Triple combination dry powder formulation of pretomanid, moxifloxacin, and pyrazinamide for treatment of multidrug-resistant tuberculosis.

Both latent and multidrug-resistant tuberculosis (TB) have been causing significant concern worldwide. A novel drug, pretomanid (PA-824), has shown a potent bactericidal effect against both active and latent forms of Mycobacterium tuberculosis (MTb) and a synergistic effect when combined with pyrazinamide and moxifloxacin. This study aimed to develop triple combination spray dried inhalable formulations composed of antitubercular drugs, pretomanid, moxifloxacin, and pyrazinamide (1:2:8 w/w/w), alone (PaMP) and in combination with an aerosolization enhancer, L-leucine (20 % w/w, PaMPL). The formulation PaMPL consisted of hollow, spherical, dimpled particles (<5 µm) and showed good aerosolization behaviour with a fine particle fraction of 70 %. Solid-state characterization of formulations with and without L-leucine confirmed the amorphous nature of moxifloxacin and pretomanid and the crystalline nature of pyrazinamide with polymorphic transformation after the spray drying process. Further, the X-ray photoelectron spectroscopic analysis revealed the predominant surface composition of L-leucine on PaMPL dry powder particles. The dose-response cytotoxicity results showed pyrazinamide and moxifloxacin were non-toxic in both A549 and Calu-3 cell lines up to 150 µg/mL. However, the cell viability gradually decreased to 50 % when the pretomanid concentration increased to 150 µg/mL. The in vitro efficacy studies demonstrated that the triple combination formulation had more prominent antibacterial activity with a minimum inhibitory concentration (MIC) of 1 µg/mL against the MTb H37Rv strain as compared to individual drugs. In conclusion, the triple combination of pretomanid, moxifloxacin, and pyrazinamide as an inhalable dry powder formulation will potentially improve treatment efficacy with fewer systemic side effects in patients suffering from latent and multidrug-resistant TB.

Impact of explanted valve type on aortic valve reoperations: nationwide UK experience.

OBJECTIVES: This nationwide retrospective cohort study assessed the impact of the explanted valve type on reoperative outcomes in aortic valve surgery within the UK over a 23-year period. METHODS: Data were sourced from the National Institute for Cardiovascular Outcomes Research (NICOR) database. All patients undergoing first-time isolated reoperative aortic valve replacement between 1996 and 2019 in the UK were included. Concomitant procedures, homograft implantation or aortic root enlargement were excluded. Propensity score matching was utilized to compare outcomes and risk factors for in-hospital mortality was evaluated through multivariable logistic regression. Final model selection was conducted using Akaike Information Criterion through bootstrapping. The primary end point was in-hospital mortality, and secondary end points included postoperative morbidities. RESULTS: Out of 2371 patients, 24.9% had mechanical and 75% had bioprosthetic valves implanted during the primary procedure. Propensity matched groups of 324 patients each, were compared. In-hospital mortality for mechanical and bioprosthetic valve explants was 7.1% and 5.9%, respectively (P = 0.632). On multivariable logistic regression analysis, valve type was not a risk factor for mortality [odds ratio (OR) 0.62, 95% confidence interval (CI) 0.37-1.05; P = 0.1]. Age (OR 1.03, 95% CI 1.01-1.05; P < 0.05), left ventricular ejection fraction (OR 1.62, 95% CI 1.08-2.42; P < 0.05), creatinine ≥ 200 mg/dl (OR 2.21, 95% CI 1.17-4.04; P < 0.05) and endocarditis (OR 2.66, 95% CI 1.71-4.14; P < 0.05) emerged as risk factors for mortality. CONCLUSIONS: The type of valve initially implanted (mechanical or bioprosthetic) did not determine mortality. Instead, age, left ventricular ejection fraction, renal impairment and endocarditis were significant risk factors for in-hospital mortality.

Up against the wall - emergency double myocardial rupture repair.

