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Percutaneous coronary intervention (PCI) is increasingly used in revascularisation of patients with left main coronary artery disease in place of the standard treatment, coronary artery bypass grafting (CABG). The NOBLE trial aimed to evaluate whether PCI was non-inferior to CABG in the treatment of left main coronary artery disease and reported outcomes after a median follow-up of 3·1 years. We now report updated 5-year outcomes of the trial. The prospective, randomised, open-label, non-inferiority NOBLE trial was done at 36 hospitals in nine northern European countries. Patients with left main coronary artery disease requiring revascularisation were enrolled and randomly assigned (1:1) to receive PCI or CABG. The primary endpoint was major adverse cardiac or cerebrovascular events (MACCE), a composite of all-cause mortality, non-procedural myocardial infarction, repeat revascularisation, and stroke. Non-inferiority of PCI to CABG was defined as the upper limit of the 95% CI of the hazard ratio (HR) not exceeding 1·35 after 275 MACCE had occurred. Secondary endpoints included all-cause mortality, non-procedural myocardial infarction, and repeat revascularisation. Outcomes were analysed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT01496651. Between Dec 9, 2008, and Jan 21, 2015, 1201 patients were enrolled and allocated to PCI (n=598) or CABG (n=603), with 17 subsequently lost to early follow-up. 592 patients in each group were included in this analysis. At a median of 4·9 years of follow-up, the predefined number of events was reached for adequate power to assess the primary endpoint. Kaplan-Meier 5-year estimates of MACCE were 28% (165 events) for PCI and 19% (110 events) for CABG (HR 1·58 [95% CI 1·24–2·01]); the HR exceeded the limit for non-inferiority of PCI compared to CABG. CABG was found to be superior to PCI for the primary composite endpoint (p=0·0002). All-cause mortality was estimated in 9% after PCI versus 9% after CABG (HR 1·08 [95% CI 0·74–1·59]; p=0·68); non-procedural myocardial infarction was estimated in 8% after PCI versus 3% after CABG (HR 2·99 [95% CI 1·66–5·39]; p=0·0002); and repeat revascularisation was estimated in 17% after PCI versus 10% after CABG (HR 1·73 [95% CI 1·25–2·40]; p=0·0009). In revascularisation of left main coronary artery disease, PCI was associated with an inferior clinical outcome at 5 years compared with CABG. Mortality was similar after the two procedures but patients treated with PCI had higher rates of non-procedural myocardial infarction and repeat revascularisation. Biosensors.

Coronary artery bypass grafting (CABG) is the standard treatment for revascularisation in patients with left main coronary artery disease, but use of percutaneous coronary intervention (PCI) for this indication is increasing. We aimed to compare PCI and CABG for treatment of left main coronary artery disease. In this prospective, randomised, open-label, non-inferiority trial, patients with left main coronary artery disease were enrolled in 36 centres in northern Europe and randomised 1:1 to treatment with PCI or CABG. Eligible patients had stable angina pectoris, unstable angina pectoris, or non-ST-elevation myocardial infarction. Exclusion criteria were ST-elevation myocardial infarction within 24 h, being considered too high risk for CABG or PCI, or expected survival of less than 1 year. The primary endpoint was major adverse cardiac or cerebrovascular events (MACCE), a composite of all-cause mortality, non-procedural myocardial infarction, any repeat coronary revascularisation, and stroke. Non-inferiority of PCI to CABG required the lower end of the 95% CI not to exceed a hazard ratio (HR) of 1·35 after up to 5 years of follow-up. The intention-to-treat principle was used in the analysis if not specified otherwise. This trial is registered with ClinicalTrials.gov identifier, number NCT01496651. Between Dec 9, 2008, and Jan 21, 2015, 1201 patients were randomly assigned, 598 to PCI and 603 to CABG, and 592 in each group entered analysis by intention to treat. Kaplan-Meier 5 year estimates of MACCE were 28% for PCI (121 events) and 18% for CABG (80 events), HR 1·51 (95% CI 1·13–2·00), exceeding the limit for non-inferiority, and CABG was significantly better than PCI (p=0·0044). As-treated estimates were 28% versus 18% (1·48, 1·11–1·98, p=0·0069). Comparing PCI with CABG, 5 year estimates were 11% versus 9% (1·08, 0·67–1·74, p=0·84) for all-cause mortality, 6% versus 2% (2·87, 1·40–5·89, p=0·0040) for non-procedural myocardial infarction, 15% versus 10% (1·50, 1·04–2·17, p=0·0304) for any revascularisation, and 5% versus 2% (2·20, 0·91–5·36, p=0·08) for stroke. The findings of this study suggest that CABG might be better than PCI for treatment of left main stem coronary artery disease. Biosensors, Aarhus University Hospital, and participating sites.

