Search

Background: Mycobacterium abscessus is an emerging pathogen causing severe pulmonary infections, particularly in individuals with underlying conditions, such as cystic fibrosis or chronic obstructive pulmonary disease. Macrolides, such as clarithromycin (CLR) or azithromycin (AZM), represent the cornerstone of antibiotherapy against the M. abscessus species. However, prolonged exposure to these macrolides can induce of Erm(41)-mediated resistance, limiting their spectrum of activity and leading to therapeutic failure. Therefore, inhibiting Erm(41) could thwart this resistance mechanism to maintain macrolide susceptibility, thus increasing the rate of treatment success. In our previous study, the Erm(41) methyltransferase was identified as a possible target enzyme of Cyclipostins and Cyclophostin compounds (CyC)., Methods: Herein, we exploited this feature to evaluate the in vitro activity of CLR and AZM in combination with different CyC via the checkerboard assay on macrolide-susceptible and induced macrolide-resistant M. abscessus strains selected in vitro following exposure CLR and AZM., Results: Our results emphasize the use of the CyC to prevent/overcome Erm(41)‑induced resistance and to restore macrolide susceptibility., Conclusion: This work should expand our therapeutic arsenal in the fight against a antibioticresistant mycobacterial species and could provide the opportunity to revisit the therapeutic regimen for combating M. abscessus pulmonary infections in patients, and particularly in erm(41)-positive strains., Competing Interests: Declarations. Ethics approval and consent to participate: Not applicable. Consent for publication and references: Not applicable. Competing interests: The authors declare that they have no competing interests. Not applicable., (© 2024. The Author(s).)

Mycobacterium abscessus causes severe lung infections in cystic fibrosis patients and exhibits smooth (S) or rough (R) morphotypes. Disruption of glycopeptidolipid (GPL) production results in the S-to-R transition but the underlying molecular mechanisms of this transition remain incompletely understood. Herein, we characterized MAB_4111c in relation to GPL synthesis and investigated the effects of MAB_4111c deletion in M. abscessus pathogenicity. An enzymatic assay indicated that MAB_4111c, also designated Tle for Talose epimerase, is converting dTDP-L-Rhamnose into dTDP-6-deoxy-L-Talose. A tle deletion mutant was constructed in the S variant of M. abscessus and relative areas of Rhamnose and 6-deoxy-Talose and their methylated forms expressed as ratios of total monosaccharides, showed an altered GPL profile lacking 6-deoxy-Talose. Thus, Tle provides dTDP-6-deoxy-L-Talose, subsequently used by the glycosyltransferase Gtf1 to transfer 6-deoxy-Talose to the GPL backbone. Strikingly, the tle mutant exhibited an R morphotype, showed impaired sliding motility and biofilm formation, and these phenotypes were rescued upon functional complementation. Moreover, deletion of tle in M. abscessus results in increased pathogenicity and killing in zebrafish embryos. Together, our results underscore the importance of the dTDP-L-Rhamnose 4-epimerase activity in GPL biosynthesis and in influencing M. abscessus virulence., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interests with the contents of this article., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Aortic valve disease results in left ventricular (LV) dilation and/or hypertrophy. Valve intervention may improve, but not normalize flow dynamics. We hypothesized that LV remodeling would be more favorable following the Ross procedure versus mechanical aortic valve replacement (mAVR). Methods: Patients who were 18 to 50 years of age and underwent Ross or mAVR from 2000 to 2016 at a single institution were retrospectively reviewed. Propensity score matching was performed and yielded 27 well-matched pairs. Demographics and echocardiographic variables of LV morphology and wall thickness were collected. Those with > mild residual valve disease were excluded. Primary endpoints included LV morphology. T test and Fisher exact test analysis were used for statistical comparison. Results: Average age at operation (Ross 35.3 ± 10.2 vs mAVR 37.3 ± 8.9 years) did not differ. Indication for operation was similar between groups. Preoperative echocardiographic variables did not differ. At average follow-up duration (Ross 7.9 ± 2.4 vs mAVR 7.3 ± 2.4 years), wall thickness was significantly smaller for Ross compared with mAVR ( P  = .00715). Only 4/27 (15%) of mAVR patients had normalized LV parameters compared with 16/27 (59%) of Ross patients ( P  = .000813). Residual hypertrophy was the most common long-term abnormality for mAVR. Conclusion: Following aortic valve replacement with the Ross procedure or mechanical aortic valve prosthesis, the Ross conferred more favorable LV remodeling compared with mAVR. Future directions include analyzing longer follow-up to determine if patterns persist and the impact on cardiac morbidity and mortality., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Given improved contemporary survival of adults with congenital heart disease (ACHD), we aimed to evaluate trends in ACHD surgery and outcomes at a single center over a 27-year period., Methods: Surgical databases were retrospectively queried for patients >18 years old who underwent ACHD surgery between January 1, 1994, and December 31, 2020. A total of 2,195 included patients underwent 2,425 cardiac surgical procedures within the specified time frame. Patients were grouped by era: I, 1994-2000; 2, 2001-2010; and 3, 2011-2020. Trends in primary cardiac diagnosis and surgical management were evaluated., Results: The median age increased across the eras. The most common primary cardiac diagnoses (n = 2,425) overall were left ventricular outflow tract anomalies (n = 2,019, 83%), atrial septal defect (n = 407, 17%), right ventricular outflow tract anomalies (n = 360, 15%), and ventricular septal defect (n = 110, 4.5%). The most commonly observed procedures overall were operations on the left ventricular outflow tract (n = 1,633, 67%), aorta (n = 675, 28%), coronary arteries (n = 449, 19%), right ventricular outflow tract (n = 323, 13%), and atrial septal defect (n = 264, 11%). Major complications occurred in 10% of cases, and 58 patients died within 30 days of their operation yielding an operative mortality of 2.4%., Conclusion: To our knowledge, this is the largest single center report on surgery for adults with congenital heart disease. Surgery for ACHD has been performed at our center with relatively low morbidity and mortality over the last few decades., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Extubation failure and its associated complications are not uncommon after pediatric cardiac surgery, especially in neonates and young infants. We aimed to identify the frequency, etiologies, and clinical characteristics associated with extubation failure after cardiac surgery in neonates and young infants. Methods: We conducted a single center prospective observational study of patients ≤180 days undergoing cardiac surgery between June 2022 and May 2023 with at least one extubation attempt. Patients who failed extubation, defined as reintubation within 72 h of first extubation attempt, were compared with patients extubated successfully using χ 2 , Fisher exact, or Wilcoxon rank-sum tests as appropriate. Results: We prospectively enrolled 132 patients who met inclusion criteria, of which 11 (8.3%) failed extubation. Median time to reintubation was 25.5 h (range 0.4-55.8). Extubation failures occurring within 12 h (n = 4) were attributed to upper airway obstruction or apnea, whereas extubation failures occurring between 12 and 72 h (n = 7) were more likely to be due to intrinsic lung disease or cardiac dysfunction. Underlying genetic anomalies, greater weight relative to baseline at extubation, or receiving positive end expiratory pressure (PEEP) > 5 cmH 2 O at extubation were significantly associated with extubation failure. Conclusions: In this study of neonates and young infants recovering from cardiac surgery, etiologies of early versus later extubation failure involved different pathophysiology. We also identified weight relative to baseline and PEEP at extubation as possible modifiable targets for future investigations of extubation failure in this patient population., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Mycobacterium abscessus belongs to the largest group of mycobacteria, the rapid-growing saprophytic mycobacteria, and is one of the most difficult-to-treat opportunistic pathogen. Several features pertain to the high adaptability of M. abscessus to the host. These include the capacity to survive and persist within amoebae, to transition from a smooth to a rough morphotype that occurs during the course of the disease and to express of a wide array of virulence factors., Objectives: The main objective of this narrative review consists to report major assets of M. abscessus that contribute to the virulence of these rapid-growing saprophytic mycobacteria. Strikingly, many of these determinants, whether they are from a mycobacterial origin or acquired by horizontal gene transfer, are known virulence factors found in slow-growing and strict pathogens for humans and animals., Sources: In the light of recent published work in the field we attempted to highlight major features characterizing M. abscessus pathogenicity and to explain why this led to the emergence of this mycobacterial species in patients with cystic fibrosis., Content: M. abscessus genome plasticity, the smooth-to-rough transition, and the expression of a panel of enzymes associated with virulence in other bacteria are key players in M. abscessus virulence. In addition, the very large repertoire of lipid transporters, known as mycobacterial membrane protein large and small (MmpL and MmpS respectively), deeply influences the pathogenicity of M. abscessus, as exemplified here for some of them., Implications: All these traits largely contribute to make M. abscessus a unique mycobacterium regarding to its pathophysiological processes, ranging from the early colonization steps to the establishment of severe and chronic pulmonary diseases., (Copyright © 2023 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Lsr2, a small protein mainly found in actinobacteria, plays a crucial role in the virulence and adaptation of mycobacteria to environmental conditions. As a member of the nucleoid-associated protein (NAPs) superfamily, Lsr2 influences DNA organization by facilitating the formation of chromosomal loops in vitro and, therefore, may be a major player in the three-dimensional folding of the genome. Additionally, Lsr2 also acts as a transcription factor, regulating the expression of numerous genes responsible for coordinating a myriad of cellular and molecular processes essential for the actinobacteria. Similar to the H-NS protein, its ortholog in enterobacteria, its role in transcriptional repression likely relies on oligomerization, rigidifying, and bridging of DNA, thereby disrupting RNA polymerase recruitment as well as the elongation of RNA transcripts., (© 2024 médecine/sciences – Inserm.)

