Blood lactate predicts mortality after surgical repair of type A acute aortic dissection.

BACKGROUND: Ischemia and malperfusion are strong predictors of poor postoperative outcomes in type A acute aortic dissection (TAAAD). Serum lactate is an accurate surrogate point-of-care marker of malperfusion. The aim of this study is to investigate the correlation between lactate, in-hospital outcomes, and 1-year survival following TAAAD repair. METHODS: One hundred and thirty-two patients underwent operative repair of TAAAD over a 4-year period at our institution 128 patients had serum lactate measurements at three stages peri-operatively-preoperatively, at the end of cardiopulmonary bypass (post-CPB) and 6 h postintensive care unit (ICU) admission. The primary outcomes were in-hospital mortality and 1-year survival. The secondary outcomes were the incidences of in-hospital morbidities. RESULTS: Patients were divided into two groups: 88 (68.8%) with normal lactate and 40 (31.2%) with elevated lactate (>2.2 mmol/L). Lactate measured preoperatively (odds ratio 1.52, 95% confidence interval 1.17-2.07, p < .01), post-CPB (1.34, 1.14-1.64, p < .01) and 6 h post-ICU admission (1.29, 1.08-1.55, p < .01) was an independent predictor of in-hospital mortality. Following adjustment for the Penn Classification, lactate continued to have a significant correlation with in-hospital mortality at all three timepoints. There was a higher incidence of complications in the elevated lactate group and especially hemofiltration (20% vs. 9.1%, p = .08). 1-year survival was similar in both groups (p = .23). CONCLUSIONS: There is a direct correlation between elevated serum lactate and postoperative mortality after TAAAD repair, which is independent of the Penn Classification status on admission.

Surgical outcomes of post-infarct ventricular septal defect repair: Insights from the UK national adult cardiac surgery audit database.

OBJECTIVES: Ventricular septal defect (VSD) is becoming a progressively less frequent mechanical complication of myocardial infarction (MI). However, this event is still associated with high operative mortality. We aimed to describe the trends and the risk factors associated with surgical VSD repair outcomes and to provide a clinical benchmark for percutaneous VSD closure strategies. METHODS: Using the UK National Adult Cardiac Surgery Audit database, we identified 1010 patients undergoing surgical VSD repair from 1996 to 2018. The primary outcome was operative mortality. Mixed-model, multivariable logistic regression was used to identify the risk factors associated with operative mortality taking into account the variation related to the centre, the surgeon and the year of the operation. RESULTS: Both the number of surgical VSD repair and the mortality rate did not change significantly over the 23-year timeframe. Operative mortality was 38.9% overall and was higher when patients were operated within the first 6 h (75%) or the first 24 h (61.3%) from the index MI. Risk factors associated with higher odds of mortality were early surgery, older age, cardiogenic shock, renal failure, previous percutaneous coronary intervention and urgent/emergent operations. Moreover, the mortality rate was similar among patients undergoing isolated VSD repair and VSD repaired combined with surgical coronary revascularization alone or with concomitant mitral valve procedures. CONCLUSIONS: Post MI VSD remains a dreaded mechanical complication characterized by high surgical operative mortality. A delayed operation, whenever possible, appears to be the most beneficial strategy to reduce mortality.

Surgical outcomes and optimal approach to treatment of aortic valve endocarditis with aortic root abscess.

OBJECTIVES: To evaluate the impact of aortic root abscess (ARA) on the postoperative outcomes of surgically managed infective endocarditis (IE) and to inform optimal surgical approach. METHODS: Between 2009 and 2020, 143 consecutive patients who underwent surgical management for aortic-valve IE were included in a retrospective cohort study. Multivariable and propensity-weighted analyses were used to adjust for demographic imbalances between those without (n = 93; NARA) and with an ARA (n = 50). Additionally, empirical subgroup analysis appraised the two most used surgical techniques; patch reconstruction (PR) and aortic root replacement (ARR). RESULTS: Demographic characteristics were similar between ARA and NARA except for logistic EuroSCORE, previous valve surgery, and multivalvular infection. In-hospital mortality was 8% and 12% in NARA and ARA, respectively (p = .38), with mortality rates consistently nonsignificantly higher in ARA across all time periods. The overall reoperation rate was also higher in ARA (27% vs. 14%; p = .09) and ARA was shown to be associated with late reoperation (odds ratio [OR] = 2.74; 95% confidence interval [CI] = 1.18-6.36). Patients treated with an ARR showed a 16% increase in late mortality when compared with PR (40% vs. 24%; p = .27) and a 17% lower reoperation rate (14% vs. 31%; p = .24). Propensity-weighted analysis identified ARR as a significant protective factor for reoperation (hazard ratio = 0.05; 95% CI = 0.01-0.34). CONCLUSIONS: The presence of an ARA in aortic valve endocarditis was not associated with significantly higher early and late mortality but is linked with a higher reoperation rate at our institution. ARR in ARA is protective from reoperation so should be considered best practice in this setting.

