Publications by authors named "Jakko van Ingen"

185 Publications

RNA-sequencing elucidates drug-specific mechanisms of antibiotic tolerance and resistance in .

Antimicrob Agents Chemother 2021 Oct 11:AAC0150921. Epub 2021 Oct 11.

Radboudumc Center for Infectious Diseases, Department of Medical Microbiology, Radboud University Medical Center, Nijmegen, the Netherlands.

is an opportunistic pathogen notorious for its resistance to most classes of antibiotics and low cure rates. carries an array of mostly unexplored defence mechanisms. A deeper understanding of antibiotic resistance and tolerance mechanisms is pivotal in development of targeted therapeutic regimens. We provide the first description of all major transcriptional mechanisms of tolerance to all antibiotics recommended in current guidelines, using RNA sequencing-guided experiments. ATCC 19977 bacteria were subjected to sub-inhibitory concentrations of clarithromycin, amikacin, tigecycline, cefoxitin and clofazimine for 4- and 24-hours, followed by RNA sequencing. To confirm key mechanisms of tolerance suggested by transcriptomic responses, we performed time-kill kinetic analysis using bacteria after pre-exposure to clarithromycin, amikacin or tigecycline for 24-hours and we constructed isogenic knockout and knockdown strains. To assess strain specificity, pan-genome analysis of 35 strains from all three subspecies was performed. shows both drug-specific and common transcriptomic responses to antibiotic exposure. Ribosome-targeting antibiotics clarithromycin, amikacin and tigecycline elicit a common response characterized by upregulation of ribosome structural genes, the WhiB7 regulon and transferases, accompanied by downregulation of respiration through NuoA-N. Exposure to any of these drugs decreases susceptibility to ribosome-targeting drugs from multiple classes. The cytochrome bd-type quinol oxidase contributes to clofazimine tolerance in and the sigma factor sigH but not anti-sigma factor MAB_3542c is involved in tigecycline resistance. The observed transcriptomic responses are not strain-specific, as all genes involved in tolerance, except erm(41), are found in all included strains.
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http://dx.doi.org/10.1128/AAC.01509-21DOI Listing
October 2021

Nontuberculous mycobacterial lung disease caused by complex - disease burden, unmet needs, and advances in treatment developments.

Expert Rev Respir Med 2021 Oct 18:1-15. Epub 2021 Oct 18.

Department of Medicine, National Jewish Health, Denver, Co, and the University of Colorado School of Medicine, Aurora, CO, US.

Introduction: Nontuberculous mycobacterial (NTM) lung disease (LD) is the most common clinical manifestation of NTM infection and is a growing health concern. Up to 85% of NTM-LD cases are caused by complex (MAC). Increased awareness of NTM-LD caused by MAC is needed as patients with this disease experience substantial burden and unmet treatment needs.

Areas Covered: This review provides clinicians and regulatory and healthcare decision makers an overview of the clinical, economic, and humanistic burden of NTM-LD and the unmet treatment needs faced by patients and clinicians. The review focuses on NTM-LD caused by MAC. A summary of the 2020 NTM guidelines specifically for MAC-LD and an overview of novel treatment options, including amikacin liposome inhalation suspension (ALIS) as the first approved therapy for refractory MAC-LD, and investigational drugs in testing phase are provided.

Expert Opinion: Key advancements in NTM-LD management include recent updates to clinical practice guidelines, approval of ALIS for the treatment of refractory MAC-LD, and ongoing clinical trials of investigational treatments. Yet opportunities still exist to improve patient outcomes, including development of better screening tools, such as reliable and responsive biomarkers to help identify high-risk patients, and addressing unmet treatment needs.
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http://dx.doi.org/10.1080/17476348.2021.1987891DOI Listing
October 2021

Prediction of moxifloxacin concentrations in tuberculosis patient populations by physiologically-based pharmacokinetic modeling.

J Clin Pharmacol 2021 Sep 23. Epub 2021 Sep 23.

Department of Pharmacy, Radboud Institute for Health Sciences & Radboudumc Center for Infectious Diseases, Radboud university medical center, Nijmegen, The Netherlands.