BACKGROUND: Left ventricular free wall rupture (LVFWR) and interventricular septal rupture (VSR) are potentially catastrophic mechanical complications after acute myocardial infarction (AMI). When they occur together, "double myocardial rupture" (DMR), survival is unlikely. DMR is seen in only 0.3% of all AMIs. With or without surgical intervention, the odds are against the patient. CASE PRESENTATION: A 57-year-old male self-referred to the emergency department of a remote hospital 5 days after first experiencing chest pain. Investigations in ED confirmed an inferior ST-segment elevation myocardial infarction (STEMI) complicated by DMR. Coronary angiography revealed a mid-course total occlusion of the right coronary artery (RCA). He was rapidly transferred to our regional cardiac surgical unit, arriving straight into the operating theatre, in cardiogenic shock. He was briefly conscious, before arresting prior to intubation and being massaged onto bypass. Not only did he survive the all-night operation, requiring a mitral valve replacement in the process, but he survived multiple postoperative complications to be eventually transferred on postoperative day 66, neurologically intact, to a peripheral unit to complete his rehabilitation. He was subsequently discharged home 88 days after the operation and was able to ambulate with a walking frame into his first postoperative follow-up clinic appointment. CONCLUSIONS: Our patient, against all odds, has survived DMR and multiple postoperative complications. We present the details of his case and the literature surrounding the condition. The patient's mental fortitude and his supportive family played a significant role, along with excellent multidisciplinary team work, in assuring his survival.

Comparative Analysis of Coronary Artery Bypass Grafting Outcomes in Women Using Different Conduits in the National UK Data Set.

BACKGROUND: There is limited report of outcomes in women undergoing isolated coronary artery bypass grafting (CABG) with left internal thoracic artery and different second conduits (saphenous vein graft [SVG], radial artery [RA], and right internal thoracic artery [RITA]). METHODS: The National Adult Cardiac Surgery Audit database was queried for women undergoing isolated CABG with left internal thoracic artery graft in the United Kingdom from 1996 to 2019. Propensity score-based pairwise comparisons were performed between graft types. The primary outcome was in-hospital mortality. RESULTS: The study included 58,063 women (SVG, n = 48,881 [84.2%]; RA, n = 6136 [10.6%]; RITA, n = 2445 [4.2%]). SVG use was stable over the years; RA and RITA use decreased. In-hospital mortality was similar between the RA and RITA grafts (2.3% vs 2.8%; odds ratio [OR], 0.80; 95% CI, 0.53-1.22; P = .39) and between the RA and SVG (2.3% vs 2.0%; OR, 1.20; 95% CI, 0.93-1.55; P = .17) but higher in the RITA group compared with the SVG (2.7% vs 1.4%; OR, 2.04; 95% CI, 1.27-3.36; P = .004). Women receiving the RITA graft were more likely to have sternal wound infection (SWI) compared with the RA (0.6% vs 0.06%; P = .004) and the SVG (0.6% vs 0.2%; P = .032). SWI was consistently associated with higher risk of in-hospital mortality. CONCLUSIONS: Conduit selection may affect operative outcomes in women undergoing CABG. The RA shows similar mortality and risk of deep SWI as the SVG.

A systematic review and meta-analysis of internal thoracic artery harvesting techniques: Skeletonized vs pedicled.

OBJECTIVES: The aim of this meta-analysis was to compare clinical and angiographic outcomes of skeletonized versus pedicled internal thoracic artery for coronary artery bypass grafting. METHODS: A comprehensive search on Ovid MEDLINE, Ovid EMBASE and Scopus was performed from inception to December 2022. The primary outcome was follow-up mortality and graft failure. Secondary outcomes were repeat revascularization, cardiovascular death and operative mortality, myocardial infarction, stroke, and sternal wound complications (SWCs). Pooled estimate for follow-up outcomes was summarized as incidence rate ratio (IRR) and 95% confidence interval (CI) while short-term outcomes were pooled as odds ratio (OR) and 95% CI. For all outcomes, inverse variance weighting was used for pooling. RESULTS: Twenty-eight studies, including 7 randomized trials and 21 observational studies, for a total of 5664 patients in the skeletonized group and 7434 in the pedicled group, were included in the analysis. At a mean weighted follow-up of 4.8 years, there was no difference in mortality between the two groups (IRR 1.14; 95% CI 0.59-2.20). However, the skeletonized group had a higher incidence of graft failure compared to the pedicled group (IRR 1.87, 95% CI 1.33-2.63) but a lower risk of SWCs (OR 0.42; 95% CI 0.30-0.60). There was no difference in short-term outcomes. CONCLUSIONS: Compared to the pedicled harvesting technique, skeletonization of the internal thoracic artery is associated with higher rate of graft failure and lower risk of SWCs without mortality difference.

Inhalable dry powder containing remdesivir and disulfiram: Preparation and in vitro characterization.

