFs were exposed to EGFRi (Erlotinib) or MEKi (Cobimetinib) (n=5 patients, each). Samples were assessed by quantatitive immunohistomorphometry, RNAseq and in situ hybridization. RESULTS: The Chronic-EGFRi cohort showed CD8+ T cell infiltration of the bulge alongside a partial collapse of the HF's IP, evidenced by upregulated MHC class I, ß2-microglobulin and MHC class II and decreased TGF-ß1 protein expression. Healthy HFs treated with EGFRi/MEKi ex vivo also showed partial HF IP collapse and increased transcription of HLA-A, HLA-DR, ß2-microglobulin transcripts. RNAseq anlysis showed increased transcription of chemokines (CXCL1, CXCL13, CCL18, CCL3, CCL7) and IL-26 in Chronic-EGFRi biopsies, as well as increased interlukin IL-33 and decreased IL-37 expesssion in both Acute-EGFRi biopsies and organ-cultured HFs. CONCLUSION: These data show that EGFRi/MEKi compromise the physiological IP of human scalp HFs and suggest that future clinical management of EGFRi/MEKi-induced folliculitis requires HF IP protection and inhibition of IL-33.

Impact of vessel volume on thermodilution measurements in patients with coronary microvascular dysfunction.

BACKGROUND: Two invasive methods are available to estimate microvascular resistance: bolus and continuous thermodilution. Comparative studies have revealed a lack of concordance between measurements of microvascular resistance obtained through these techniques. AIMS: This study aimed to examine the influence of vessel volume on bolus thermodilution measurements. METHODS: We prospectively included patients with angina with non-obstructive coronary arteries (ANOCA) undergoing bolus and continuous thermodilution assessments. All patients underwent coronary CT angiography to extract vessel volume. Coronary microvascular dysfunction was defined as coronary flow reserve (CFR) < 2.0. Measurements of absolute microvascular resistance (in Woods units) and index of microvascular resistance (IMR) were compared before and after volumetric adjustment. RESULTS: Overall, 94 patients with ANOCA were included in this study. The mean age was 64.7 ± 10.8 years, 48% were female, and 19% had diabetes. The prevalence of CMD was 16% based on bolus thermodilution, while continuous thermodilution yielded a prevalence of 27% (Cohen's Kappa 0.44, 95% CI 0.23-0.65). There was no correlation in microvascular resistance between techniques (r = 0.17, 95% CI -0.04 to 0.36, p = 0.104). The adjustment of IMR by vessel volume significantly increased the agreement with absolute microvascular resistance derived from continuous thermodilution (r = 0.48, 95% CI 0.31-0.63, p < 0.001). CONCLUSIONS: In patients with ANOCA, invasive methods based on coronary thermodilution yielded conflicting results for the assessment of CMD. Adjusting IMR with vessel volume improved the agreement with continuous thermodilution for the assessment of microvascular resistance. These findings strongly suggest the importance of considering vessel volume when interpreting bolus thermodilution assessment.

Grasslands and flood mitigation - Contrasting forages improve surface water infiltration rates.

Grasslands globally deliver many ecosystem services, including water management to alleviate flood risk reduction. Two replicated field experiments were conducted to study how agricultural forage species with diverse rooting systems, sown as single species, affected rooting, soil structure and earthworm populations, and consequently water infiltration to understand how they each might influence flood risk from grasslands. Experiment One showed soils under red clover (Trifolium pratense), white clover (Trifolium repens) and chicory (Cichorium intybus) had higher infiltration rates three years after establishment, compared to perennial ryegrass (Lolium perenne). Higher red clover and chicory root biomass or increased earthworm abundance under white clover may have caused these effects. Experiment Two monitored infiltration at intervals over several years post establishment to understand the timeframe for changes in rates; plantain (Plantago lanceolata) was sown as an additional forage. Infiltration declined post establishment, the timing and extent of decline varying with forages; forage effects were significant after 27 months (P < 0.05). Infiltration rates were higher under red and white clover compared to ryegrass, with chicory and plantain intermediate (P < 0.05). Forages again differed in likely mechanisms delivering higher water infiltration, notably between the two clover species. White clover had higher earthworm biomass (P < 0.05), whereas red clover had a higher average root diameter compared to the other forages (P < 0.05). Drivers of intermediate benefits of chicory and plantain also differed: chicory had higher earthworm abundance (month 38) compared to plantain, which had higher average root diameter compared to ryegrass (month 41); 30 months post-establishment soil bulk density was lower under both forages compared to ryegrass and red clover, with white clover intermediate (P < 0.05); bulk density and penetration resistance did not relate to infiltration. Findings demonstrate that a shift from perennial ryegrass-dominated pastures to swards with more contrasting forages provides an ecohydrological approach to mitigating flood risk and climate adaptation.