Moxifloxacin has an important role in the treatment of tuberculosis (TB). Unfortunately, co-administration with the cornerstone TB drug rifampicin results in sub-optimal plasma exposure. We aimed to gain insight into the moxifloxacin pharmacokinetics and the interaction with rifampicin. Moreover, we provided a mechanistic framework to understand moxifloxacin pharmacokinetics. We developed a physiologically-based pharmacokinetic (PBPK) model in Simcyp version 19, with available and newly generated in vitro and in vivo data, to estimate PK parameters of moxifloxacin alone and when administered with rifampicin. By combining these strategies, we illustrate that the role of P-gp in moxifloxacin transport is limited and implicate MRP2 as transporter of moxifloxacin-glucuronide followed by rapid hydrolysis in the gut. Simulations of multiple dose area under the plasma concentration-time curves (AUC) of moxifloxacin (400 mg QD) with and without rifampicin (600 mg QD) were in accordance with clinically observed data (predicted/observed (P/O) ratio of 0.87 and 0.80, respectively). Importantly, increasing the moxifloxacin dose to 600 mg restored the plasma exposure both in actual TB patients as well as in our simulations. Furthermore, we extrapolated the single dose model to pediatric populations (P/O AUC ratios 1.04-1.52) and the multiple dose model to children with TB (P/O AUC ratio 1.51). In conclusion, our combined approach resulted in new insights into moxifloxacin PK and accurate simulations of moxifloxacin exposure with and without rifampicin. Finally, various knowledge gaps were identified, which may be considered as avenues for further PBPK refinement. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1002/jcph.1972DOI Listing
September 2021

Dissemination of Mycobacterium abscessus via global transmission networks.

Nat Microbiol 2021 Oct 20;6(10):1279-1288. Epub 2021 Sep 20.

Department of Veterinary Medicine, University of Cambridge, Cambridge, UK.

Mycobacterium abscessus, a multidrug-resistant nontuberculous mycobacterium, has emerged as a major pathogen affecting people with cystic fibrosis (CF). Although originally thought to be acquired independently from the environment, most individuals are infected with one of several dominant circulating clones (DCCs), indicating the presence of global transmission networks of M. abscessus. How and when these clones emerged and spread globally is unclear. Here, we use evolutionary analyses of isolates from individuals both with and without CF to reconstruct the population history, spatiotemporal spread and recent transmission networks of the DCCs. We demonstrate synchronous expansion of six unrelated DCCs in the 1960s, a period associated with major changes in CF care and survival. Each of these clones has spread globally as a result of rare intercontinental transmission events. We show that the DCCs, but not environmentally acquired isolates, exhibit a specific smoking-associated mutational signature and that current transmission networks include individuals both with and without CF. We therefore propose that the DCCs initially emerged in non-CF populations but were then amplified and spread through the CF community. While individuals with CF are probably the most permissive host, non-CF individuals continue to play a key role in transmission networks and may facilitate long-distance transmission.
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http://dx.doi.org/10.1038/s41564-021-00963-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8478660PMC
October 2021

Risk factors for nontuberculous mycobacterial pulmonary disease (NTM-PD) in Croatia.

Wien Klin Wochenschr 2021 Aug 17. Epub 2021 Aug 17.

Clinic for Respiratory diseases Jordanovac, University Hospital Centre Zagreb, Zagreb, Croatia.

Background: The incidence, geographical distribution and clinical relevance of different nontuberculous mycobacteria (NTM) in Croatia are well described. There are few data on the risk factors for developing NTM pulmonary disease (NTM-PD) in this setting.

Methods: We conducted a retrospective cohort study on all Croatian residents with NTM isolated from respiratory samples in the period from 2006 to 2015 with follow-up to 2018. The American Thoracic Society/Infectious Diseases Society of America (ATS/IDSA) guidelines were used to establish NTM-PD diagnosis. Clinical, radiological and treatment data were collected from hospital records.

Results: Risk analysis calculations were made on the 439 isolation episodes that were classified as definitive NTM-PD (n = 137) or no disease (n = 302). Female gender, presence of bronchiectasis, low BMI and long-term systemic corticosteroid treatment were independent risk factors associated with NTM-PD. Hemoptysis and malaise were presenting symptoms independently associated with NTM-PD. Chronic obstructive pulmonary disease (COPD) and low/moderate dose inhaled corticosteroid (ICS) treatment were not associated with NTM-PD. High dose ICS treatment was a significant risk factor for developing NTM-PD (aOR = 4.73, CI 1.69-13.23 p = 0.003).