The respiratory tract, as the first and most afflicted target of many viruses such as SARS-CoV-2, seems to be the logical choice for delivering antiviral agents against this and other respiratory viruses. A combination of remdesivir and disulfiram, targeting two different steps in the viral replication cycle, has showed synergistic activity against SARS-CoV-2 in-vitro. In this study, we have developed an inhalable dry powder containing a combination of remdesivir and disulfiram utilizing the spray-drying technique, with the final goal of delivering this drug combination to the respiratory tract. The prepared dry powders were spherical, and crystalline. The particle size was between 1 and 5 µm indicating their suitability for inhalation. The spray-dried combinational dry powder containing remdesivir and disulfiram (RDSD) showed a higher emitted dose (ED) of >88% than single dry powder of remdesivir (RSD) (∼72%) and disulfiram (DSD) (∼84%), with a fine particle fraction (FPF) of ∼55%. Addition of L-leucine to RDSD showed >60% FPF with a similar ED. The in vitro aerosolization was not significantly affected after the stability study conducted at different humidity conditions. Interestingly, the single (RSD and DSD) and combined (RDSD) spray-dried powders showed limited cellular toxicity (CC50 values from 39.4 to >100 µM), while maintaining their anti-SARS-CoV-2 in vitro (EC50 values from 4.43 to 6.63 µM). In a summary, a combinational dry powder formulation containing remdesivir and disulfiram suitable for inhalation was developed by spray-drying technique which showed high cell viability in the respiratory cell line (Calu-3 cells) retaining their anti-SARS-CoV-2 property. In the future, in vivo studies will test the ability of these formulations to inhibit SARS-CoV-2 which is essential for clinical translation.

Spray-Dried Inhalable Microparticles Combining Remdesivir and Ebselen against SARS-CoV-2 Infection.

There is a continuous effort to develop efficient treatments for coronavirus disease 2019 (COVID-19) and other viral respiratory diseases. Among the different strategies, inhaled treatment is considered one of the most logical and efficient approaches to treating COVID-19, as the causative "SARS-CoV-2 virus RNA" predominantly infects the respiratory tract. COVID-19 treatments initially relied on repurposed drugs, with a few additional strategies developed during the last two years, and all of them are based on monotherapy. However, drug combinations have been found to be more effective than monotherapy in other viral diseases such as HIV, influenza, and hepatitis C virus. In the case of SARS-CoV-2 infection, in vitro studies have shown synergistic antiviral activity combining remdesivir with ebselen, an organoselenium compound. Therefore, these drug combinations could ensure better therapeutic outcomes than the individual agents. In this study, we developed a dry powder formulation containing remdesivir and ebselen using a spray-drying technique and used L-leucine as an aerosolization enhancer. The prepared dry powders were spherical and crystalline, with a mean particle size between 1 and 3 µm, indicating their suitability for inhalation. The emitted dose (ED) and fine particle fraction (FPF) of remdesivir- and ebselen-containing dry powders were ~80% and ~57% when prepared without L-leucine. The ED as well as the FPF significantly increased with values of >86% and >67%, respectively, when L-leucine was incorporated. More importantly, the single and combinational dry powder of remdesivir and ebselen showed minimal cytotoxicity (CC50 > 100 µM) in Calu-3 cells, retaining their anti-SARS-CoV-2 properties (EC50 2.77 to 18.64 µM). In summary, we developed an inhalable dry powder combination of remdesivir and ebselen using a spray-drying technique. The spray-dried inhalable microparticles retained their limited cytotoxicity and specific antiviral properties. Future in vivo studies are needed to verify the potential use of these remdesivir/ebselen combinational spray-dried inhalable microparticles to block the SARS-CoV-2 replication in the respiratory tract.

Inhalable Combination Powder Formulations for Treating Latent and Multidrug-Resistant Tuberculosis: Formulation and In Vitro Characterization.

Tuberculosis (TB) is an infectious disease resulting in millions of deaths annually worldwide. TB treatment is challenging due to a huge number of global latent infections and due to multidrug-resistant forms of TB. Inhaled administration of anti-TB drugs using dry powder inhalers has various advantages over oral administration due to its direct drug delivery and minimization of systemic side effects. Pretomanid (PA-824, PA) is a relatively new drug with potent activity against both active and latent forms of Mycobacterium tuberculosis (Mtb). It is also known for its synergistic effects in combination with pyrazinamide (PYR) and moxifloxacin (MOX). Fixed-dose combination powder formulations of either PYR and PA or PYR and MOX were prepared for inhaled delivery to the deep lung regions where the Mtb habitats were located. Powder formulations were prepared by spray drying using L-leucine as the aerosolization enhancer and were characterized by their particle size, morphology and solid-state properties. In vitro aerosolization behaviour was studied using a Next Generation Impactor, and stability was assessed after storage at room temperature and 30% relative humidity for three months. Spray drying with L-leucine resulted in spherical dimpled particles, 1.9 and 2.4 µm in size for PYR-PA and PYR-MOX combinations, respectively. The powder formulations had an emitted dose of >83% and a fine particle fraction of >65%. PA and MOX showed better stability in the combination powders compared to PYR. Combination powder formulations with high aerosolization efficiency for direct delivery to the lungs were developed in this study for use in the treatment of latent and multidrug-resistant TB infections.