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.

Determinants of outcomes following surgery for type A acute aortic dissection: the UK National Adult Cardiac Surgical Audit.

AIMS: Operability of type A acute aortic dissections (TAAAD) is currently based on non-standardized decision-making process, and it lacks a disease-specific risk evaluation model that can predict mortality. We investigated patient, intraoperative data, surgeon, and centre-related variables for patients who underwent TAAAD in the UK. METHODS AND RESULTS: We identified 4203 patients undergoing TAAAD surgery in the UK (2009-18), who were enrolled into the UK National Adult Cardiac Surgical Audit dataset. The primary outcome was operative mortality. A multivariable logistic regression analysis was performed with fast backward elimination of variables and the bootstrap-based optimism-correction was adopted to assess model performance. Variation related to hospital or surgeon effects were quantified by a generalized mixed linear model and risk-adjusted funnel plots by displaying the individual standardized mortality ratio against expected deaths. Final variables retained in the model were: age [odds ratio (OR) 1.02, 95% confidence interval (CI) 1.02-1.03; P < 0.001]; malperfusion (OR 1.79, 95% CI 1.51-2.12; P < 0.001); left ventricular ejection fraction (moderate: OR 1.40, 95% CI 1.14-1.71; P = 0.001; poor: OR 2.83, 95% CI 1.90-4.21; P < 0.001); previous cardiac surgery (OR 2.29, 95% CI 1.71-3.07; P < 0.001); preoperative mechanical ventilation (OR 2.76, 95% CI 2.00-3.80; P < 0.001); preoperative resuscitation (OR 3.36, 95% CI 1.14-9.87; P = 0.028); and concomitant coronary artery bypass grafting (OR 2.29, 95% CI 1.86-2.83; P < 0.001). We found a significant inverse relationship between surgeons but not centre annual volume with outcomes. CONCLUSIONS: Patient characteristics, intraoperative factors, cardiac centre, and high-volume surgeons are strong determinants of outcomes following TAAAD surgery. These findings may help refining clinical decision-making, supporting patient counselling and be used by policy makers for quality assurance and service provision improvement.

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.

Determinants of QRS duration in patients with tetralogy of Fallot after pulmonary valve replacement.

BACKGROUND: Following the repair of TOF patients may be left with pulmonary regurgitation and a dilated right ventricle (RV), which in turn can lead to ventricular arrhythmias and sudden death. A prolonged QRS is a predictor of ventricular arrhythmias. However, whether subsequent pulmonary valve replacement (PVR) can reverse QRS-prolongation is controversial. We hypothesized that changes in QRS duration following PVR are determined by preoperative QRS-duration and RV volumes METHODS: A retrospective single-center cohort study was conducted on 142 post-TOF repair patients (mean age 25 ± 13 years) who underwent PVR between 1995 and 2019. Information on QRS duration and RV volumes measured by cardiac MRI (available in 83 patients) were collected. A linear mixed model was used to investigate the association between the preoperative QRS duration and RV volumes and the postoperative QRS duration. RESULTS: The QRS-duration following PVR continued to increase in all subjects with a prolonged preoperative QRS-duration(>160 ms, rate of increase of 0.87 msec ± 0.33 per year; p = .01), markedly raised RV end-diastolic volume (RVEDV; ≥166 ml/m2, rate of increase of 2.0 msec ± 0.37 per year; p < .01) or RV end-systolic volume (RVESV; ≥89 ml/m2 , rate of increase of 1.25 msec ± 0.43 per year; p = .01). In contrast, in patients with preoperative QRS-duration <160 msec (p = .16), RVEDV <166 ml/m2 (p = .14), or RVESV < 89 ml/m2 (p = .37), the QRS-duration did not change significantly when compared to preoperative values. CONCLUSIONS: In subjects with shorter QRS and smaller RV volumes, QRS duration did not show further prolongation following PVR. While markedly prolonged QRS and increased RV volumes were associated with a small but constant increase in QRS duration despite PVR.