Serratia marcescens is a versatile opportunistic pathogen that can cause a variety of infections, including bacteremia. Our previous work established that the capsule polysaccharide (CPS) biosynthesis and translocation locus contributes to the survival of S . marcescens in a murine model of bacteremia and in human serum. In this study, we determined the degree of capsule genetic diversity among S . marcescens isolates. Capsule loci (KL) were extracted from >300 S . marcescens genome sequences and compared. A phylogenetic comparison of KL sequences demonstrated a substantial level of KL diversity within S . marcescens as a species and a strong delineation between KL sequences originating from infection isolates versus environmental isolates. Strains from five of the identified KL types were selected for further study and electrophoretic analysis of purified CPS indicated the production of distinct glycans. Polysaccharide composition analysis confirmed this observation and identified the constituent monosaccharides for each strain. Two predominant infection-associated clades, designated KL1 and KL2, emerged from the capsule phylogeny. Bacteremia strains from KL1 and KL2 were determined to produce ketodeoxynonulonic acid and N -acetylneuraminic acid, two sialic acids that were not found in strains from other clades. Further investigation of KL1 and KL2 sequences identified two genes, designated neuA and neuB , that were hypothesized to encode sialic acid biosynthesis functions. Disruption of neuB in a KL1 isolate resulted in the loss of sialic acid and CPS production. The absence of sialic acid and CPS production also led to increased susceptibility to internalization by a human monocytic cell line, demonstrating that S . marcescens phagocytosis resistance requires CPS. Together, these results establish the capsule genetic repertoire of S . marcescens and identify infection-associated clades with sialic acid CPS components.

Sepsis resulting from microbial colonization of the bloodstream is a serious health concern associated with high mortality rates. The objective of this study was to define the physiologic requirements of Citrobacter freundii in the bloodstream as a model for bacteremia caused by opportunistic Gram-negative pathogens. A genetic screen in a murine host identified 177 genes that contributed significantly to fitness, the majority of which were broadly classified as having metabolic or cellular maintenance functions. Among the pathways examined, the Tat protein secretion system conferred the single largest fitness contribution during competition infections and a putative Tat-secreted protein, SufI, was also identified as a fitness factor. Additional work was focused on identifying relevant metabolic pathways for bacteria in the bloodstream environment. Mutations that eliminated the use of glucose or mannitol as carbon sources in vitro resulted in loss of fitness in the murine model and similar results were obtained upon disruption of the cysteine biosynthetic pathway. Finally, the conservation of identified fitness factors was compared within a cohort of Citrobacter bloodstream isolates and between Citrobacter and Serratia marcescens , the results of which suggest the presence of conserved strategies for bacterial survival and replication in the bloodstream environment.

Serratia marcescens is an opportunistic pathogen that causes a range of human infections, including bacteremia, keratitis, wound infections, and urinary tract infections. Compared to other members of the Enterobacteriaceae family, the genetic factors that facilitate Serratia proliferation within the mammalian host are less well defined. An in vivo screen of transposon insertion mutants identified 212 S. marcescens fitness genes that contribute to bacterial survival in a murine model of bloodstream infection. Among those identified, 11 genes were located within an 18-gene cluster encoding predicted extracellular polysaccharide biosynthesis proteins. A mutation in the wzx gene contained within this locus conferred a loss of fitness in competition infections with the wild-type strain and a reduction in extracellular uronic acids correlating with capsule loss. A second gene, pgm , encoding a phosphoglucomutase exhibited similar capsule-deficient phenotypes, linking central glucose metabolism with capsule production and fitness of Serratia during mammalian infection. Further evidence of the importance of central metabolism was obtained with a pfkA glycolytic mutant that demonstrated reduced replication in human serum and during murine infection. An MgtB magnesium transporter homolog was also among the fitness factors identified, and an S. marcescens mgtB mutant exhibited decreased growth in defined medium containing low concentrations of magnesium and was outcompeted ~10-fold by wild-type bacteria in mice. Together, these newly identified genes provide a more complete understanding of the specific requirements for S. marcescens survival in the mammalian host and provide a framework for further investigation of the means by which S. marcescens causes opportunistic infections. IMPORTANCE Serratia marcescens is a remarkably prolific organism that replicates in diverse environments, including as an opportunistic pathogen in human bacteremia. The genetic requirements for S. marcescens survival in the mammalian bloodstream were defined in this work by transposon insertion sequencing. In total, 212 genes that contribute to bacterial fitness were identified. When sorted via biological function, two of the major fitness categories identified herein were genes encoding capsule polysaccharide biogenesis functions and genes involved in glucose utilization. Further investigation determined that certain glucose metabolism fitness genes are also important for the generation of extracellular polysaccharides. Together, these results identify critical biological processes that allow S. marcescens to colonize the mammalian bloodstream. Serratia marcescens is a remarkably prolific organism that replicates in diverse environments, including as an opportunistic pathogen in human bacteremia. The genetic requirements for S. marcescens survival in the mammalian bloodstream were defined in this work by transposon insertion sequencing. In total, 212 genes that contribute to bacterial fitness were identified. When sorted via biological function, two of the major fitness categories identified herein were genes encoding capsule polysaccharide biogenesis functions and genes involved in glucose utilization. Further investigation determined that certain glucose metabolism fitness genes are also important for the generation of extracellular polysaccharides. Together, these results identify critical biological processes that allow S. marcescens to colonize the mammalian bloodstream.