Performance of Thyroid Fine-Needle Aspiration Biopsy in a Low- and Middle-Income Country.

INTRODUCTION: The 6 categories of the Bethesda System for Reporting Thyroid Cytology (TBSRTC) with associated risk of malignancy (ROM) provide evidence-based clinical management guidelines. This study aimed to determine the ROM and accuracy of FNAB in South Africa (SA). METHODS: Thyroid specimens from 3 pathology laboratories registered between January 2015 and December 2019 were considered for inclusion. ROM was obtained per TBSRTC category by cytohistological correlation and dividing the total number of specimens with malignant histology by the total number of cases operated. Accuracy was calculated based on the Bethesda category and eventual malignant histology. RESULTS: Seventeen thousand seven hundred and seventy-three histology and 4,791 cytology cases were identified. Of the 4,791 cytology cases, 931 (19%) underwent surgery. More than a third (333, 35.8%) of cases were confirmed as malignant following histological assessment, with the majority being benign (584, 62.7%). The ROM for the nondiagnostic and benign categories was 24.3% and 20.5%. The highest ROM was for category VI (91.5%), followed by categories V (69.5%), IV (51.9%), and III (38.8%). Thyroid FNAB had a sensitivity of 73%, specificity of 74%, and overall accuracy of 74%. CONCLUSION: Bethesda categories II and IV have a relatively higher ROM in SA compared to findings from other developed countries. The diagnostic accuracy of thyroid FNAB in SA and the high rate of nondiagnostic diagnoses (38%) require further investigation. A national thyroid registry could provide location-specific data to aid the implementation of appropriate local policies and national guidelines for practicing thyroid surgeons.

Fatty acid desaturase insertion-deletion polymorphism rs66698963 predicts colorectal polyp prevention by the n-3 fatty acid eicosapentaenoic acid: a secondary analysis of the seAFOod polyp prevention trial.

BACKGROUND: A fatty acid desaturase (FADS) insertion-deletion (Indel) polymorphism (rs66698963) influences the expression of FADS1, which controls the synthesis of n-6 highly unsaturated fatty acid (HUFA) arachidonic acid (AA). The anti-inflammatory activity of the n-3 HUFA eicosapentaenoic acid (EPA) may be explained by competition with AA for proinflammatory lipid mediator synthesis. A precision medicine approach based on stratification by FADS Indel genotype could identify individuals, who benefit from greatest disease risk reduction by n-3 HUFAs. OBJECTIVES: We tested the hypothesis that the FADS insertion (I) allele predicts colorectal polyp risk reduction in a secondary analysis of the randomized, placebo-controlled, 2×2 factorial seAFOod polyp prevention trial of EPA 2000 mg daily and aspirin 300 mg daily for 12 mo (ISRCTN05926847). METHODS: Participant Indel genotype was determined by polymerase chain reaction (PCR) blind to trial outcomes. Colorectal polyp outcomes were included in negative binomial (polyp number) and logistic (polyp detection rate [PDR; percentage with one or more polyps]) regression models comparing each active intervention with its placebo. Presence of ≥1 Indel I allele and an interaction term (I allele × active intervention) were covariates. RESULTS: In 528 participants with colonoscopy and FADS Indel data, EPA use irrespective of Indel genotype, was not associated with reduced colorectal polyp number (incidence rate ratio [IRR]: 0.92; 95% confidence interval: 0.74, 1.16), mirroring original seAFOod trial analysis. However, the presence of ≥1 I allele identified EPA users with a significant reduction in colorectal polyp number (IRR: 0.50 [0.28, 0.90]), unlike aspirin, for which there was no interaction. Similar findings were obtained for the PDR. CONCLUSIONS: The FADS Indel I allele identified individuals, who displayed colorectal polyp prevention by EPA with a similar effect size to aspirin. Assessment of rs66698963 as a biomarker of therapeutic response to n-3 HUFAs in other populations and healthcare settings is warranted. The seAFOod polyp prevention trial and STOP-ADENOMA study were registered at International Standard Randomised Controlled Trial Number registry as ISRCTN05926847.