Conclusion: The NTM-PD patients in Croatia are similar to those in other published cohorts in terms of their characteristics and risk factors. The significant dose-dependent association between ICS use and NTM-PD adds to the body of evidence suggesting that high dose ICS use is associated with NTM-PD.
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http://dx.doi.org/10.1007/s00508-021-01923-xDOI Listing
August 2021

Mycobacterium Growth Indicator Tube Time-To-Positivity Can Serve As an Early Biomarker of Treatment Response in Mycobacterium avium Complex Pulmonary Disease.

Chest 2021 Aug 13. Epub 2021 Aug 13.

Department of Medical Microbiology, Radboud University Medical Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands. Electronic address:

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http://dx.doi.org/10.1016/j.chest.2021.08.046DOI Listing
August 2021

Standard therapy of Mycobacterium avium complex pulmonary disease shows limited efficacy in an open source hollow fibre system that simulates human plasma and epithelial lining fluid pharmacokinetics.

Clin Microbiol Infect 2021 Jul 28. Epub 2021 Jul 28.

Radboudumc Center for Infectious Diseases, Department of Medical Microbiology, Radboud University Medical Center, Nijmegen, the Netherlands. Electronic address:

Objectives: Mycobacterium avium complex (MAC) bacteria can cause chronic pulmonary disease (PD). Current treatment regimens of azithromycin, ethambutol and rifampicin have culture conversion rates of around 65%. Dynamic, preclinical models to assess the efficacy of treatment regimens are important to guide clinical trial development. The hollow fibre system (HFS) has been applied but reports lack experimental details.

Methods: We simulated the human pharmacokinetics of azithromycin, ethambutol and rifampicin both in plasma and epithelial lining fluid (ELF) in a HFS, exposing THP-1 cells infected with M. avium to the triple-drug regimen for 3 weeks. We accounted for drug-drug interactions and protein-binding and provide all laboratory protocols. We differentiated the effects on the intracellular and extracellular mycobacterial population.

Results: The antibiotic concentrations in the HFS accurately reflected the time to peak concentration (T), the peak concentration (C) and half-life of azithromycin, rifampicin and ethambutol in plasma and ELF reported in literature. We find that plasma drug concentrations fail to hold the MAC bacterial load static (ΔLog10 CFU/mL = 0.66 ± 0.76 and 0.45 ± 0.28 at 3 and 21 days); ELF concentrations do hold the bacterial load static for 3 days and inhibit bacterial growth for the duration of the experiment (ΔLog10 CFU/mL = 1.1 ± 0.1 and 1.64 ± 0.59 at 3 and 21 days).

Discussion: In our model, the current therapy against MAC is ineffective, even when accounting for antibiotic accumulation at the site of infection and intracellularly. New treatment regimens need to be developed and be compared with currently recommended regimens in dynamic models prior to clinical evaluation. With the publication of all protocols we aim to open this technology to new users.
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http://dx.doi.org/10.1016/j.cmi.2021.07.015DOI Listing
July 2021

The role of amikacin in the treatment of nontuberculous mycobacterial disease.

Expert Opin Pharmacother 2021 Oct 22;22(15):1961-1974. Epub 2021 Jul 22.

Radboudumc Center for Infectious Diseases, Department of Medical Microbiology, Radboud University Medical Center, Nijmegen, The Netherlands.

: Guidelines recommend the use of amikacin in the treatment of nontuberculous mycobacterial (NTM) disease. The authors have evaluated the evidence for the position of amikacin in NTM disease treatment.: The authors performed a literature search for original research on amikacin in NTM disease, including its mechanism of action, emergence of resistance, pre-clinical and clinical investigations.: Amikacin shows moderate activity against the clinically most relevant NTM species ( complex and ). It is synergistic with ethambutol, clofazimine, and macrolides and these combinations are effective in animal models. Liposomal encapsulation increases amikacin efficacy. Clinically, the recommended dose of 15 mg/kg intravenous amikacin does not lead to PK/PD target attainment in all patients and a positive impact on long-term treatment outcomes remains unproven in both complex and disease. Adding the amikacin liposome inhalation suspension did prove to be effective in short and long term in patients not responding to recommended treatment for complex pulmonary disease. Its optimal use in complex and pulmonary disease warrants further evaluation.
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http://dx.doi.org/10.1080/14656566.2021.1953472DOI Listing
October 2021

Liposomal drug delivery to manage nontuberculous mycobacterial pulmonary disease and other chronic lung infections.