Trend and early clinical outcomes of off-pump coronary artery bypass grafting in the UK.

OBJECTIVES: The popularity of off-pump coronary artery bypass grafting (CABG) varies across the world, ranging from 20% in Europe and the USA to 56% in Asia. We present the trend and early clinical outcomes in off pump in the UK. METHODS: All patients who underwent elective or urgent isolated CABG from 1996 to 2019 were extracted from the National Adult Cardiac Surgery Audit database. The trend in operating surgeons and units volume and training in off pump were analysed. Early clinical outcomes between off- and on-pump CABG were compared using propensity score matching. RESULTS: A total of 351 422 patients were included. The overall off-pump rate during the study period was 15.17%, it peaked in 2008 (19.8%), followed by a steady decreased to 2018 (7.63%). Its adoption varied across centres and surgeons, ranging from <1% to 48.36% and <1% to 85.5%, respectively, of total cases performed. After propensity score matching for the period 1996-2019, off pump, when compared to on pump, was associated with a lower in-hospital/30-day mortality (1.2% vs 1.5%, P < 0.001), return to theatre (3.7% vs 4.5%, P < 0.001), cerebrovascular accident (transient ischaemic attack: 0.3% vs 0.6%, stroke: 0.3% vs 0.6%, P < 0.001) and deep sternal wound infection (0.8% vs 1.2%, P ≤ 0.001). In a sub-analysis from the introduction of EuroScore II (2012-2019), there were no differences in-hospital/30-day mortality (1.0% vs 1.0%, P = 0.71). However, on pump, had a higher return to theatre (4.2% vs 2.7%, P < 0.001), cerebrovascular accident (transient ischaemic attack: 0.4% vs 0.2%, stroke: 0.5% vs 0.3%, P = 0.003) and deep sternal wound infection (1.0% vs 0.6%, P = 0.004). CONCLUSIONS: Our data show a decreasing trend in the use of off pump in the UK since 2008. This is likely to be multifactorial and raises the question of whether it should be a specialized revascularization technique.

Trends and outcomes of concomitant aortic valve replacement and coronary artery bypass grafting in the UK and a survey of practices.

OBJECTIVES: Concomitant revascularization of coronary artery disease at the same time as treatment for aortic valvopathy favourably impacts survival. However, combined surgery may be associated with increased adverse outcomes compared to aortic valve replacement (AVR) or coronary artery bypass grafting in isolation. METHODS: We retrospectively analyzed all patients who underwent AVR with bypass grafting between February 1996 and March 2019 using data from the National Adult Cardiac Surgery Audit. We used a generalized mixed-effects model to assess the effect of the number and type of bypass grafts associated with surgical AVR on in-hospital mortality, postoperative stroke, and the need for renal dialysis. Furthermore, we conducted an international cross-sectional survey of cardiac surgeons to explore their views about concomitant AVR with coronary bypass grafting interventions. RESULTS: Fifty-one thousand two hundred and seventy-two patients were included in the study. Patients receiving 2 or more bypass grafts demonstrated more significant preoperative comorbidity and disease severity. Patients undergoing 2 and >2 grafts in addition to AVR had increased mortality as compared to patients undergoing AVR and only 1 graft [odds ratio (OR) 1.17, 95% confidence interval (CI) [1.05-1.30], P = 0.005 and OR 1.15, 95% CI [1.02-1.30], P = 0.024 respectively]. A single arterial conduit was associated with a reduction in mortality (OR 0.75, 95% CI [0.68-0.82], P < 0.001) and postoperative dialysis (OR 0.87, 95% CI [0.78-0.96], P = 0.006), but this association was lost with >1 arterial conduit. One hundred and three surgeons responded to our survey, with only a small majority believing that the number of bypass grafts can influence short- or long-term postoperative outcomes in these patients, and an almost equal split in responders supporting the use of staged or hybrid interventions for patients with concomitant pathology. CONCLUSIONS: The number of grafts performed during combined AVR and coronary artery bypass grafting is associated with increased morbidity and mortality. The use of an arterial graft was also associated with reduced mortality. Future studies are needed to assess the effect of incomplete revascularization and measure long-term outcomes. Based on our data, current published evidence, and the collective expert opinion we gathered, we endorse future work to investigate the short and long-term efficacy and safety of hybrid intervention for patients with concomitant advanced coronary and aortic valve disease.