The aim of this study is to analyze the relationship between QRS duration after pulmonary valve replacement (PVR) and ventricular arrhythmias (VA) in patients with repaired tetralogy of Fallot (ToF). ToF patients may face complications such as heart failure and VA after primary repair, often mitigated by PVR. Prior studies have shown a decrease in QRS duration and right ventricular (RV) size following PVR. It remains unclear whether a lack of QRS duration reduction identifies patients at risk of VA. We retrospectively identified adult patients with repaired ToF who underwent surgical or transcatheter PVR. EKG data (pre-PVR, 30 days to 1-year post-PVR, and closest to CMR) was collected. The primary endpoint was sustained ventricular tachycardia (VT), ICD shock for sustained VT, or inducible VT on EP study. 85 patients were included (median follow-up 3.6 years; median age 34 years; 51% females). The primary outcome was noted in 8 patients. Mean QRS duration decreased by 5 ms following PVR (p = 0.0001). Increased age at PVR, QRS ≥ 180 ms post-PVR, no reduction in QRS after PVR, and a history of VT were associated with higher risk of the primary endpoint. The change in QRS was linearly correlated with the change in RVEDVi (R = 0.66). Adults with repaired ToF experience a reduction in QRS duration post-PVR that correlates with the change of the RV size. Patients with QRS ≥ 180 ms post-PVR, no reduction in QRS, increased age at repair, and a history of VT are at risk for recurrent VT and warrant closer monitoring/ICD consideration., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: We aimed to identify factors independently associated with the need for inotropic support for low cardiac output or haemodynamic instability after pulmonary artery banding surgery for CHD., Methods: We performed a retrospective chart review of all neonates and infants who underwent pulmonary banding between January 2016 and June 2019 at our institution. Bivariate and multivariable analyses were performed to identify factors independently associated with the use of post-operative inotropic support, defined as the initiation of inotropic infusion(s) for depressed myocardial function, hypotension, or compromised perfusion within 24 hours of pulmonary artery banding., Results: We reviewed 61 patients. Median age at surgery was 10 days (25%,75%:7,30). Cardiac anatomy was biventricular in 38 patients (62%), hypoplastic right ventricle in 14 patients (23%), and hypoplastic left ventricle in 9 patients (15%). Inotropic support was implemented in 30 patients (49%). Baseline characteristics of patients who received inotropic support, including ventricular anatomy and pre-operative ventricular function, were not statistically different from the rest of the cohort. Patients who received inotropic support, however, were exposed to larger cumulative doses of ketamine intraoperatively - median 4.0 mg/kg (25%,75%:2.8,5.9) versus 1.8 mg/kg (25%,75%:0.9,4.5), p < 0.001. In a multivariable model, cumulative ketamine dose greater than 2.5mg/kg was associated with post-operative inotropic support (odds ratio 5.5; 95% confidence interval: 1.7,17.8), independent of total surgery time., Conclusions: Inotropic support was administered in approximately half of patients who underwent pulmonary artery banding and more commonly occurred in patients who received higher cumulative doses of ketamine intraoperatively, independent of the duration of surgery.