Eur Respir Rev 2021 Sep 20;30(161). Epub 2021 Jul 20.

Université Paris-Saclay, UVSQ, INSERM, Infection and Inflammation, Montigny-le-Bretonneux, France.

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.
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http://dx.doi.org/10.1183/16000617.0010-2021DOI Listing
September 2021

The epidemiology of nontuberculous mycobacterial pulmonary disease in the Netherlands.

ERJ Open Res 2021 Jul 12;7(3). Epub 2021 Jul 12.

Dept of Medical Microbiology, Radboudumc Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, the Netherlands.

Background: Nontuberculous mycobacteria (NTM) are emerging opportunistic pathogens of humans. Because NTM pulmonary disease (PD) is not a notifiable disease in Europe, the epidemiology of NTM-PD is not well known. However, the prevalence of NTM-PD is thought to be increasing, particularly in countries where tuberculosis rates have decreased. Here we aim to determine the prevalence of NTM-PD in the Netherlands.

Methods: Annual prevalence estimates of NTM-PD in the Netherlands (2012-2019) were derived from four separate databases, including two drug dispensing databases, an ICD-10 code database and a hospitalisation database. Databases covered a fraction of the Dutch population and were extrapolated. In addition, annual NTM-PD prevalence was also estimated by means of a pulmonologist survey.

Results: The estimated annual prevalence of NTM-PD using databases is between 2.3 and 5.9 patients per 100 000 inhabitants. Prevalence estimates derived from the drug dispensing databases, the hospitalisation database and the claims database were 2.3, 5.9, 3.5 and 4.5 per 100 000 inhabitants, respectively. The annual prevalence estimated in the pulmonologist survey was between 6.2 and 9.9 per 100 000 inhabitants. The annual prevalence remained stable over the included period.

Conclusion: The estimated annual prevalence of NTM-PD using databases was between 2.3 and 5.9 patients per 100 000 inhabitants. Due to the possible presence of tuberculosis patients and low coverage in one dispensing database, we believe an annual prevalence of between 2.3 and 4.5 patients per 100 000 inhabitants is more probable, which still renders NTM-PD a serious health threat. This estimate is lower than the estimate from the pulmonologist survey, indicating physicians likely overestimate prevalence.
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http://dx.doi.org/10.1183/23120541.00207-2021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8273392PMC
July 2021

Application of the hollow fibre infection model (HFIM) in antimicrobial development: a systematic review and recommendations of reporting.

J Antimicrob Chemother 2021 Aug;76(9):2252-2259

Institute for Global Health, University College London, London, UK.

Objectives: This systematic review focuses on the use of the in vitro hollow fibre infection model (HFIM) for microbial culture. We summarize the direction of the field to date and propose best-practice principles for reporting of the applications.

Methods: Searches in six databases (MEDLINE®, EMBASE®, PubMed®, BIOSIS®, SCOPUS® and Cochrane®) up to January 2020 identified 129 studies meeting our inclusion criteria. Two reviewers independently assessed and extracted data from each publication. The quality of reporting of microbiological and technical parameters was analysed.

Results: Forty-seven out of 129 (36.4%) studies did not report the minimum pharmacokinetic parameters required in order to replicate the pharmacokinetic profile of HFIM experiments. Fifty-three out of 129 (41.1%) publications did not report the medium used in the HFIM. The overwhelming majority of publications did not perform any technical repeats [107/129 (82.9%)] or biological repeats [97/129 (75.2%)].

Conclusions: This review demonstrates that most publications provide insufficient data to allow for results to be evaluated, thus impairing the reproducibility of HFIM experiments. Therefore, there is a clear need for the development of laboratory standardization and improved reporting of HFIM experiments.
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http://dx.doi.org/10.1093/jac/dkab160DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8361333PMC
August 2021

Interferon-Gamma Release Assays Differentiate between Mycobacterium avium Complex and Tuberculous Lymphadenitis in Children.

J Pediatr 2021 Sep 10;236:211-218.e2. Epub 2021 May 10.