Cardiac surgery risk prediction using ensemble machine learning to incorporate legacy risk scores: A benchmarking study.

Objective: The introduction of new clinical risk scores (e.g. European System for Cardiac Operative Risk Evaluation (EuroSCORE) II) superseding original scores (e.g. EuroSCORE I) with different variable sets typically result in disparate datasets due to high levels of missingness for new score variables prior to time of adoption. Little is known about the use of ensemble learning to incorporate disparate data from legacy scores. We tested the hypothesised that Homogenenous and Heterogeneous Machine Learning (ML) ensembles will have better performance than ensembles of Dynamic Model Averaging (DMA) for combining knowledge from EuroSCORE I legacy data with EuroSCORE II data to predict cardiac surgery risk. Methods: Using the National Adult Cardiac Surgery Audit dataset, we trained 12 different base learner models, based on two different variable sets from either EuroSCORE I (LogES) or EuroScore II (ES II), partitioned by the time of score adoption (1996-2016 or 2012-2016) and evaluated on holdout set (2017-2019). These base learner models were ensembled using nine different combinations of six ML algorithms to produce homogeneous or heterogeneous ensembles. Performance was assessed using a consensus metric. Results: Xgboost homogenous ensemble (HE) was the highest performing model (clinical effectiveness metric (CEM) 0.725) with area under the curve (AUC) (0.8327; 95% confidence interval (CI) 0.8323-0.8329) followed by Random Forest HE (CEM 0.723; AUC 0.8325; 95%CI 0.8320-0.8326). Across different heterogenous ensembles, significantly better performance was obtained by combining siloed datasets across time (CEM 0.720) than building ensembles of either 1996-2011 (t-test adjusted, p = 1.67×10-6) or 2012-2019 (t-test adjusted, p = 1.35×10-193) datasets alone. Conclusions: Both homogenous and heterogenous ML ensembles performed significantly better than DMA ensemble of Bayesian Update models. Time-dependent ensemble combination of variables, having differing qualities according to time of score adoption, enabled previously siloed data to be combined, leading to increased power, clinical interpretability of variables and usage of data.

Comparison of machine learning techniques in prediction of mortality following cardiac surgery: analysis of over 220 000 patients from a large national database.

OBJECTIVES: To perform a systematic comparison of in-hospital mortality risk prediction post-cardiac surgery, between the predominant scoring system-European System for Cardiac Operative Risk Evaluation (EuroSCORE) II, logistic regression (LR) retrained on the same variables and alternative machine learning techniques (ML)-random forest (RF), neural networks (NN), XGBoost and weighted support vector machine. METHODS: Retrospective analyses of prospectively routinely collected data on adult patients undergoing cardiac surgery in the UK from January 2012 to March 2019. Data were temporally split 70:30 into training and validation subsets. Mortality prediction models were created using the 18 variables of EuroSCORE II. Comparisons of discrimination, calibration and clinical utility were then conducted. Changes in model performance, variable-importance over time and hospital/operation-based model performance were also reviewed. RESULTS: Of the 227 087 adults who underwent cardiac surgery during the study period, there were 6258 deaths (2.76%). In the testing cohort, there was an improvement in discrimination [XGBoost (95% confidence interval (CI) area under the receiver operator curve (AUC), 0.834-0.834, F1 score, 0.276-0.280) and RF (95% CI AUC, 0.833-0.834, F1, 0.277-0.281)] compared with EuroSCORE II (95% CI AUC, 0.817-0.818, F1, 0.243-0.245). There was no significant improvement in calibration with ML and retrained-LR compared to EuroSCORE II. However, EuroSCORE II overestimated risk across all deciles of risk and over time. The calibration drift was lowest in NN, XGBoost and RF compared with EuroSCORE II. Decision curve analysis showed XGBoost and RF to have greater net benefit than EuroSCORE II. CONCLUSIONS: ML techniques showed some statistical improvements over retrained-LR and EuroSCORE II. The clinical impact of this improvement is modest at present. However the incorporation of additional risk factors in future studies may improve upon these findings and warrants further study.

Mitral repair versus replacement: 20-year outcome trends in the UK (2000-2019).