The Effect of Hydrostatic Pressure on Coronary Flow and Pressure-Based Indices of Coronary Stenosis Severity.

Background: To assess whether hydrostatic pressure gradients caused by coronary height differences in supine versus prone positioning during invasive physiological stenosis assessment affect resting and hyperaemic pressure-based indices or coronary flow. Methods: Twenty-three coronary stenoses were assessed in twenty-one patients with stable coronary artery disease. All patients had a stenosis of at least 50% visually defined on previous coronary angiography. Pd/Pa, iFR, FFR, and coronary flow velocity (APV) measured using a Doppler were recorded across the same stenosis, with the patient in the prone position, followed by repeat measurements in the standard supine position. Results: When comparing prone to supine measurements in the same stenosis, in the LAD, there was a significant change in mean Pd/Pa of 0.08 ± 0.04 (p = 0.0006), in the iFR of 0.06 ± 0.07 (p = 0.02), and in the FFR of 0.09 ± 0.07 (p = 0.003). In the Cx, there was a change in mean Pd/Pa of 0.05 ± 0.04 (p = 0.009), iFR of 0.07 ± 0.04 (p = 0.01), and FFR of 0.05 ± 0.03 (p = 0.006). In the RCA, there was a change in Pd/Pa of 0.05 ± 0.04 (p = 0.032), iFR of 0.04 ± 0.05 (p = 0.19), and FFR of 0.04+-0.03 (p = 0.004). Resting and hyperaemic coronary flow did not change significantly (resting delta APV = 1.6 cm/s, p = 0.31; hyperaemic delta APV = 0.9 cm/s, p = 0.85). Finally, 36% of iFR measurements and 26% of FFR measurements were re-classified across an ischaemic threshold when prone and supine measurements were compared across the same stenosis. Conclusions: Pd/Pa, iFR, and FFR were affected by hydrostatic pressure variations caused by coronary height differences in prone versus supine positioning. Coronary flow did not change signifying a purely pressure-based phenomenon.

Systemic Inflammation, the Peripheral Blood Transcriptome, and Primary Melanoma.

Peripheral blood transcriptomes from 383 patients with newly diagnosed melanoma were subjected to differential gene expression analysis. The hypotheses were that impaired systemic immunity is associated with poorer prognosis (thicker tumors and fewer tumor-infiltrating lymphocytes) and evidence of systemic inflammation (high-sensitivity CRP and fibrinogen levels). Higher fibrinogen levels were associated with thicker primary tumors. In single-gene analysis, high-sensitivity CRP levels were significantly associated with higher blood CD274 expression (coding for PD-L1), but each was independently prognostic, with high-sensitivity CRP associated with increased mortality and higher CD274 protective, independent of age. Pathway analysis identified downregulation of immune cell signaling pathways in the blood of people with thicker tumors and notable upregulation of signal transducer and activator of transcription 1 gene STAT1 in people with brisk tumor-infiltrating lymphocytes. Transcriptomic data provided evidence for increased NF-kB signaling with higher inflammatory markers but with reduction in expression of HLA class II molecules and higher CD274, suggesting that aberrant systemic inflammation is a significant mediator of reduced immune function in melanoma. In summary, transcriptomic data revealed evidence of reduced immune function in patients with thicker tumors and fewer tumor-infiltrating lymphocytes at diagnosis. Inflammatory markers were associated with thicker primaries and independently with death from melanoma, suggesting that systemic inflammation contributes to that reduced immune function.

Preclinical and translational pharmacology of afucosylated anti-CCR8 antibody for depletion of tumour-infiltrating regulatory T cells.