Infectious Diseases and Systemic Inflammatory Response in Pediatrics, Infectious Diseases Unit, Department of Pediatrics, Institut de Recerca Sant Joan de Déu, Barcelona, Spain; Translational Research Network of Pediatric Infectious Diseases (RITIP), Madrid, Spain; Center for Biomedical Network Research on Epidemiology and Public Health (CIBERESP), Madrid, Spain; Department of Pediatrics, University of Barcelona, Barcelona, Spain. Electronic address:

Objectives: To assess the performance of interferon-gamma release assays (IGRAs) in the differential diagnosis between Mycobacterium avium complex (MAC) and tuberculosis (TB) in children affected with subacute/chronic submandibular/cervical lymphadenitis.

Study Design: Multicenter observational study comparing children with microbiologically confirmed MAC lymphadenitis from the European NontuberculouS MycoBacterial Lymphadenitis in childrEn study with children with TB lymphadenitis from the Spanish Network for the Study of Pediatric TB database.

Results: Overall, 78 patients with MAC and 34 with TB lymphadenitis were included. Among MAC cases, 44 out of 74 (59.5%) had positive tuberculin skin test (TST) results at the 5-mm cut-off, compared with 32 out of 33 (97%) TB cases (P < .001); at the 10-mm cut-off TST results were positive in 23 out of 74 (31.1%) vs 26 out of 31 (83.9%), respectively (P < .001). IGRA results were positive in only 1 out of 32 (3.1%) patients with MAC who had undergone IGRA testing, compared with 21 out of 23 (91.3%) TB cases (P < .001). Agreement between TST and IGRA results was poor in MAC (23.3%; κ = 0.017), but good in TB cases (95.6%; κ = 0.646). IGRAs had a specificity of 96.9% (95% CI 84.3%-99.8%), positive predictive value of 95.4% (95% CI 78.2%-99.8%), and negative predictive value of 93.9% (95% CI 80.4%-98.9%) for TB lymphadenitis.

Conclusions: In contrast to TST, IGRAs have high specificity, negative predictive value, and positive predictive value for TB lymphadenitis in children with subacute/chronic lymphadenopathy, and consequently can help to discriminate between TB and MAC disease. Therefore, IGRAs are useful tools in the diagnostic work-up of children with lymphadenopathy, particularly when culture and polymerase chain reaction results are negative.
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http://dx.doi.org/10.1016/j.jpeds.2021.05.008DOI Listing
September 2021

An Perspective on What Individual Antimicrobials Add to Mycobacterium avium Complex Therapies.

Antimicrob Agents Chemother 2021 07 16;65(8):e0273020. Epub 2021 Jul 16.

Radboudumc Center for Infectious Diseases, Department of Medical Microbiology, Radboud University Medical Centre, Nijmegen, The Netherlands.

For Mycobacterium avium complex pulmonary disease (MAC-PD), current treatment regimens yield low cure rates. To obtain an evidence-based combination therapy, we assessed the activity of six drugs, namely, clarithromycin (CLR), rifampin (RIF), ethambutol (EMB), amikacin (AMK), clofazimine (CLO), and minocycline (MIN), alone and in combination, against Mycobacterium avium and studied the contributions of individual antibiotics to efficacy. The MICs of all antibiotics against M. avium ATCC 700898 were determined by broth microdilution. We performed kinetic time-kill assays of all single drugs and clinically relevant two-, three-, four-, and five-drug combinations against M. avium. Pharmacodynamic interactions of these combinations were assessed using area under the time-kill curve-derived effect size and Bliss independence. Adding a second drug yielded an average increase of the effect size (E) of 18.7% ± 32.9%, although antagonism was seen in some combinations. Adding a third drug showed a smaller increase in effect size (+12.2% ± 11.5%). The RIF-CLO-CLR (E of 102 log CFU/ml · day), RIF-AMK-CLR (E of 101 log CFU/ml · day), and AMK-MIN-EMB (E of 97.8 log CFU/ml · day) regimens proved more active than the recommended RIF-EMB-CLR regimen (E of 89.1 log CFU/ml · day). The addition of a fourth drug had little impact on effect size (+4.54% ± 3.08%). , several two- and three-drug regimens are as effective as the currently recommended regimen for MAC-PD. Adding a fourth drug to any regimen had little additional effect. , the most promising regimen would be RIF-AMK-macrolide or RIF-CLO-macrolide.
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http://dx.doi.org/10.1128/AAC.02730-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8284439PMC
July 2021

Outbreaks of healthcare-associated infections linked to water-containing hospital equipment: a literature review.