OBJECTIVES: Using a large national database, we sought to describe outcome trends in mitral valve surgery between 2000 and 2019. METHODS: The study cohort was split into mitral valve repair (MVr) or replacement, including all patients regardless of concomitant procedures. Patients were grouped by four-year admission periods into groups (A to E). The primary outcome was in hospital mortality and secondary outcomes were return to theatre, postoperative stroke and postoperative length of stay. We investigated trends over time in patient demographics, comorbidities, intraoperative characteristics and postoperative outcomes. We used a multivariable binary logistic regression model to assess the relationship between mortality and time. Cohorts were further stratified by sex and aetiology. RESULTS: Of the 63 000 patients in the study cohort, 31 644 had an MVr and 31 356 had a replacement. Significant demographic shifts were observed. Aetiology has shifted towards degenerative disease; endocarditis rates in MVr dropped initially but are now rising (period A = 6%, period C = 4%, period E = 6%; P < 0.001). The burden of comorbidities has increased over time. In the latest time period, women had lower repair rates (49% vs 67%, P < 0.001) and higher mortality rates when undergoing repair (3% vs 2%, P = 0.001) than men. Unadjusted postoperative mortality dropped in MVr (5% vs 2%, P < 0.001) and replacement (9% vs 7%, P = 0.015). Secondary outcomes have improved. Time period was an independent predictor for reduced mortality in both repair (odds ratio: 0.41, 95% confidence interval: 0.28-0.61, P < 0.001) and replacement (odds ratio: 0.50, 95% confidence interval: 0.41-0.61, P < 0.001). CONCLUSIONS: In-hospital mortality has dropped significantly over time for mitral valve surgery in the UK. MVr has become the more common procedure. Sex-based discrepancies in repair rates and mortality require further investigation. Endocarditis rates in MVS are rising.

Incorporation of SARS-CoV-2 spike NTD to RBD protein vaccine improves immunity against viral variants.

Emerging SARS-CoV-2 variants pose a threat to human health worldwide. SARS-CoV-2 receptor binding domain (RBD)-based vaccines are suitable candidates for booster vaccines, eliciting a focused antibody response enriched for virus neutralizing activity. Although RBD proteins are manufactured easily, and have excellent stability and safety properties, they are poorly immunogenic compared to the full-length spike protein. We have overcome this limitation by engineering a subunit vaccine composed of an RBD tandem dimer fused to the N-terminal domain (NTD) of the spike protein. We found that inclusion of the NTD (1) improved the magnitude and breadth of the T cell and anti-RBD response, and (2) enhanced T follicular helper cell and memory B cell generation, antibody potency, and cross-reactive neutralization activity against multiple SARS-CoV-2 variants, including B.1.1.529 (Omicron BA.1). In summary, our uniquely engineered RBD-NTD-subunit protein vaccine provides a promising booster vaccination strategy capable of protecting against known SARS-CoV-2 variants of concern.

Risk Factors and Outcomes of Reoperative Surgical Aortic Valve Replacement in the United Kingdom.

BACKGROUND: Mortality after reoperative aortic valve surgery continues to decline but remains high compared with primary isolated replacement. We sought to examine temporal trends, morbidity, and mortality among patients undergoing isolated first-time reoperative aortic valve surgery. METHODS: The study included all patients undergoing reoperative aortic valve surgery in the United Kingdom between January 2007 and March 2019. Patients undergoing isolated reoperative aortic valve replacement (AVR) were compared with a propensity matched cohort of patients undergoing isolated primary AVR. Outcomes measured included inhospital mortality, neurologic dysfunction, postoperative dialysis, deep sternal wound infections, and hospital length of stay. RESULTS: During the study period, 40,858 primary isolated AVRs and 3015 first-time isolated reoperative AVRs were carried out in the United Kingdom. In the propensity matched reoperative group, median age of participants was 69.8 years (60.8-76.2) with median duration between the initial surgery and the reoperation being 7.69 years. Overall mortality was 3.1% (94) for reoperative AVR compared with 1.9% (56) for primary AVR. Mortality of both primary and reoperative AVR declined during the study period. Reoperation, age, New York Heart Association class, and chronic kidney disease were independently associated with early mortality. CONCLUSIONS: Reoperative isolated AVR can be performed with acceptable inhospital mortality and provides a benchmark against which alternative strategies should be compared.

Impact of Preoperative Atrial Fibrillation on In-Hospital Outcomes of Coronary Artery Bypass Grafting.