Carrier-free combination dry powder inhaler formulation of ethionamide and moxifloxacin for treating drug-resistant tuberculosis.

This study aimed to develop a combination dry powder formulation of ethionamide and moxifloxacin HCl as this combination is synergistic against drug-resistant Mycobacterium tuberculosis (Mtb). L-leucine (20% w/w) was added in the formulations to maximize the process yield. Moxifloxacin HCl and/or ethionamide powders with/without L-leucine were produced using a Buchi Mini Spray-dryer. A next generation impactor was used to determine the in vitro aerosolization efficiency. The powders were also characterized for other physicochemical properties and cytotoxicity. All the spray-dried powders were within the aerodynamic size range of <5.0 µm except ethionamide-only powder (6.0 µm). The combination powders with L-leucine aerosolized better (% fine particle fraction (FPF): 61.3 and 61.1 for ethionamide and moxifloxacin, respectively) than ethionamide-only (%FPF: 9.0) and moxifloxacin-only (%FPF: 30.8) powders. The combination powder particles were collapsed with wrinkled surfaces whereas moxifloxacin-only powders were spherical and smooth and ethionamide-only powders were angular-shaped flakes. The combination powders had low water content (<2.0%). All the powders were physically stable at 15% RH and 25 ± 2 °C during 1-month storage and tolerated by bronchial epithelial cell-lines up to 100 µg/ml. The improved aerosolization of the combination formulation may be helpful for the effective treatment of drug-resistant tuberculosis. Further studies are required to understand the mechanisms for improved aerosolization and test the synergistic activity of the combination powder.

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.

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.

Performance Drift in Machine Learning Models for Cardiac Surgery Risk Prediction: Retrospective Analysis.

Background: The Society of Thoracic Surgeons and European System for Cardiac Operative Risk Evaluation (EuroSCORE) II risk scores are the most commonly used risk prediction models for in-hospital mortality after adult cardiac surgery. However, they are prone to miscalibration over time and poor generalization across data sets; thus, their use remains controversial. Despite increased interest, a gap in understanding the effect of data set drift on the performance of machine learning (ML) over time remains a barrier to its wider use in clinical practice. Data set drift occurs when an ML system underperforms because of a mismatch between the data it was developed from and the data on which it is deployed. Objective: In this study, we analyzed the extent of performance drift using models built on a large UK cardiac surgery database. The objectives were to (1) rank and assess the extent of performance drift in cardiac surgery risk ML models over time and (2) investigate any potential influence of data set drift and variable importance drift on performance drift. Methods: We conducted a retrospective analysis of prospectively, routinely gathered data on adult patients undergoing cardiac surgery in the United Kingdom between 2012 and 2019. We temporally split the data 70:30 into a training and validation set and a holdout set. Five novel ML mortality prediction models were developed and assessed, along with EuroSCORE II, for relationships between and within variable importance drift, performance drift, and actual data set drift. Performance was assessed using a consensus metric. Results: A total of 227,087 adults underwent cardiac surgery during the study period, with a mortality rate of 2.76% (n=6258). There was strong evidence of a decrease in overall performance across all models (P<.0001). Extreme gradient boosting (clinical effectiveness metric [CEM] 0.728, 95% CI 0.728-0.729) and random forest (CEM 0.727, 95% CI 0.727-0.728) were the overall best-performing models, both temporally and nontemporally. EuroSCORE II performed the worst across all comparisons. Sharp changes in variable importance and data set drift from October to December 2017, from June to July 2018, and from December 2018 to February 2019 mirrored the effects of performance decrease across models. Conclusions: All models show a decrease in at least 3 of the 5 individual metrics. CEM and variable importance drift detection demonstrate the limitation of logistic regression methods used for cardiac surgery risk prediction and the effects of data set drift. Future work will be required to determine the interplay between ML models and whether ensemble models could improve on their respective performance advantages.

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.

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 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.

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.

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.

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.

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.

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.