Mycobacterium abscessus, an intracellular nontuberculous mycobacterium, is considered the most pathogenic species among the group of rapidly growing mycobacteria. The resistance of M. abscessus to the host innate response contributes to its pathogenicity in addition to several virulence factors. We have recently shown in Drosophila that antimicrobial peptides (AMPs), whose production is induced by M. abscessus, are unable to control mycobacterial infection. This could be due to their inability to kill mycobacteria and/or the hidden location of the pathogen in phagocytic cells. Here, we demonstrate that the rapid internalization of M. abscessus by Drosophila macrophages allows it to escape the AMP-mediated humoral response. By depleting phagocytes in AMP-deficient flies, we found that several AMPs were required for the control of extracellular M. abscessus. This was confirmed in the Tep4 opsonin-deficient flies, which we show can better control M. abscessus growth and have increased survival through overproduction of some AMPs, including Defensin. Furthermore, Defensin alone was sufficient to kill extracellular M. abscessus both in vitro and in vivo and control its infection. Collectively, our data support that Tep4-mediated opsonization of M. abscessus allows its escape and resistance toward the Defensin bactericidal action in Drosophila . IMPORTANCE Mycobacterium abscessus, an opportunistic pathogen in cystic fibrosis patients, is the most pathogenic species among the fast-growing mycobacteria. How M. abscessus resists the host innate response before establishing an infection remains unclear. Using Drosophila , we have recently demonstrated that M. abscessus resists the host innate response by surviving the cytotoxic lysis of the infected phagocytes and the induced antimicrobial peptides (AMPs), including Defensin. In this work, we demonstrate that M. abscessus resists the latter response by being rapidly internalized by Drosophila phagocytes. Indeed, by combining in vivo and in vitro approaches, we show that Defensin is able to control extracellular M. abscessus infection through a direct bactericidal action. In conclusion, we report that M. abscessus escapes the host AMP-mediated humoral response by taking advantage of its internalization by the phagocytes., Competing Interests: The authors declare no conflict of interest.

Cutibacterium avidum is an emerging causative agent of orthopedic device-related infections (ODRIs). There are no guidelines for the antimicrobial treatment of C. avidum ODRI, but oral rifampin is frequently used in combination with a fluoroquinolone following intravenous antibiotics. We describe the in vivo emergence of combined resistance to rifampin and levofloxacin in a C. avidum strain isolated from a patient with early-onset ODRI treated with debridement, antibiotic treatment, and implant retention (DAIR) using rifampin combined with levofloxacin as the oral treatment. Whole-genome sequencing of C. avidum isolates before and after antibiotic exposure confirmed strain identity and identified new mutations in rpoB and gyrA , leading to amino acid substitutions previously reported to be associated with resistance to rifampin (S446P) and fluoroquinolones (S101L), respectively, in other microbial agents, in the posttherapy isolate. Aside from the molecular insights reported here, this study highlights potential limitations of the combination of oral rifampin and levofloxacin in patients undergoing a DAIR procedure for C. avidum ODRI and the potential need to evaluate specific optimal therapy for emerging ODRI pathogens. IMPORTANCE In this study, we report for the first time the in vivo emergence of dual resistance to levofloxacin and rifampin in C. avidum isolated from a patient who received both antibiotics orally in the setting of a salvage debridement and implant retention of an ODRI. Aside from the molecular insights reported here, this study highlights potential limitations of the combination of oral rifampin and levofloxacin in patients undergoing these surgical procedures and the potential need to evaluate specific optimal therapy for emerging ODRI pathogens., Competing Interests: The authors declare no conflict of interest.