Perioperative atrial fibrillation (AF) is associated with increased mortality, morbidity, and excess healthcare costs. The objective of our study was to assess if preoperative AF in patients undergoing coronary artery bypass grafting is a predictor of operative mortality, postoperative stroke, and need for postoperative dialysis by interrogating a large registry database. We included all isolated procedures performed between February 1996 and March 2019. We used a generalized linear mixed model to assess the effect of preoperative AF on mortality stroke and the need for postoperative dialysis after adjusting for the relevant confounders derived from EuroSCORE 2. Confounders considered included age, gender, neurological dysfunction, renal dysfunction, recent myocardial infarction, pulmonary disease, unstable angina, NYHA class, pulmonary hypertension, diabetes on insulin and peripheral vascular disease, and urgency of the operation. We treated the hospital and operating consultant as random effect variables. We also performed LV function subgroup analyses to assess the effect of preoperative AF on the outcomes of interest. The incidence of pre-existent AF in the cohort of patients we analyzed (N = 356,040 patients) was 3.5% (N = 12,664). In the unadjusted baseline characteristics, preoperative AF patients had more associated comorbidities. After adjustment, preoperative AF remained a significant predictor of increased mortality (odds ratio [OR]: 1.63, confidence interval [CI] 1.48-1.79, p < 0.001), stroke (OR: 1.33, CI 1.16-1.54, p = 0.001), and need for renal dialysis (OR:1.61, CI 1.46-1.78, p < 0.001). Preoperative AF was a significant predictor of adverse outcomes in patients with moderate and good LV function but not in patients with poor LV function (EF <30%). Our study suggests that preoperative AF is associated with an increased risk for perioperative mortality and stroke in patients undergoing coronary artery bypass grafting.

In-hospital outcomes predictors and trends of redo sternotomy aortic root replacements: insights from a UK registry analysis.

Background: Redo sternotomy aortic root surgery is technically demanding, and the evidence on outcomes is mostly from retrospective, small sample, single-centre studies. We report the trend, early clinical results and outcome predictors of redo aortic root replacement over 20 years in the United Kingdom. Methods: We retrospectively analysed collected data from the UK National Adult Cardiac Surgery Audit (NACSA) on all redo sternotomy aortic root replacements performed between 30th January 1998 and 19th March 2019. We analysed trends in the volume of operations, characteristics of hospital survivors vs. non-survivors, and predictors of in-hospital outcomes. Results: During the study period, 1,107 redo sternotomy aortic root replacements were performed (median age 59, 26% of patients were females). Eighty-four per cent of cases (N = 931) underwent a composite root replacement, 11% (N = 119) had homograft root replacement and valve-sparing root replacement was performed in 5.1% (N = 57) of cases. There was a steady increase in the volume of redo sternotomy root replacements beyond 2006, from an annual volume of 22 procedures in 2006 to 106 procedures in 2017. Hospital mortality was 17% (n = 192), postoperative stroke or TIA occurred in 5.2% (n = 58), and postoperative dialysis was required in 11% (n = 109) of patients. Return to the theatre for bleeding/tamponade was required in 9% (n = 102) and median in-hospital stay was 9 days. Age >59 (OR: 2.99, CI: 1.92-4.65, P < 0.001), recent myocardial infarction (OR: 6.42, CI: 2.24-18.41, P = 0.001) were associated with increased in-hospital mortality. Emergency surgery (OR: 3.95, 2.27-6.86, P < 0.001), surgery for endocarditis (OR: 2.05, CI: 1.26-3.33, P = 0.001), salvage coronary artery bypass grafting (OR: 2.20, CI: 1.37-3.54, P < 0.001), arch surgery (OR: 2.47, CI: 1.30-3.61, P = 0.018) and aortic cross-clamp longer than 169 min (OR: 2.17, CI: 1.00-1.01, P = 0.003) were associated with increased risk of mortality. We found no effect of the centre or surgeon volume on mortality (P > 0.05). Conclusions: Redo sternotomy aortic root replacement still carries significant morbidity and mortality and is sporadically performed across surgeons and centres in the UK.

Surgical outcomes and optimal approach to treatment of aortic valve endocarditis with aortic root abscess - systematic review and meta-analysis.

BACKGROUND: Data on the postoperative outcomes for patients with infective endocarditis complicated by an aortic root abscess is sparse due to the condition's low incidence and high mortality rates. This systematic review and meta-analysis aims to evaluate existing data on the impact of aortic root abscesses on the postoperative outcomes and to inform optimal surgical approach. METHODS: The online databases MEDLINE, EMBASE and Cochrane library were searched from 1990 to 2022 for studies comparing cohorts of surgically managed infective endocarditis patients with and without an aortic root abscess. Data was extracted by two independent investigators and aggregated in a random-effects model. Risk of bias was assessed using an adapted version of the Newcastle-Ottawa scale. RESULTS: Six clinical studies were included in the meta-analysis (n 1982). The abscess group was associated with increased in-hospital mortality (OR 1.74 95%: CI 1.18-2.56) and late mortality (HR 1.27 95% CI:1.03-1.58). The reoperation meta-analysis was complicated by high rates of heterogeneity (I2 = 59%) and found no significant differences in reoperation between abscess and no abscess groups (HR=1.48: 95% CI:0.92-2.40). Post-hoc scatter graph showed a strong linear relationship (r 0.998), suggesting hospitals with higher rates of aortic root replacement achieve lower rates of reoperation for aortic root abscess patients compared with patch reconstruction. CONCLUSIONS: The presence of an aortic root abscess in aortic valve endocarditis is associated with elevated early and late mortality despite modern standards of care. Additionally, aortic root replacement should be considered to have a favourable postoperative profile for use in this context.