Background and AimsCoronary function testing performed as an adjunct during invasive angiography, aids diagnosis of coronary microvascular dysfunction. Intravenous (IV) adenosine infusion for the induction of stable hyperaemia is the reference approach for this assessment. However, logistics and systemic side-effects limit clinical adoption. Intracoronary (IC) adenosine represents a quicker, alternative means of achieving myocardial hyperaemia. We investigated the feasibility and diagnostic value of intracoronary adenosine-derived indices of microvascular function.Methods and ResultsWe performed invasive coronary function testing with a thermistor/pressure diagnostic guidewire (PressureWire X, Abbott) in 100 arteries from 76 consecutive patients undergoing investigation for suspected angina between Nov 2022 - Sep 2023 in 2 regional cardiac centres. All patients provided written informed consent. Repeated 3-ml thermodilution injections of room-temperature normal saline were performed at rest, after low-dose (90-microgram), and subsequently high-dose (210-microgram) IC bolus injection of adenosine via the guiding catheter. Finally, thermodilution was repeated during systemic hyperaemia from IV adenosine infusion (140 micrograms/kg/min). Responses were recorded on linked software (CoroFlow, Coroventis). Coronary flow reserve (CFR) and index of microvascular resistance (IMR) were calculated using mean (MeanTmn), first (1stTmn) and minimum (MinTmn) transit times for both low- and high-dose IC adenosine. ROC curves were used to determine the accuracy for each, and identify optimal cut-offs to predict IV CFR<2.0 and IMR≥25.The study population included 43.4% females, median age 62 (IQR 57–68) years. The presentation was stable angina in 69 (90.8%) patients. Smoking history was present in 40 (52.6%), hypertension 40 (52.6%), and diabetes mellitus 11 (14.5%). The evaluated coronary arteries (n=100) comprised the left anterior descending in 66, left circumflex in 28 and right coronary in 6. The median (IQR) IV adenosine fractional flow reserve (FFR)= 0.89 (0.83–0.94), CFR 3.1 (2.1–4.7) and IMR 17 (13–28). Low-dose IC adenosine demonstrated greater accuracy versus high-dose for predicting IV adenosine-derived CFR and IMR. Indices derived from MeanTmn outperformed those calculated from 1stTmn and MinTmn. Low-dose IC adenosine CFR<2.8 (AUC 0.97 [95% CI: 0.94–1.00]) had the best sensitivity (100.0%), specificity (81.6%), PPV (63.2%) and NPV (100.0%) for predicting IV adenosine CFR<2.0. Low-dose IC adenosine IMR≥20 (AUC 0.93 [95% CI: 0.88–0.98]) had the best sensitivity (96.8%), specificity (78.3%), PPV (66.7%), NPV (98.2%) for predicting IV adenosine IMR≥25. There were good correlations between MeanTmn-derived low-dose IC adenosine CFR and IV adenosine CFR (r=0.79, r2=0.62; p<0.001), and MeanTmn-derived low-dose IC adenosine IMR and IV adenosine IMR (r=0.78, r2=0.60; p<0.001). Transient (<5 sec) AV block occurred in 1 patient with low-dose IC adenosine and 17 with high-dose. Four patients had chest pain with IC, versus 72 with IV adenosine (Fisher’s p<0.001).ConclusionsOur study provides novel data on the feasibility and diagnostic value of IC adenosine for estimating CFR and IMR, compared with systemic hyperaemia using IV adenosine. A hybrid algorithm incorporating IC adenosine CFR≥2.8 and IMR<20 for the rapid exclusion of abnormal IV CFR/IMR may encourage uptake of microvascular function testing amongst clinicians. External validation in larger populations is warranted.Conflict of InterestNil