Mycobacterium abscessus is the most pathogenic species among the predominantly saprophytic fast-growing mycobacteria. This opportunistic human pathogen causes severe infections that are difficult to eradicate. Its ability to survive within the host was described mainly with the rough (R) form of M. abscessus, which is lethal in several animal models. This R form is not present at the very beginning of the disease but appears during the progression and the exacerbation of the mycobacterial infection, by transition from a smooth (S) form. However, we do not know how the S form of M. abscessus colonizes and infects the host to then multiply and cause the disease. In this work, we were able to show the hypersensitivity of fruit flies, Drosophila melanogaster, to intrathoracic infections by the S and R forms of M. abscessus. This allowed us to unravel how the S form resists the innate immune response developed by the fly, both the antimicrobial peptides- and cellular-dependent immune responses. We demonstrate that intracellular M. abscessus was not killed within the infected phagocytic cells, by resisting lysis and caspase-dependent apoptotic cell death of Drosophila infected phagocytes. In mice, in a similar manner, intra-macrophage M. abscessus was not killed when M. abscessus-infected macrophages were lysed by autologous natural killer cells. These results demonstrate the propensity of the S form of M. abscessus to resist the host's innate responses to colonize and multiply within the host., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Touré et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Aortic dilation occurs in patients with repaired tetralogy of Fallot (TOF), but the rate of growth is incompletely characterized. The aim of this study was to assess the rates of growth of the aortic root and ascending aorta in a cohort of pediatric and adult patients with sequential magnetic resonance angiography Magnetic Resonance Imaging (MRI) data. Using serial MRI data from pediatric and adult patients with repaired TOF, we performed a retrospective analysis of the rates of growth and associations with growth of the aortic root and ascending aorta. Patients with pulmonary atresia or absent pulmonary valve were excluded. Between years 2005 to 2021, a total of 99 patients were enrolled. A follow-up MRI was performed an average of 5.9 ± 3.7 years from the initial study. For the cohort aged ≥16 years, the mean rate of change in diameter was 0.2 ± 0.5 mm/year at the ascending aorta and 0.2 ± 0.6 mm/year at the sinus of Valsalva. For the entire cohort, the mean change in cross-sectional area indexed to height at the ascending aorta was 7 ± 12 mm 2 /m/year and at the sinus of Valsalva was 10 ± 16 mm 2 /m/year. Younger age was associated with higher rates of growth of the sinus of Valsalva while the use of β blockers or angiotensin-converting enzyme inhibitors was associated with a slower rate of growth. There were no cases of aortic dissection in this cohort. We conclude that serial MRI demonstrates a slow rate of growth of the aorta in the TOF., Competing Interests: Disclosures The authors have no conflicts of interest to declare., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Osteomyelitis-complicating pressure ulcers are frequent among patients with spinal cord injuries (SCIs), and the optimal management is unknown. In our referral center, the current management is debridement and flap coverage surgeries, followed by a short antibiotic treatment. We aimed to evaluate patients' outcomes a year after surgery., Methods: We performed a quasi-experimental retrospective before/after study on SCI patients with presumed osteomyelitis associated with perineal pressure ulcers. We included all patients who underwent surgery with debridement and flap covering, followed by effective antibiotic treatment, between May 1, 2016, and October 30, 2020. The effective antimicrobial treatment duration included the 10 days leading up to January 1, 2018 (before period), and the 5 to 7 days after (after period). We also compared the efficacy of 5-7-day vs 10-day antibiotic treatment and performed uni- and multivariable analyses to identify factors associated with failure., Results: Overall, 415 patients were included (77.6% male patients; mean age ± SD, 53.0 ± 14.4 years). Multidrug-resistant organisms (MDROs) were involved in 20.7% of cases. Favorable outcomes were recorded in 69.2% of cases: 117/179 (65.3%) in the 10-day treatment group vs 169/287 (71.9%) in the 5-7-day treatment group ( P = .153). The only factor associated with failure in the multivariate analysis was a positive culture from suction drainage (odds ratio, 1.622; 95% CI, 1.005-2.617; P = .046). Effective treatment duration >7 days and intraoperative samples negative for MDROs were not associated with better outcomes ( P = .153 and P = .241, respectively)., Conclusions: A treatment strategy combining surgical debridement and flap covering, followed by 5 to 7 days of effective antibiotic treatment seems safe., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Nutritional management and home monitoring programs (HMPs) may be beneficial for improving interstage morbidity and mortality following stage I Norwood palliation (S1P) for hypoplastic left heart syndrome (HLHS). We recognized an increasing trend towards early feeding gastrostomy tube (GT) placement prior to discharge in our institution, and we aimed to investigate the effect of HMPs and GTs on interstage mortality and growth parameters. Single-institutional review at a tertiary referral center between 2008 and 2018. Individual patient charts were reviewed in the electronic medical record. Those listed for transplant or hybrid procedures were excluded. Baseline demographics, operative details, and interstage outcomes were analyzed in GT and non-GT patients (nGT). Our HMP was instituted in 2009, and patients were analyzed by era: I (early, 2008-2012), II (intermediate, 2013-2016), and III (recent, 2017-2018). 79 patients were included in the study: 29 nGTs and 50 GTs. GTs had higher number of preoperative risk factors more S1P complications, longer ventilation times, longer lengths of stay, and shorter times to readmission. There were no differences in interstage mortality or overall mortality between groups. There was one readmission for a GT-related issue with no periprocedural complications in the group. Weight gain doubled after GT placement in the interstage period while waiting periods for placement decreased across Eras. HMPs and early GTs, especially for patients with high-risk features, provide a dependable mode of nutritional support to optimize somatic growth following S1P., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Mycobacterial infections, both tuberculosis and nontuberculous, are more common in patients with haematological malignancies and haematopoietic stem cell transplant recipients than in the general population-although these infections remain rare. Mycobacterial infections pose both diagnostic and therapeutic challenges. The management of mycobacterial infections is particularly complicated for patients in haematology because of the many drug-drug interactions between antimycobacterial drugs and haematological and immunosuppressive treatments. The management of mycobacterial infections must also consider the effect of delaying haematological management. We surveyed the management practices for latent tuberculosis infection (LTBI) in haematology centres in Europe. We then conducted a meticulous review of the literature on the epidemiology, diagnosis, and management of LTBI, tuberculosis, and nontuberculous mycobacterial infections among patients in haematology, and we formulated clinical guidelines according to standardised European Conference on Infections in Leukaemia (ECIL) methods. In this Review, we summarise the available literature and the recommendations of ECIL 8 for managing mycobacterial infections in patients with haematological malignancies., Competing Interests: Declaration of interests CL reports funding from German Center of Infection Research (DZIF). DG reports consultancy and lectures for Amgen, Biogen, Biomerieux, Cellgene, Diasorin, Eli Lilly, Janssen, PBD Biotech, Qiagen, Quidel. DG reports funding from the Italian Ministry of Health (Ricerca Corrente Linea 4). All other authors declare no competing interests. The eighth ECIL meeting (Sept 19–21, 2019) was supported by unrestricted educational grants of Basilea Pharmaceuticals, Cidara Therapeutics, F2G, Gilead Sciences, Merck Sharp and Dohme, and Takeda. Basilea Pharmaceuticals, Cidara Therapeutics, F2G, Gilead Sciences, Merck Sharp and Dohme, and Takeda had no role in the selection of experts and the design of the guideline, in the collection, analysis, and interpretation of the data at any time including the consensus conference, or in the writing and editing of the guideline and in the decision to submit it for publication., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Mycobacterium abscessus (Mabs), a rapidly growing Mycobacterium species, is considered an MDR organism. Among the standard antimicrobial multi-drug regimens against Mabs, amikacin is considered as one of the most effective. Parenteral amikacin, as a consequence of its inability to penetrate inside the cells, is only active against extracellular mycobacteria. The use of inhaled liposomal amikacin may yield improved intracellular efficacy by targeting Mabs inside the cells, while reducing its systemic toxicity., Objectives: To evaluate the colocalization of an amikacin liposomal inhalation suspension (ALIS) with intracellular Mabs, and then to measure its intracellular anti-Mabs activity., Methods: We evaluated the colocalization of ALIS with Mabs in eukaryotic cells such as macrophages (THP-1 and J774.2) or pulmonary epithelial cells (BCi-NS1.1 and MucilAir), using a fluorescent ALIS and GFP-expressing Mabs, to test whether ALIS reaches intracellular Mabs. We then evaluated the intracellular anti-Mabs activity of ALIS inside macrophages using cfu and/or luminescence., Results: Using confocal microscopy, we demonstrated fluorescent ALIS and GFP-Mabs colocalization in macrophages and epithelial cells. We also showed that ALIS was active against intracellular Mabs at a concentration of 32 to 64 mg/L, at 3 and 5 days post-infection. Finally, ALIS intracellular activity was confirmed when tested against 53 clinical Mabs isolates, showing intracellular growth reduction for nearly 80% of the isolates., Conclusions: Our experiments demonstrate the intracellular localization and intracellular contact between Mabs and ALIS, and antibacterial activity against intracellular Mabs, showing promise for its future use for Mabs pulmonary infections., (© The Author(s) 2022. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background Our cardiac center established a systematic approach for inpatient cardiovascular genetics evaluations of infants with congenital heart disease, including routine chromosomal microarray (CMA) testing. This provides a new opportunity to investigate correlation between genetic abnormalities and postoperative course. Methods and Results Infants who underwent congenital heart disease surgery as neonates (aged ≤28 days) from 2015 to 2020 were identified. Cases with trisomy 21 or 18 were excluded. Diagnostic genetic results or CMA with variant of uncertain significance were considered abnormal. We compared postoperative outcomes following initial congenital heart disease surgery in patients found to have genetic abnormality to those who had negative CMA. Among 355 eligible patients, genetics consultations or CMA were completed in 88%. A genetic abnormality was identified in 73 patients (21%), whereas 221 had negative CMA results. Genetic abnormality was associated with prematurity, extracardiac anomaly, and lower weight at surgery. Operative mortality rate was 9.6% in patients with a genetic abnormality versus 4.1% in patients without an identified genetic abnormality ( P =0.080). Mortality was similar when genetic evaluations were diagnostic (9.3%) or identified a variant of uncertain significance on CMA (10.0%). Among 14 patients with 22q11.2 deletion, the 2 mortality cases had additional CMA findings. In patients without extracardiac anomaly, genetic abnormality was independently associated with increased mortality ( P =0.019). CMA abnormality was not associated with postoperative length of hospitalization, extracorporeal membrane oxygenation, or >7 days to initial extubation. Conclusions Routine genetic evaluations and CMA may help to stratify mortality risk in severe congenital heart disease with syndromic or nonsyndromic presentations.