BACKGROUND AND PURPOSE: RO7502175 is an afucosylated antibody designed to eliminate C-C motif chemokine receptor 8 (CCR8)+ Treg cells in the tumour microenvironment through enhanced antibody-dependent cellular cytotoxicity (ADCC). EXPERIMENTAL APPROACH: We report findings from preclinical studies characterizing pharmacology, pharmacokinetics (PK)/pharmacodynamics (PD) and safety profile of RO7502175 and discuss the translational PK/PD approach used to inform first-in-human (FiH) dosing strategy and clinical development in solid tumour indications. KEY RESULTS: RO7502175 demonstrated selective ADCC against human CCR8+ Treg cells from dissociated tumours in vitro. In cynomolgus monkeys, RO7502175 exhibited a biphasic concentration-time profile consistent with immunoglobulin G1 (IgG1) antibodies, reduced CCR8+ Treg cells in the blood, induced minimal and transient cytokine secretion, and was well tolerated with a no-observed-adverse-effect level (NOAEL) of 100 mg·kg-1. Moreover, RO7502175 caused minimal cytokine release from peripheral blood mononuclear cells (PBMCs) in vitro. A quantitative model was developed to capture surrogate anti-murine CCR8 antibody PK/PD and tumour dynamics in mice and RO7502175 PK/PD in cynomolgus monkeys. Subsequently, the model was used to project RO7502175 human PK and receptor occupancy (RO) in patients. Because traditional approaches resulted in a low FiH dose for this molecule, even with its superior preclinical safety profile, an integrated approach based on the totality of preclinical data and modelling insights was used for starting dose selection. CONCLUSION AND IMPLICATIONS: This work demonstrates a translational research strategy for collecting and utilizing relevant nonclinical data, developing a mechanistic PK/PD model and using a comprehensive approach to inform clinical study design for RO7502175.

Assessing the Impact of Prolonged Averaging of Coronary Continuous Thermodilution Traces.

Continuous Thermodilution is a novel method of quantifying coronary flow (Q) in mL/min. To account for variability of Q within the cardiac cycle, the trace is smoothened with a 2 s moving average filter. This can sometimes be ineffective due to significant heart rate variability, ventricular extrasystoles, and deep inspiration, resulting in a fluctuating temperature trace and ambiguity in the location of the "steady state". This study aims to assess whether a longer moving average filter would smoothen any fluctuations within the continuous thermodilution traces resulting in improved interpretability and reproducibility on a test-retest basis. Patients with ANOCA underwent repeat continuous thermodilution measurements. Analysis of traces were performed at averages of 10, 15, and 20 s to determine the maximum acceptable average. The maximum acceptable average was subsequently applied as a moving average filter and the traces were re-analysed to assess the practical consequences of a longer moving average. Reproducibility was then assessed and compared to a 2 s moving average. Of the averages tested, only 10 s met the criteria for acceptance. When the data was reanalysed with a 10 s moving average filter, there was no significant improvement in reproducibility, however, it resulted in a 12% diagnostic mismatch. Applying a longer moving average filter to continuous thermodilution data does not improve reproducibility. Furthermore, it results in a loss of fidelity on the traces, and a 12% diagnostic mismatch. Overall, current practice should be maintained.

APOE genotype, eicosapentaenoic acid (EPA) supplementation and n-3 highly unsaturated fatty acid (HUFA) levels in patients with multiple colorectal polyps: A secondary analysis of the seAFOod polyp prevention trial.

INTRODUCTION: We examined the relationship between Apolipoprotein E (APOE) genotype and n-3 highly unsaturated fatty acid (HUFA) levels in participants of the seAFOod trial, who were undergoing colonoscopy surveillance after removal of colorectal polyps. METHODS: Baseline and on-treatment (eicosapentaenoic acid [EPA] 2 g daily or placebo for 6 months) levels of n-3 HUFAs, and plasma 18-hydroxyeicosapentaenoic acid (HEPE), were analysed according to APOE genotype (based on polymorphisms rs429358 and rs7412) in 584 participants. RESULTS: Before treatment, APOE2/2 individuals had lower levels, and APOE4/4 participants had higher levels, of n-3 HUFAs, including EPA, than APOE3/3 counterparts (P < 0.01 for the APOE2/2 versus APOE4/4 comparison). After EPA supplementation, n-3 HUFA levels were not significantly different when stratified by APOE genotype, although APOE4 carriers displayed lower plasma 18-HEPE levels than individuals without an APOE4 allele (P = 0.002). CONCLUSIONS: APOE genotype is associated with differential n-3 HUFA and 18-HEPE levels in individuals with multiple colorectal polyps.

Lung Transplant Immunomodulation with Genetically Engineered Mesenchymal Stromal Cells-Therapeutic Window for Interleukin-10.