Antimicrob Resist Infect Control 2021 05 10;10(1):77. Epub 2021 May 10.

Department of Medical Microbiology, Radboud Centre for Infectious Diseases, Radboud University Medical Centre, Nijmegen, The Netherlands.

Background: Healthcare-associated infections (HAIs) are a significant cause of morbidity and mortality in hospitalized patients. Water in the environment can be a source of infection linked to outbreaks and environmental transmission in hospitals. Water safety in hospitals remains a challenge. This article has summarized available scientific literature to obtain an overview of outbreaks linked to water-containing hospital equipment and strategies to prevent such outbreaks.

Methods: We made a list of water-containing hospital equipment and devices in which water is being used in a semi-closed circuit. A literature search was performed in PubMed with a search strategy containing the names of these medical devices and one or more of the following words: outbreak, environmental contamination, transmission, infection. For each medical device, we summarized the following information: the function of the medical device, causes of contamination, the described outbreaks and possible prevention strategies.

Results: The following water-containing medical equipment  or devices were identified: heater-cooler units, hemodialysis equipment, neonatal incubators, dental unit waterlines, fluid warmers, nebulizers, water traps, water baths, blanketrol, scalp cooling, and thermic stimulators. Of the latter three, no literature could be found. Of all other devices, one or more outbreaks associated with these devices were reported in the literature.

Conclusions: The water reservoirs in water-containing medical devices can be a source of microbial growth and transmissions to patients, despite the semi-closed water circuit. Proper handling and proper cleaning and disinfection can help to reduce the microbial burden and, consequently, transmission to patients. However, these devices are often difficult to clean and disinfect because they cannot be adequately opened or disassembled, and the manufacturer's cleaning guidelines are often not feasible to execute. The development of equipment without water or fluid containers should be stimulated. Precise cleaning and disinfection guidelines and instructions are essential for instructing healthcare workers and hospital cleaning staff to prevent potential transmission to patients.
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http://dx.doi.org/10.1186/s13756-021-00935-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8108015PMC
May 2021

Amikacin Liposome Inhalation Suspension for Refractory Mycobacterium avium Complex Lung Disease: Sustainability and Durability of Culture Conversion and Safety of Long-term Exposure.

Chest 2021 Sep 19;160(3):831-842. Epub 2021 Apr 19.

Division of Infectious Disease, Oregon Health and Science University School of Medicine, Portland, OR.

Background: In the CONVERT study, treatment with amikacin liposome inhalation suspension (ALIS) added to guideline-based therapy (GBT) met the primary end point of increased culture conversion by month 6 in patients with treatment-refractory Mycobacterium avium complex lung disease (ALIS plus GBT, 29% [65/224] vs GBT alone, 8.9% [10/112]; P < .0001).

Research Question: In patients who achieved culture conversion by month 6 in the CONVERT study, was conversion sustained (negative sputum culture results for 12 months with treatment) and durable (negative sputum culture results for 3 months after treatment) and were there any additional safety signals associated with a full treatment course of 12 months after conversion?

Study Design And Methods: Adults were randomized 2:1 to receive ALIS plus GBT or GBT alone. Patients achieving culture conversion by month 6 continued therapy for 12 months followed by off-treatment observation.

Results: More patients randomized to ALIS plus GBT (intention-to-treat population) achieved conversion that was both sustained and durable 3 months after treatment vs patients randomized to GBT alone (ALIS plus GBT, 16.1% [36/224] vs GBT alone, 0% [0/112]; P < .0001). Of the patients who achieved culture conversion by month 6, 55.4% of converters (36/65) in the ALIS plus GBT treated arm vs no converters (0/10) in the GBT alone arm achieved sustained and durable conversion (P = .0017). Relapse rates through 3 months after treatment were 9.2% (6/65) in the ALIS plus GBT arm and 30.0% (3/10) in the GBT alone arm. Common adverse events among ALIS plus GBT-treated patients (dysphonia, cough, dyspnea, hemoptysis) occurred mainly within the first 8 months of treatment.

Interpretation: In a refractory population, conversion was sustained and durable in more patients treated with ALIS plus GBT for 12 months after conversion than in those treated with GBT alone. No new safety signals were associated with 12 months of treatment after conversion.