Inhalable ceftazidime-roflumilast powder targeting infection and inflammation: Influence of incorporating roflumilast into ceftazidime-leucine co-amorphous formulation.

Co-amorphization of a single drug with amino acid is a technique to improve aerosolization of inhalable spray-dried formulation for inhalation therapy. However, the incorporation of a second drug molecule into drug-amino acid co-amorphous particles to prepare combination formulations has not been explored. Here, we prepared combination powders using two model drugs, ceftazidime and roflumilast, which when concurrently used can potentially improve therapeutic outcome in non-cystic fibrosis bronchiectasis by counteracting both infection and inflammation. The study was performed using a two-step approach. The first step involved the identification of an amino acid and its concentration (% w/w) for the best aerosolization enhancement of ceftazidime by varying the ratios of leucine and tryptophan in combination (0-25 % w/w). In the second step, roflumilast (5-20 % w/w) was incorporated into the formulation containing the selected concentration of the amino acid to understand the impact of introducing a second drug into ceftazidime-amino acid(s) co-amorphous particles. In total, 10 formulations were prepared and characterized in terms of solid-state and aerosol performance. Leucine introduced surface asperity which correlated well with improved aerosolization of the particles. The best fine particle fraction (FPF) (75 %) was achieved with 25 % leucine; hence, leucine was selected as the ideal amino acid at the given concentration to understand the impact of roflumilast inclusion on ceftazidime-leucine system. The ceftazidime-roflumilast powder retained their anti-bacterial and anti-inflammatory properties following formulation. However, inclusion of roflumilast at 5 % dramatically decreased the FPF to 55 % and higher roflumilast concentration did not have much effect on FPF. The decrease in FPF ascribed to the change in particle surface as roflumilast was found to decrease surface asperity. In addition, leucine crystallized with inclusion of roflumilast. This study indicates that inclusion of a second drug into drug-amino acid amorphous matrix particles can affect its solid-state dynamics and aerosol performance; hence, such parameters should be cautiously considered while undertaking similar endeavors of preparing combination formulations.

Females have an increased risk of short-term mortality after cardiac surgery compared to males: Insights from a national database.

OBJECTIVES: Female sex is considered a risk factor for mortality and morbidity following cardiac surgery. This study is the first to review the UK adult cardiac surgery national database to compare outcomes following surgical coronary revascularisation and valvular procedures between females and males. METHODS: Using data from National Adult Cardiac Surgery Audit, we identified all elective and urgent, isolated coronary artery by-pass grafting (CABG), aortic valve replacement (AVR) and mitral valve replacement/repair (MVR) procedures from 2010 to 2018. We compared baseline data, operative data and outcomes of mortality, stroke, renal failure, deep sternal wound infection, return to theater for bleeding, and length of hospital stay. Multivariable mixed-effect logistical/linear regression models were used to assess relationships between sex and outcomes, adjusting for baseline characteristics. RESULTS: Females, compared to males, had greater odds of experiencing 30-day mortality (CABG odd ratio [OR] 1.76, confidence interval [CI] 1.47-2.09, p < .001; AVR OR 1.59, CI 1.27-1.99, p < .001; MVR OR 1.37, CI 1.09-1.71, p = .006). After CABG, females also had higher rates of postoperative dialysis (OR 1.31, CI 1.12-1.52, p < .001), deep sternal wound infections (OR 1.43, CI 1.11-1.83, p = .005) and longer length of hospital stay (ß 1.2, CI 1.0-1.4, p < .001) compared to males. Female sex was protective against returning to theater for postoperative bleeding following CABG (OR 0.76, CI 0.65-0.87, p < .001) and AVR (OR 0.72, CI 0.61-0.84, p < .001). CONCLUSION: Females in the United Kingdom have an increased risk of short-term mortality after cardiac surgery compared to males. This highlights the need to focus on the understanding of the causes behind these disparities and implementation of strategies to improve outcomes in females.