Lung transplantation results are compromised by ischemia-reperfusion injury and alloimmune responses. Ex vivo lung perfusion (EVLP) is used to assess marginal donor lungs before transplantation but is also an excellent platform to apply novel therapeutics. We investigated donor lung immunomodulation using genetically engineered mesenchymal stromal cells with augmented production of human anti-inflammatory hIL-10 (MSCsIL-10). Pig lungs were placed on EVLP for 6 h and randomized to control (n = 7), intravascular delivery of 20 × 106 (n = 5, low dose) or 40 × 106 human MSCs IL-10 (n = 6, high dose). Subsequently, single-lung transplantation was performed, and recipient pigs were monitored for 3 days. hIL-10 secretion was measured during EVLP and after transplantation, and immunological effects were assessed by cytokine profile, T and myeloid cell characterization and mixed lymphocyte reaction. MSCIL-10 therapy rapidly increased hIL-10 during EVLP and resulted in transient hIL-10 elevation after lung transplantation. MSCIL-10 delivery did not affect lung function but was associated with dose-related immunomodulatory effects, with the low dose resulting in a beneficial decrease in apoptosis and lower macrophage activation, but the high MSCIL-10 dose resulting in inflammation and cytotoxic CD8+ T cell activation. MSCIL-10 therapy during EVLP results in a rapid and transient perioperative hIL-10 increase and has a therapeutic window for its immunomodulatory effects.

Comparison of bolus versus continuous thermodilution derived indices of microvascular dysfunction in revascularized coronary syndromes.

Background: The assessment of coronary microvascular dysfunction (CMD) using invasive methods is a field of growing interest, however the preferred method remains debated. Bolus and continuous thermodilution are commonly used methods, but weak agreement has been observed in patients with angina with non-obstructive coronary arteries (ANOCA). This study examined their agreement in revascularized acute coronary syndromes (ACS) and chronic coronary syndromes (CCS) patients. Objective: To compare bolus thermodilution and continuous thermodilution indices of CMD in revascularized ACS and CCS patients and assess their diagnostic agreement at pre-defined cut-off points. Methods: Patients from two centers underwent paired bolus and continuous thermodilution assessments after revascularization. CMD indices were compared between the two methods and their agreements at binary cut-off points were assessed. Results: Ninety-six patients and 116 vessels were included. The mean age was 64 ± 11 years, and 20 (21 %) were female. Overall, weak correlations were observed between the Index of Microcirculatory Resistance (IMR) and continuous thermodilution microvascular resistance (Rµ) (rho = 0.30p = 0.001). The median coronary flow reserve (CFR) from continuous thermodilution (CFRcont) and bolus thermodilution (CFRbolus) were 2.19 (1.76-2.67) and 2.55 (1.50-3.58), respectively (p < 0.001). Weak correlation and agreement were observed between CFRcont and CFRbolus (rho = 0.37, p < 0.001, ICC 0.228 [0.055-0.389]). When assessed at CFR cut-off values of 2.0 and 2.5, the methods disagreed in 41 (35 %) and 45 (39 %) of cases, respectively. Conclusions: There is a significant difference and weak agreement between bolus and continuous thermodilution-derived indices, which must be considered when diagnosing CMD in ACS and CCS patients.

N-of-1 Trial of Angina Verification Before Percutaneous Coronary Intervention.

BACKGROUND: In stable coronary artery disease, 30% to 60% of patients remain symptomatic despite successful revascularization. Perhaps not all symptoms reported by a patient with myocardial ischemia are, in fact, angina. OBJECTIVES: This study sought to determine whether independent symptom verification using a placebo-controlled ischemic stimulus could distinguish which patients achieve greatest symptom relief from percutaneous coronary intervention (PCI). METHODS: ORBITA-STAR was a multicenter, n-of-1, placebo-controlled study in patients undergoing single-vessel PCI for stable symptoms. Participants underwent 4 episodes (60 seconds each) of low-pressure balloon occlusion across their coronary stenosis, randomly paired with 4 episodes of placebo inflation. Following each episode, patients reported the similarity of the induced symptom in comparison with their usual symptom. The similarity score ranged from -10 (placebo replicated the symptom more than balloon occlusion) to +10 (balloon occlusion exactly replicated the symptom). The primary endpoint was the ability of the similarity score to predict symptom relief with PCI. RESULTS: Fifty-one patients were recruited, aged 62.9 ± 8.6 years. The median fractional flow reserve was 0.68 (Q1-Q3: 0.57-0.79), and the instantaneous wave-free ratio was 0.80 (Q1-Q3: 0.48-0.89). The median similarity score was 3 (Q1-Q3: 0.875-5.25). The similarity score was a strong predictor of symptom improvement following PCI: a patient with an upper quartile similarity score of 5.25 was significantly more likely to have lower angina frequency at follow-up (OR: 8.01; 95% credible interval: 2.39-15.86) than a patient with a lower quartile similarity score of 0.875 (OR: 1.31; 95% credible interval: 0.71-1.99), Pr(difference) >99.9%. CONCLUSIONS: Similarity score powerfully predicted symptom improvement from PCI. These data lay the foundation for independent symptom mapping to target PCI to those patients most likely to benefit. (Systematic Trial of Angina Assessment Before Revascularization [ORBITA-STAR]; NCT04280575).