Background: The ideal aortic valve replacement strategy in young- and middle-aged adults remains up for debate. Clinical practice guidelines recommend mechanical prostheses for most patients less than 50 years of age undergoing aortic valve replacement. However, risks of major hemorrhage and thromboembolism associated with long-term anticoagulation may make the pulmonary autograft technique, or Ross procedure, a preferred approach in select patients., Methods: Data were retrospectively collected for patients 18-50 years of age who underwent either the Ross procedure or mechanical aortic valve replacement (mAVR) between January 2000 and December 2016 at a single institution. Propensity score matching was performed and yielded 32 well-matched pairs from a total of 216 eligible patients., Results: Demographic and preoperative characteristics were similar between the two groups. Median follow-up was 7.3 and 6.9 years for Ross and mAVR, respectively. There were no early mortalities in either group and no statistically significant differences were observed with respect to perioperative outcomes or complications. Major hemorrhage and stroke events were significantly more frequent in the mAVR population (p < .01). Overall survival (p = .93), freedom from reintervention and valve dysfunction free survival (p = .91) were equivalent., Conclusions: In this mid-term propensity score-matched analysis, the Ross procedure offers similar perioperative outcomes, freedom from reintervention or valve dysfunction as well as overall survival compared to traditional mAVR but without the morbidity associated with long-term anticoagulation. At specialized centers with sufficient expertize, the Ross procedure should be strongly considered in select patients requiring aortic valve replacement., (© 2022 The Authors. Journal of Cardiac Surgery published by Wiley Periodicals LLC.)

Background: Mycobacterium abscessus infections remain difficult to manage in both cystic fibrosis (CF) and non-CF patients and reported clinical outcomes are largely unsatisfactory. Clinical trial data are limited and no approved therapies are currently available for the management of M abscessus lung diseases. As an alternative, cohort studies may provide insightful information into the management of M abscessus pulmonary disease., Methods: Based on a retrospective observational cohort study, we investigated the safety and efficacy of amikacin liposome inhaled suspension (ALIS) as an adjunct to a standard antibiotic regimen for M abscessus lung infection in both CF and non-CF patients. We also assessed the association of patient drug compliance with culture conversion and clinical outcomes., Results: Twenty-six patients had long-term follow-up data available. Culture conversion was achieved in 54% (14/26) of the patients with no difference between CF and non-CF patients after an average treatment duration of 10 months. Patient treatment compliance was significantly better in the converter group compared to nonconverters with an odds ratio of 44.78 associated with good compared to poor patient compliance. Overall, 9 patients (35%) experienced an adverse event that led to treatment discontinuation., Conclusions: ALIS appears beneficial in both CF and non-CF populations with M abscessus lung disease., Competing Interests: Potential conflicts of interest. The authors: No reported conflicts of interest., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

ESX type VII secretion systems are complex secretion machineries spanning across the mycobacterial membrane and play an important role in pathogenicity, nutrient uptake and conjugation. We previously reported the role of ESX-4 in modulating Mycobacterium abscessus intracellular survival. The loss of EccB4 was associated with limited secretion of two effector proteins belonging to the WXG-100 family, EsxU and EsxT, and encoded by the esx-4 locus. This prompted us to investigate the function of M. abscessus EsxU and EsxT in vitro and in vivo. Herein, we show that EsxU and EsxT are substrates of ESX-4 and form a stable 1:1 heterodimer that permeabilizes artificial membranes. While expression of esxU and esxT was up-regulated in M. abscessus-infected macrophages, their absence in an esxUT deletion mutant prevented phagosomal membrane disruption while maintaining M. abscessus in an unacidified phagosome. Unexpectedly, the esxUT deletion was associated with a hyper-virulent phenotype, characterised by increased bacterial loads and mortality in mouse and zebrafish infection models. Collectively, these results demonstrate that the presence of EsxU and EsxT dampens survival and persistence of M. abscessus during infection., Competing Interests: The authors have declared that no competing interests exist.

The immunoglobulin A (IgA) status of cystic fibrosis (CF) patients, presenting with or without a non-tuberculous mycobacterial (NTM) infection, has to date not been fully elucidated toward two antigenic preparations previously described. We have chosen to determine the clinical values of an IgA ELISA for the diagnosis of NTM and/or Mycobacterium abscessus infections in CF patients. One hundred and 73 sera from CF patients, comprising 33 patients with M. abscessus positive cultures, and 31 non-CF healthy controls were assessed. IgA levels were evaluated by indirect ELISAs using a surface antigenic extract named TLR2eF for TLR2 positive extract and a recombinant protein, the phospholipase C (rMAB&#95;0555 or rPLC). These assays revealed a sensitivity of 52.6% (95% CI = 35.8% to 69%) and 42.1% (95% CI = 26.3% to 59.2%) using TLR2eF and rPLC, respectively, and respective specificities of 92.6% (95% CI = 87.5% to 96.1%) and 92% (95% CI = 86.7% to 95.7%) for samples culture positive for M. abscessus. Overall sensitivity and specificity of 66.7% and 85.4%, respectively, were calculated for IgA detection in M. abscessus-culture positive CF patients, when we combine the results of the two used antigens, thus demonstrating the efficiency in detection of positive cases for these two antigens with IgA isotype. CF patients with a positive culture for M. abscessus had the highest IgA titers against TLR2eF and rPLC. The diagnosis of NTM infections, including those due to M. abscessus, can be improved by the addition of an IgA serological assay, especially when cultures, for example, are negative. Based on these promising results, a serological follow-up of a larger number of patients should be performed to determine if the IgA response may be correlated with an active/acute infection state or a very recent infection. IMPORTANCE Mycobacterium abscessus is currently the most frequently isolated rapid growing mycobacterium in human pathology and the major one involved in lung infections. It has recently emerged as responsible for severe pulmonary infections in patients with cystic fibrosis (CF) or those who have undergone lung transplantation. In addition, it represents the most antibiotic resistant mycobacterial species. However, despite its increasing clinical importance, very little is known about the use of M. abscessus parietal compounds and the host response. This has led to the development of serological tests to measure the antibody response in infected patients, and potentially to link this to the culture of respiratory samples. Herein, we describe an important analysis of the serological IgA response from CF patients, and we demonstrate the full diagnostic usefulness of this assay in the diagnosis of NTM infections, and more particularly M. abscessus, in CF patients.