Trial Registry: ClinicalTrials.gov; No.: NCT02344004; URL: www.clinicaltrials.gov.
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http://dx.doi.org/10.1016/j.chest.2021.03.070DOI Listing
September 2021

Population Pharmacokinetic Evaluation of Amikacin Liposome Inhalation Suspension in Patients with Treatment-Refractory Nontuberculous Mycobacterial Lung Disease.

Eur J Drug Metab Pharmacokinet 2021 Mar 17;46(2):277-287. Epub 2021 Feb 17.

Oregon Health and Science University, 3375 SW Terwilliger Boulevard, Portland, OR, USA.

Background And Objectives: Use of parenteral amikacin to treat refractory nontuberculous mycobacterial (NTM) lung disease is limited by systemic toxicity. A population pharmacokinetic model was developed using data pooled from two randomized trials to evaluate the pharmacokinetic properties of once-daily amikacin liposome inhalation suspension (ALIS) in patients with treatment-refractory NTM lung disease.

Methods: In phase 2 (TR02-112) and phase 3 (CONVERT) studies, patients with sputum cultures positive for Mycobacterium avium complex (both studies) or M. abscessus (TR02-112) despite ≥ 6 months of guideline-based therapy were treated with once-daily ALIS 590 mg.

Results: Fifty-three patients (28 Japanese; 25 White) were assessed. At baseline and ≈ 6 months after daily dosing, median maximum concentration (C) was < 2 mg/L and median area under the concentration-time curve (AUC) was < 20 mg·h/L, suggesting low systemic exposure at both time points. Exposure estimates were similar between Japanese and White patients. The median unchanged amikacin fraction excreted in urine was < 10% of inhaled dose throughout the TR02-112 study, indicating that relatively small amounts reached systemic circulation. Median t was 5.5 h. Amikacin concentrations were much higher in sputum than in serum, demonstrating the ability to achieve higher drug concentration at the site of infection. Median sputum amikacin concentrations in the CONVERT study were high at 1-4 h postdose (range 242-426 μg/g) and decreased by 8 h (median 7 μg/g).

Conclusions: Systemic exposure to amikacin in serum and urine following once-daily ALIS administration in patients with treatment-refractory NTM lung disease was notably lower than that previously reported for parenteral amikacin.

Trial Registration: ClinicalTrials.gov NCT01315236 (registered March 15, 2011) and NCT02344004 (registered January 22, 2015).
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http://dx.doi.org/10.1007/s13318-020-00669-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7935831PMC
March 2021

The Benzimidazole SPR719 Shows Promising Concentration-Dependent Activity and Synergy against Nontuberculous Mycobacteria.

Antimicrob Agents Chemother 2021 03 18;65(4). Epub 2021 Mar 18.

Radboudumc Center for Infectious Diseases, Department of Medical Microbiology, Radboud University Medical Center, Nijmegen, the Netherlands

Nontuberculous mycobacterial pulmonary disease (NTM-PD) is emerging worldwide. Currently recommended multidrug treatment regimens yield poor outcomes, and new drugs and regimens are direly needed. SPR719, the active moiety of SPR720, is a new benzimidazole antibiotic with limited data on antimycobacterial activity. We determined MICs and MBCs against 138 clinical and reference strains of complex (MAC), , , , , and and determined synergy with antimycobacterial drugs by checkerboard titrations. To study pharmacodynamics, we performed time-kill kinetics assays of SPR719 alone and in combinations against , , and and assessed synergy by response surface analysis according to Bliss independence. SPR719 showed potent activity against MAC (MIC, 2 mg/liter) and (MIC, 0.125 mg/liter) and modest activity against (MIC, 8 mg/liter); its activity is bacteriostatic and concentration-dependent. We recorded a potential for combination therapy with ethambutol against and and synergy with clarithromycin against Ethambutol increased the SPR719 kill rate against but only prevented SPR719 resistance in SPR719 is active against NTM; its activity is strongest against , followed by MAC and SPR719 shows promise for combination therapy with ethambutol against MAC and and synergy with clarithromycin against The parent drug SPR720 could have a role especially in MAC pulmonary disease treatment. Further studies in dynamic models and trials are ongoing to advance clinical development.
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http://dx.doi.org/10.1128/AAC.02469-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8097464PMC
March 2021

Amikacin Liposome Inhalation Suspension for Complex Lung Disease: A 12-Month Open-Label Extension Clinical Trial.

Ann Am Thorac Soc 2021 07;18(7):1147-1157

The University of Texas Health Science Center at Tyler, Tyler, Texas; and.