Coronary microvascular dysfunction may cause myocardial ischemia with no obstructive coronary artery disease (INOCA). If functional testing is not performed INOCA may pass undetected. Stress perfusion cardiovascular MRI (CMR) quantifies myocardial blood flow (MBF) but the clinical utility of stress CMR in the management of patients with suspected angina with no obstructive coronary arteries (ANOCA) is uncertain. First, to undertake a diagnostic study using stress CMR in patients with ANOCA following invasive coronary angiography and, second, in a nested, double-blind, randomized, controlled trial to assess the effect of disclosure on the final diagnosis and health status in the longer term. All-comers referred for clinically indicated coronary angiography for the investigation of suspected coronary artery disease will be screened in 3 regional centers in the United Kingdom. Following invasive coronary angiography, patients with ANOCA who provide informed consent will undergo noninvasive endotyping using stress CMR within 3 months of the angiogram. Stress perfusion CMR imaging to assess the prevalence of coronary microvascular dysfunction and clinically significant incidental findings in patients with ANOCA. The primary outcome is the between-group difference in the reclassification rate of the initial diagnosis based on invasive angiography versus the final diagnosis after CMR imaging. Participants will be randomized to inclusion (intervention group) or exclusion (control group) of myocardial blood flow to inform the final diagnosis. The primary outcome of the clinical trial is the mean within-subject change in the Seattle Angina Questionnaire summary score (SAQSS) at 6 months. Secondary outcome assessments include the EUROQOL EQ-5D-5L questionnaire, the Brief Illness Perception Questionnaire (Brief-IPQ), the Treatment Satisfaction Questionnaire (TSQM-9), the Patient Health Questionnaire-4 (PHQ-4), the Duke Activity Status Index (DASI), the International Physical Activity Questionnaire- Short Form (IPAQ-SF), the Montreal Cognitive Assessment (MOCA) and the 8-item Productivity Cost Questionnaire (iPCQ). Health and economic outcomes will be assessed using electronic healthcare records. To clarify if routine stress perfusion CMR imaging reclassifies the final diagnosis in patients with ANOCA and whether this strategy improves symptoms, health-related quality of life and health economic outcomes. NCT04805814

Background and AimsCoronary function testing to measure index of microcirculatory resistance (IMR) and coronary flow reserve (CFR) may be performed at the time of invasive coronary angiography to aid the diagnosis of microvascular angina. Intravenous (IV) adenosine infusion is used to induce stable hyperaemia. Logistics and systemic side-effects limit clinical adoption. Iodinated contrast medium (iohexol) is used during standard diagnostic angiography and induces transient, submaximal hyperaemia. We investigated the feasibility and diagnostic value of contrast-derived indices of coronary microvascular function.Methods and ResultsConsecutive patients with suspected angina who underwent clinically-indicated invasive coronary angiography at 2 regional cardiac centres between Jul 2021 and Nov 2022 were included. Coronary function testing was performed using a temperature/pressure diagnostic guidewire (PressureWire X; Abbott). Exclusion criteria include advanced kidney disease. Repeated 3 ml thermodilution injections were performed at rest, immediately after an 8 ml bolus of iohexol, and during IV adenosine (140 micrograms/kg/min) infusion. Responses were recorded on linked software (CoroFlow; CoroVentis). Contrast-derived IMR (cIMR) and CFR (cCFR) were calculated using the mean, minimum and first measured transit times respectively. ROC analysis was performed for each.In total, 106 vessels from n=93 patients were included. The median age was 63 years; 62.4% female. Co-morbidities include 46.2% smoking history, 12.9% diabetes mellitus and 66.7% hypertension. The vessels tested were 88.2% left anterior descending, 4.3% circumflex and 7.5% right coronary artery. 90.6% of vessels were non-obstructive, with median FFR=0.88 (IQR 0.85–0.92). cIMR derived from mean transit times of the second contrast bolus (ROC AUC 0.88 [95% CI: 0.81–0.96]) cutoff of >46 had the best sensitivity (89.3%; 25/28), specificity (76.7%; 56/73), PPV (59.5%; 25/42), and NPV (94.9%; 56/59) by the Youden index for predicting IV adenosine IMR≥25. There was good correlation between cIMR and IV adenosine IMR (r=0.74, r2=0.55; p<0.001). cCFR derived from the first transit time of the second contrast bolus (ROC AUC 0.75 [95% CI: 0.63–0.87]) cutoff of ≤2.2 had the best sensitivity (93.8%; 15/16), specificity (61.2%; 52/85), PPV (31.3%; 15/48), and NPV (98.1%; 52/53) by the Youden index for predicting IV adenosine CFR<2.0. There was good correlation between cCFR and IV adenosine CFR (r=0.42, r2=0.18; p<0.001). No adverse events were noted.ConclusionsOur study provides novel data on the feasibility and diagnostic value of contrast-derived IMR and CFR. The enhanced diagnostic yield from repeat contrast injection is potentially an effect of incremental hyperaemia. A hybrid algorithm incorporating contrast-derived IMR≤46 and CFR>2.2 for the rapid exclusion of microvascular angina may be considered. External validation in larger populations is warranted.Conflict of InterestNil