Symptoms as a Predictor of the Placebo-Controlled Efficacy of PCI in Stable Coronary Artery Disease.

BACKGROUND: Placebo-controlled evidence from ORBITA-2 (Objective Randomised Blinded Investigation with Optimal Medical Therapy of Angioplasty in Stable Angina-2) found that percutaneous coronary intervention (PCI) in stable coronary artery disease with little or no antianginal medication relieved angina, but residual symptoms persisted in many patients. The reason for this was unclear. OBJECTIVES: This ORBITA-2 secondary analysis investigates the relationship between presenting symptoms and disease severity (anatomic, noninvasive, and invasive ischemia) and the ability of symptoms to predict the placebo-controlled efficacy of PCI. METHODS: Prerandomization symptom severity and nature were assessed using the ORBITA smartphone application and symptom and quality of life questionnaires including the World Health Organization Rose angina questionnaire (Rose). Disease severity was assessed using quantitative coronary angiography, stress echocardiography, fractional flow reserve, and instantaneous wave-free ratio. Bayesian ordinal regression was used. RESULTS: At prerandomization, the median number of daily angina episodes was 0.8 (Q1-Q3: 0.4-1.6), 64% had Rose angina, quantitative coronary angiography diameter stenosis was 61% (Q1-Q3: 49%-74%), stress echocardiography score was 1.0 (Q1-Q3: 0.0-2.7), fractional flow reserve was 0.63 (Q1-Q3: 0.49-0.75), and instantaneous wave-free ratio was 0.78 (Q1-Q3: 0.55-0.87). There was little relationship between symptom severity and nature and disease severity: angina symptom score with quantitative coronary angiography ordinal correlation coefficient: 0.06 (95% credible interval [CrI]: 0.00-0.08); stress echocardiography: 0.09 (95% CrI: 0.02-0.10); fractional flow reserve: 0.04 (95% CrI: -0.03 to 0.07); and instantaneous wave-free ratio: 0.04 (95% CrI: -0.01 to 0.07). However, Rose angina and guideline-based typical angina were strong predictors of placebo-controlled PCI efficacy (angina symptom score: OR: 1.9; 95% CrI: 1.6-2.1; probability of interaction [PrInteraction] = 99.9%; and OR: 1.8; 95% CrI: 1.6-2.1; PrInteraction = 99.9%, respectively). CONCLUSIONS: Although symptom severity and nature were poorly associated with disease severity, the nature of symptoms powerfully predicted the placebo-controlled efficacy of PCI.

Designing agricultural grasses to help mitigate proteolysis during ensiling to optimize protein feed provisions for livestock.