The development of resistome analysis, i.e. the comprehensive analysis of antibiotic-resistance genes (ARGs), is enabling a better understanding of the mechanisms of antibiotic-resistance emergence. The respiratory microbiome is a dynamic and interactive network of bacteria, with a set of ARGs that could influence the response to antibiotics. Viruses such as bacteriophages, potential carriers of ARGs, may also form part of this respiratory resistome. Chronic respiratory diseases (CRDs) such as cystic fibrosis, severe asthma, chronic obstructive pulmonary disease and bronchiectasis, managed with long-term antibiotic therapies, lead to multidrug resistance. Antibiotic susceptibility testing provides a partial view of the bacterial response to antibiotics in the complex lung environment. Assessing the ARG network would allow personalised, targeted therapeutic strategies and suitable antibiotic stewardship in CRDs, depending on individual resistome and microbiome signatures. This review summarises the influence of pulmonary antibiotic protocols on the respiratory microbiome, detailing the variable consequences according to antibiotic class and duration of treatment. The different resistome-profiling methods are explained to clarify their respective place in antibiotic-resistance analysis in the lungs. Finally, this review details current knowledge on the respiratory resistome related to therapeutic strategies and provides insight into the application of resistome analysis to counter the emergence of multidrug-resistant respiratory pathogens., Competing Interests: Conflict of interest: P-R. Burgel reports grants or contracts from GSK, Boehringer Ingelheim and Vertex; consulting fees from AstraZeneca, Chiesi, GSK and Insmed; and payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Insmed, Novartis, Pfizer, Vertex and Zambon, all outside the submitted work. The remaining authors have nothing to disclose., (Copyright ©The authors 2022.)

The COVID-19 pandemic is a unique crisis challenging healthcare institutions as it rapidly overwhelmed hospitals due to a large influx of patients. This major event forced all the components of the healthcare systems to adapt and invent new workflows. Thus, our tertiary care hospital was reorganized entirely. During the cruising phase, additional staff was allocated to a one-building organization comprising an intensive care unit (ICU), an acute care unit, a physical medicine and rehabilitation unit, and a COVID-19 screening area. The transfer of patients from a ward to another was more efficient due to these organizations and pavilion structure. The observed mortality was low in the acute care ward, except in the palliative unit. No nosocomial infection with SARS-CoV-2 was reported in any other building of the hospital since this organization was set up. This type of one-building organization, integrating all the components for comprehensive patient care, seems to be the most appropriate response to pandemics., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Bessis, Dinh, Gautier, Davido, Levy, Lawrence, Lot, Bensmail, Rech, Farcy-Afif, Bouchand, de Truchis, Herrmann, Barbot, Orlikowski, Moine, Perronne, Josseran, Prigent and Annane.)

Background: Bartonella endocarditis is often a diagnostic challenge due to its variable clinical manifestations, especially when it is first presented with involvement of organs other than skin and lymph nodes, such as the kidney., Case Presentation: This was a 13-year-old girl presenting with fever, chest and abdominal pain, acute kidney injury, nephrotic-range proteinuria and low complement levels. Her kidney biopsy showed diffuse crescentic proliferative glomerulonephritis with a full-house pattern of immune complex deposition shown by immunofluorescence, which was initially considered consistent with systemic lupus erythematous-associated glomerulonephritis (lupus nephritis). After extensive workup, Bartonella endocarditis was diagnosed. Antibiotic treatment and valvular replacement surgery were undertaken with subsequent return of kidney function to normal range., Conclusion: This case demonstrates the importance of considering the full clinical picture when interpreting clinical, laboratory and biopsy findings, because the treatment strategy for infective endocarditis versus lupus nephritis is drastically different., (© 2022. The Author(s).)

Persistent neutrophilic inflammation associated with chronic pulmonary infection causes progressive lung injury and, eventually, death in individuals with cystic fibrosis (CF), a genetic disease caused by biallelic mutations in the CF transmembrane conductance regulator (CFTR) gene. Therefore, we examined whether roscovitine, a cyclin-dependent kinase inhibitor that (in other conditions) reduces inflammation while promoting host defense, might provide a beneficial effect in the context of CF. Herein, using CFTR-depleted zebrafish larvae as an innovative vertebrate model of CF immunopathophysiology, combined with murine and human approaches, we sought to determine the effects of roscovitine on innate immune responses to tissue injury and pathogens in the CF condition. We show that roscovitine exerts antiinflammatory and proresolution effects in neutrophilic inflammation induced by infection or tail amputation in zebrafish. Roscovitine reduces overactive epithelial reactive oxygen species (ROS)-mediated neutrophil trafficking by reducing DUOX2/NADPH-oxidase activity and accelerates inflammation resolution by inducing neutrophil apoptosis and reverse migration. It is important to note that, although roscovitine efficiently enhances intracellular bacterial killing of Mycobacterium abscessus in human CF macrophages ex vivo , we found that treatment with roscovitine results in worse infection in mouse and zebrafish models. By interfering with DUOX2/NADPH oxidase-dependent ROS production, roscovitine reduces the number of neutrophils at infection sites and, consequently, compromises granuloma formation and maintenance, favoring extracellular multiplication of M. abscessus and more severe infection. Our findings bring important new understanding of the immune-targeted action of roscovitine and have significant therapeutic implications for safely targeting inflammation in CF.