BackgroundThe relationship between atherosclerosis and endotypes of myocardial ischaemia with no obstructive coronary artery disease (INOCA) is unclear. We investigated potential associations between cumulative atherosclerotic plaque burden quantified using the Gensini score, novel invasive indices of coronary microvascular function (microvascular resistance reserve (MRR); resistive reserve ratio (RRR)) and related INOCA endotypes.MethodsCoronary angiography and invasive coronary function tests were simultaneously acquired in the CorMicA cohort. A comprehensive physiological assessment was performed using both a thermodilution-based diagnostic guidewire and intracoronary acetylcholine provocation testing. Angiograms were examined for luminal stenosis in each segment of the SYNTAX coronary model. Cumulative plaque burden was quantified using the Gensini score, which incorporated both the number of diseased coronary segments and stenosis severity. Results were compared with indices of microvascular function and INOCA endotypes. Angiographic analyses were performed blind to coronary physiology findings.ResultsIn 151 participants (median age 61 years; 73.5% female) without flow-limiting coronary artery disease, medical history included 41.7% smoking, 63.6% hypertension and 19.2% diabetes mellitus. The left anterior descending artery underwent diagnostic guidewire testing in 85.4%, and 55.0% of participants had abnormal coronary flow reserve (CFR) and/or Index of Microcirculatory Resistance (IMR). The median Gensini score was 6.0 (IQR 2.5–11.0). CFR (p=0.012), MRR (p=0.026) and RRR (p=0.026), but not IMR (p=0.445), were univariably associated with raised Gensini scores. These significant effects persisted in multivariable models controlling for potential confounders. Considering INOCA endotypes, Gensini scores differed among participants with microvascular angina (MVA) (7.0 (2.5–11.0)), vasospastic angina (VSA) (4.5 (2.0–10.0)), mixed MVA/VSA (9.0 (5.0–11.5)) and non-cardiac symptoms (3.5 (1.5–8.0)); Kruskal-Wallis p=0.030.ConclusionsReduced CFR, MRR and RRR, and MVA were associated with increased coronary atherosclerotic plaque burden, as evidenced by higher Gensini scores. These novel findings provide a mechanistic link between INOCA and cardiovascular events, reinforcing the importance of antiatherosclerosis therapy in patients with MVA.

Background Eculizumab has transformed management of paroxysmal nocturnal hemoglobinuria (PNH) since its approval. However, its biweekly dosing regimen remains a high treatment burden. Ravulizumab administered every 8 weeks demonstrated noninferiority to eculizumab in two phase 3 trials. In regions where two PNH treatment options are available, it is important to consider patient preference. Objective The aim of this study was to assess patient preference for ravulizumab or eculizumab. Methods Study 302s (ALXN1210-PNH-302s) enrolled PNH patients who participated in the extension period of phase 3 study ALXN1210-PNH-302. In the parent study, eculizumab-experienced adult PNH patients received ravulizumab or eculizumab during a 26-week primary evaluation period. All patients in the extension period received ravulizumab. In study 302s, patient treatment preference was evaluated using an 11-item PNH-specific Patient Preference Questionnaire (PNH-PPQ©). Of 98 patients, 95 completed PNH-PPQ© per protocol for analysis. Results Overall, 93% of patients preferred ravulizumab whereas 7% of patients either had no preference (6%) or preferred eculizumab (1%) (P < 0.001). For specific aspects of treatment, ravulizumab was preferred (in comparison to no preference or eculizumab) on infusion frequency (98% vs. 0% vs. 2%), ability to plan activities (98% vs. 0% vs. 2%), and overall quality of life (88% vs. 11% vs. 1%), among other aspects. Most participants selected frequency of infusions as the most important factor determining preference (43%), followed by overall quality of life (23%). Conclusion This study shows that a substantial proportion of patients preferred ravulizumab over eculizumab and provides an important patient perspective on PNH treatment when there is more than one treatment option.