The efficient preservation of protein in silage for livestock feed is dependent on the rate and extent of proteolysis. Previous research on fresh forage indicated enhanced protein stability in certain Festulolium (ryegrass × fescue hybrids) cultivars compared to ryegrass. This is the first report of an experiment to test the hypothesis that a Lolium perenne × Festuca arundinacea var glaucescens cultivar had reduced proteolysis compared to perennial ryegrass (L. perenne) during the ensiling process. Forages were harvested in May (Cut 2) and August (Cut 4), wilted for 24 h and ensiled in laboratory-scale silos. Silage was destructively sampled at 0 h, 9 h, 24 h, 48 h, 72 h, 14 days and 90 days post-ensiling, and dry matter (DM), pH and chemical composition were determined. At Cut 2, there was no difference in crude protein between treatments but ryegrass had higher soluble nitrogen (SN) (P < 0.001) and grass × time interactions (p = 0.03) indicated higher rates of proteolysis. By Cut 4, Festulolium had (5.5% units) higher CP than ryegrass (p < 0.001) but SN did not differ. Ammonia-N did not differ between silages in either cut. DM differences (11.8% units) between treatments in Cut 4 (v.2.2% in Cut 2) may have masked effects on proteolysis, highlighting the importance of management on silage quality. This was despite higher WSC in ryegrass in both cuts (p < 0.001), with grass × time interactions (Cut 2; p = 0.03) showing slower WSC decline in ryegrass in Cut 4 (p < 0.001). Silage pH values did not differ between grasses in either cut, but grass × time interactions (p < 0.001) showed a slower decline in both ryegrass cuts, resulting in higher (p < 0.05) pH at 24 h and 72 h for Cuts 2 and 4, respectively. Overall, the hypothesis for an enhanced protein stability in Festulolium when ensiled as ruminant feed was evidenced by lower SN but not ammonia-N in an early-cut silage with a comparable DM to ryegrass.

Uma nova perspectiva sobre a biologia da osseointegração / A new perspective in the biology of osseointegration

O termo osseointegração refere-se à ancoragem de um implante no tecido ósseo, de forma que esse implante possa suportar carga funcional. O processo de osseointegração envolve vários mecanismos biológicos e o entendimento desses mecanismos e do papel da superfície dos implantes nesse processo, auxiliará o clínico de duas maneiras importantes: 1) na escolha dos implantes mais apropriados para os seus pacientes; e 2) no reconhecimento de problemas que possam surgir após a colocação de um implante. Nesse artigo, abordaremos uma nova perspectiva sobre a osseointegração, baseada em um trabalho recente que demonstrou que a reparação peri--implantar pode ser considerada um processo de restauração da homeostasia óssea. Esse processo representa um fenômeno universal, com vários exemplos nas ciências naturais e biológicas. O crescimento exponencial da ancoragem do implante no tecido ósseo através do tempo leva a um novo equilíbrio que pode ser representado por uma simples equação, onde dois parâmetros são importantes: 1) o valor máximo da ancoragem entre o implante e osso (novo equilíbrio tecidual)e 2) o período através do qual esse equilíbrio é adquirido. Portanto, em condições experimentais,é importante monitorar o processo de reparo por um longo período de tempo para que esse novo equilibrio seja obtido. Esse período de tempo necessário para que a hemostasia seja adquirida é descrito por um parâmetro matemático chamado “Tau”, que surge como uma maneira única de quantificar e comparar a performance do processo de osseointegração dos implantes. Essa nova perspectiva sobre a osseointegração será discutida em detalhes nesse artigo.

Osseointegration refers to the anchorage of an implant in bone, to a degree that can with stand functional loading. Osseointegration comprises several distinct biological mechanisms. An under standing these phenomena, and the role of implant surface topography in this process,will assist the clinician in two important ways: 1) It will inform their choice of the most appropriate implant designs for their patients, and 2) It will facilitate their recognition of problemsthat may arise after implant placement. We describe herein a new perspective on osseointegration.It is based on recent work that has demonstrated that peri-implant healing may beregarded as a restoration of bony homeostasis. Restoration of homeostasis is a universal phenomenon of which there are a multitude of examples in the natural and biological worlds. Applied to bone healing, the exponential rise in bone anchorage with time reaches the new equilibrium.This can be modeled using a simple equation where two important parameters emerge: 1) The ultimate value of implant/bone anchorage, which represents the new tissue equilibrium and 2)The rate at which this equilibrium is reached. Thus, experimentally, it is important to monitorhealing over a relatively long time so that the new bony equilibrium, can be achieved. However,the rate at which homeostasis is reached, described by a single mathematical parameter “tau”,emerges as a unique means by which the osseointegration performance of implants can bequantified and compared. This new perspective on osseointegration will be discussed in moredetails herein.

Linkage between higher education institutions and the community

Os autores examinam a interface entre as Instituiçöes de Ensino Superior e a Comunidade. Exploram um modelo teórico que tem como pressupostos a existência de forças inerciais ou de oposiçäo a mudanças. Sugerem a criaçäo de um corpo permanente - designado Forum - onde representantes das Instituiçöes de Ensino Superior e agentes externos discutam abordagens para temas relevantes reclamados pelos participantes.