Background: Culture conditions sometimes make it difficult to detect non-tuberculous mycobacteria (NTM), particularly Mycobacterium abscessus, an emerging cystic fibrosis (CF) pathogen. The diagnosis of NTM positive cases not detected by classical culture methods might benefit from the development of a serological assay., Methods: As part of a diagnostic accuracy study, a total of 173 sera CF-patients, including 33 patients with M. abscessus positive cultures, and 31 non-CF healthy controls (HC) were evaluated. Four M. abscessus antigens were used separately, comprising two surface extracts (Interphase (INP) and a TLR2 positive extract (TLR2eF)) and two recombinant proteins (rMAB&#95;2545c and rMAB&#95;0555 also known as the phospholipase C (rPLC))., Results: TLR2eF and rPLC were the most efficient antigens to discriminate NTM-culture positive CF-patients from NTM-culture negative CF-patients. The best clinical values were obtained for the detection of M. abscessus-culture positive CF-patients; with sensitivities for the TLR2eF and rPLC of 81.2% (95% CI:65.7-92.3%) and 87.9% (95% CI:71.9-95.6%) respectively, and specificities of 88.9% (95% CI:85.3-94.8%) and 84.8% (95% CI:80.6-91.5%) respectively. When considering as positive all sera, giving a positive response in at least one of the two tests, and, as negative, all sera negative for both tests, we obtained a sensitivity of 93.9% and a specificity of 80.7% for the detection of M. abscessus-culture positive CF-patients., Conclusion: High antibody titers against TLR2eF and rPLC were obtained in M. abscessus-culture positive CF-patients, allowing us to consider these serological markers as potential tools in the detection of CF-patients infected with M. abscessus., Competing Interests: Declaration of Competing Interest All authors declare no conflicts of interest regarding the study., (Copyright © 2021 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Background: Patients receiving a right ventricle to pulmonary artery conduit (PC) in infancy will require successive procedures or replacements, each with variable longevity. We sought to identify factors associated with time-related risk of a subsequent surgical replacement (PC3) or transcatheter pulmonary valve insertion (TPVI) after a second surgically placed PC (PC2)., Methods: From 2002 to 2016, 630 patients from 29 Congenital Heart Surgeons' Society member institutions survived to discharge after initial valved PC insertion (PC1) at age ≤ 2 years. Of those, 355 underwent surgical replacement (PC2) of that initial conduit. Competing risk methodology and multiphase parametric hazard analyses were used to identify factors associated with time-related risk of PC3 or TPVI., Results: Of 355 PC2 patients (median follow-up, 5.3 years), 65 underwent PC3 and 41 TPVI. Factors at PC2 associated with increased time-related risk of PC3 were smaller PC2 Z score (hazard ratio [HR] 1.6, P < .001), concomitant aortic valve intervention (HR 7.6, P = .009), aortic allograft (HR 2.2, P = .008), younger age (HR 1.4, P < .001), and larger Z score of PC1 (HR 1.2, P = .04). Factors at PC2 associated with increased time-related risk of TPVI were aortic allograft (HR: 3.3, P = .006), porcine unstented conduit (HR 4.7, P < .001), and older age (HR 2.3, P = .01)., Conclusions: Aortic allograft as PC2 was associated with increased time-related risk of both PC3 and TPVI. Surgeons may reduce risk of these subsequent procedures by not selecting an aortic homograft at PC2, and by oversizing the conduit when anatomically feasible., (Copyright © 2022 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Antibiotic treatment of native osteomyelitis caused by extended-spectrum β-lactamase-producing Enterobacterales (ESBL-PE) is a challenge. Limited epidemiological and outcome data are available. This retrospective cohort study included osteomyelitis patients with ESBL-PE infections treated in a reference centre for bone and joint infections (BJIs) between 2011-2019. Twenty-nine patients with native BJI (mean age, 44.4 ± 15.7 years) were analysed. Fifteen cases were paraplegic patients with ischial pressure sores breaching the hip capsule. Other cases included eight other hip infections, four tibial infections and two foot infections. Infections were mostly polymicrobial (n = 23; 79.3%), including Staphylococcus aureus (n = 13; 8 methicillin-resistant). Klebsiella pneumoniae (n = 13) was the most frequent ESBL-producing species identified, followed by Escherichia coli (n = 10), including 3 E. coli/K. pneumoniae co-infections, and Enterobacter spp. (n = 9). ESBL-PE were rarely susceptible to fluoroquinolones (n = 4; 13.8%). Most therapies were based on carbapenems (n = 22) and combination therapies (n = 19). The median duration of treatment was 41 (5-60) days. Primary control of the infection was achieved in 62.1% (18/29) of cases and up to 86.2% after second look surgeries, after a median follow-up of 6 (1-36) months. Infection with ESBL-producing K. pneumoniae was associated with failure (P = 0.001), whereas age, infection location, prior colonisation and antimicrobial therapy were not found to be predictors of outcome. ESBL-PE native BJIs are often polymicrobial and fluoroquinolone-resistant infections caused by K. pneumoniae, highlighting the need for expert centres with pluridisciplinary meetings with experienced surgeons., Competing Interests: Competing interests None declared., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Objectives: Blood culture bottles (BCBs) are commonly used for the diagnosis of infections associated with orthopedic devices. Although Cutibacterium acnes is an important pathogen in orthopedics, relatively little is known about its growth characteristics in BCBs. This prompted us to analyze the influence of bacterial genotype and clinical significance on time-to-detection (TTD) in BCBs., Methods: We reviewed 59 cases of orthopedic device-related infections in which at least one intraoperative specimen yielded a pure C. acnes culture from anaerobic BCBs (BD Bactec Lytic/10 Anaerobic/F; Lytic-Ana) and/or solid media. A strain was considered infectant if the same genotype was present in two or more intraoperative samples. From these cases, we isolated a total of 72 unique C. acnes strains belonging to four multilocus sequence type clonal complexes (CCs): CC18, CC28, CC36 and CC53. Growth rate and TTD in Lytic-Ana BCB were studied under experimental conditions (inoculation of standard inoculum) and in clinical samples (inoculation of periprosthetic tissue samples)., Results: Median TTD values were shorter for CC53 compared to other CCs under experimental conditions (69 vs. 103 h; p < 0.001) and from clinical specimens (70 vs. 200 h; p = 0.02). Infectant strains had a shorter median TTD compared to contaminant strains in a clinical situation, while the difference was not observed under experimental conditions., Conclusions: The detection dynamics of C. acnes in Lytic-Ana BCBs were associated with genotype. Thus, TTD not only reflects the bacterial load in clinical samples, but may also reflect the intrinsic properties of the clonal complex of C. acnes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: The stentless porcine aortic root prosthesis (SPAR) has been described as a suitable valve for right ventricular outflow tract reconstruction (RVOTR). Indiana University Methodist Hospital in Indianapolis, Indiana began using this valve for RVOTR in 1998. This study reports medium-term to late- term outcomes of the valve in the pulmonary position., Methods: A retrospective chart review was conducted of patients older than 18 years of age who underwent RVOTR with a SPAR between April 2000 and October 2019. Primary outcomes included survival and freedom from any valvular reintervention. Secondary outcomes included endocarditis and conduit dysfunction detected by routine echocardiography or cardiac magnetic resonance imaging., Results: A total of 135 patients underwent RVOTR with a SPAR at a median age of 32.4 years (range, 18 to 71 years). Of these patients, 129 had previous surgery. Indications included pulmonary insufficiency (90.4%), stenosis (34.8%), endocarditis (7.4%), and carcinoid (4.4%). Median follow-up was 2.97 years (interquartile range, 0.6 to 8.0 years). Overall survival was 93.3%, with 3 perioperative death and 6 late deaths. Endocarditis developed in 4 patients (2.9%), 2 of whom required reoperation. Progressive conduit degradation was evident at 10 years, with 22.2% and 7.7% having moderate stenosis and insufficiency, respectively. Eight (5.9%) reinterventions included 2 surgical replacements, 3 percutaneous replacements, and 3 balloon valvuloplasties at means of 8.5, 7.4, and 2.2 years, respectively. Overall freedom from reintervention at 1, 5, and 10 years was 99.1%, 94.7% and 90.7%, respectively., Conclusions: In this large, single-institution experience with a long follow-up period, use of the SPAR demonstrated excellent midterm to long-term durability, low rates of endocarditis, and high freedom from reintervention., (Copyright © 2021 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Nontuberculous mycobacterial (NTM) pulmonary disease is a chronic respiratory infection associated with declining lung function, radiological deterioration and significantly increased morbidity and mortality. Patients often have underlying lung conditions, particularly bronchiectasis and COPD. NTM pulmonary disease is difficult to treat because mycobacteria can evade host defences and antimicrobial therapy through extracellular persistence in biofilms and sequestration into macrophages. Management of NTM pulmonary disease remains challenging and outcomes are often poor, partly due to limited penetration of antibiotics into intracellular spaces and biofilms. Efficient drug delivery to the site of infection is therefore a key objective of treatment, but there is high variability in lung penetration by antibiotics. Inhalation is the most direct route of delivery and has demonstrated increased efficacy of antibiotics like amikacin compared with systemic administration. Liposomes are small, artificial, enclosed spherical vesicles, in which drug molecules can be encapsulated to provide controlled release, with potentially improved pharmacokinetics and reduced toxicity. They are especially useful for drugs where penetration of cell membranes is essential. Inhaled delivery of liposomal drug solutions can therefore facilitate direct access to macrophages in the lung where the infecting NTM may reside. A range of liposomal drugs are currently being evaluated in respiratory diseases., Competing Interests: Conflict of interest: J.D. Chalmers reports grants and personal fees from AstraZeneca, Conflict of interest: Boehringer Ingelheim, GlaxoSmithKline and Insmed; grants from Gilead Sciences and Grifols; and personal fees from Chiesi, Novartis and Zambon, outside the submitted work. Conflict of interest: J. van Ingen reports advisory board membership from Insmed, outside the submitted work. Conflict of interest: R. van der Laan is an employee of Insmed. Conflict of interest: J-L. Herrmann has nothing to disclose., (Copyright ©The authors 2021.)

Non-tuberculous mycobacteria (NTM) are a large group of micro-organisms comprising more than 200 individual species. Most NTM are saprophytic organisms and are found mainly in terrestrial and aquatic environments. In recent years, NTM have been increasingly associated with infections in both immunocompetent and immunocompromised individuals, prompting significant efforts to understand the diverse pathogenic and signalling traits of these emerging pathogens. Since the discovery of Type VII secretion systems (T7SS), there have been significant developments regarding the role of these complex systems in mycobacteria. These specialised systems, also known as Early Antigenic Secretion (ESX) systems, are employed to secrete proteins across the inner membrane. They also play an essential role in virulence, nutrient uptake and conjugation. Our understanding of T7SS in mycobacteria has significantly benefited over the last few years, from the resolution of ESX-3 structure in Mycobacterium smegmatis , to ESX-5 structures in Mycobacterium xenopi and Mycobacterium tuberculosis . In addition, ESX-4, considered until recently as a non-functional system in both pathogenic and non-pathogenic mycobacteria, has been proposed to play an important role in the virulence of Mycobacterium abscessus ; an increasingly recognized opportunistic NTM causing severe lung diseases. These major findings have led to important new insights into the functional mechanisms of these biological systems, their implication in virulence, nutrient acquisitions and cell wall shaping, and will be discussed in this review.

Objective: The timing and nature of and risk factors for reoperation after the arterial switch operation in the setting of d-transposition of the great arteries requires further elucidation., Methods: A total of 403 patients who underwent arterial switch operation from 1986 to 2017 were reviewed. Institutional preference was for pulmonary artery reconstruction using a pantaloon patch of fresh autologous pericardium. The targets for coronary artery reimplantation were identified by intermittent root distension. Multivariable analysis was used to identify risk factors for reoperation., Results: Median follow-up was 8.6 years (interquartile range [IQR]: 2-16.9). Pulmonary arterioplasty was the most common reoperation (n = 11, 2.7%) at 3.3 years (IQR: 1.4-11.4) postoperatively. Subvalvar right ventricular outflow tract reconstruction (RVOTR) was required in nine (2.2%) patients at 2.5 years (IQR: 1.1-5.3) postoperatively. Aortic valve repair or replacement (AVR/r) was required in seven (1.7%) patients at 13.6 years (IQR: 10.0-15.8) postoperatively. Aortic root replacement (ARR) and Coronary Artery Bypass Graft/coronary patch arterioplasty were required in five (1.2%) patients each at 13.6 years (IQR: 11.0-15.3) and 11.3 years (IQR: 2.3-13.6) postoperatively, respectively. Taussig-Bing anomaly was a risk factor for any reoperation ( P = .034). Risk factors for specific reoperations included ventricular septal defect for AVR/r ( P = .038), Taussig-Bing anomaly for RVOTR ( P = .004), and pulmonary artery banding for ARR ( P = .028)., Conclusions: Pantaloon patch pulmonary artery reconstruction and intermittent neo-aortic root distension during coronary reimplantation have minimized respective outflow tract reoperations. Certain anatomic subsets carry different risks for late reoperation, and pulmonary artery and/or RVOT reinterventions tend to occur sooner than aortic reinterventions. Special attention to these higher risk subpopulations will be critical to optimizing lifelong outcomes.