Patients with refractory complex (MAC) lung disease have limited treatment options. In the CONVERT study, amikacin liposome inhalation suspension (ALIS) added to guideline-based therapy (GBT) increased culture conversion rates versus GBT alone by Month 6. Limited data are available regarding >6-month treatment in a refractory population. Evaluate 12-month safety, tolerability, and efficacy of ALIS+GBT. Adults with refractory MAC lung disease not achieving culture conversion by CONVERT Month 6 could enroll in this open-label extension (INS-312) to receive 590 mg once-daily ALIS+GBT for 12 months. Two cohorts enrolled: the "ALIS-naive" cohort included patients randomized to GBT alone in CONVERT, and the "prior-ALIS" cohort included those randomized to ALIS+GBT in CONVERT. Safety and tolerability of ALIS over 12 months (primary endpoint) and culture conversion by Months 6 and 12 were assessed. In the ALIS-naive cohort, 83.3% of patients ( = 75/90) experienced respiratory treatment-emergent adverse events (TEAEs), and 35.6% ( = 32) had serious TEAEs; 26.7% ( = 24) achieved culture conversion by Month 6 and 33.3% ( = 30) by Month 12. In the prior-ALIS cohort, 46.6% of patients ( = 34/73) experienced respiratory TEAEs, and 27.4% ( = 20) had serious TEAEs; 9.6% ( = 7) achieved culture conversion by Month 6 (≤14 mo ALIS exposure) and 13.7% ( = 10) by Month 12 (≤20 mo ALIS exposure). Nephrotoxicity-related TEAEs and measured hearing decline were infrequent in both cohorts. In up to 20 months of ALIS use, respiratory TEAEs were common, nephrotoxicity and hearing decline were infrequent, and culture conversion continued beyond 6 months of therapy.Clinical trial registered with www.clinicaltrials.gov (NCT02628600).
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http://dx.doi.org/10.1513/AnnalsATS.202008-925OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8328368PMC
July 2021

Immune defects in patients with pulmonary disease without cystic fibrosis.

ERJ Open Res 2020 Oct 10;6(4). Epub 2020 Nov 10.

Radboud University Medical Centre, University Centre of Chronic Diseases Dekkerswald, Dept of Pulmonary Diseases, Nijmegen, The Netherlands.

The prevalence of infections in non-cystic fibrosis (CF) patients has increased in recent years. In this study, we investigate whether immune defects explain the apparent susceptibility to this opportunistic infection in non-CF patients. We performed stimulations of peripheral blood mononuclear cells and whole blood from 13 patients with pulmonary disease and 13 healthy controls to investigate their cytokine production after 24 h and 7 days. Patients were predominantly women (54%) with a mean age of 59 years; 62% had nodular bronchiectatic disease. Many patients had predisposing pulmonary diseases, such as COPD (46%), and asthma (23%). Patients with COPD showed an impaired interleukin (IL)-6 response to and a reduced IL-17 response to , together with a -specific enhanced IL-22 production. Patients without COPD showed higher levels of interleukin-1 receptor antagonist (IL-1Ra), an anti-inflammatory molecule. Within the non-COPD patients, those with bronchiectasis showed defective interferon (IFN)-γ production in response to . In conclusion, susceptibility to is likely determined by a combination of immunological defects and predisposing pulmonary disease. The main defect in the innate immune response was a shift of the ratio of IL-1β to IL-1Ra, which decreased the bioactivity of this pathway in the adaptive immune response. In the adaptive immune response there was defective IL-17 and IFN-γ production. Patients with COPD and bronchiectasis showed different cytokine defects. It is therefore crucial to interpret the immunological results within the clinical background of the patients tested.
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http://dx.doi.org/10.1183/23120541.00590-2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7682720PMC
October 2020

Subtle immunodeficiencies in nodular-bronchiectatic complex lung disease.

ERJ Open Res 2020 Oct 19;6(4). Epub 2020 Oct 19.

Radboudumc Center for Infectious Diseases, Dept of Pulmonary Diseases, Radboud University Medical Center, Nijmegen, The Netherlands.

https://bit.ly/33AALwx.
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http://dx.doi.org/10.1183/23120541.00548-2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7569207PMC
October 2020

The tough process of unmasking the slow-growing mycobacterium: case report of infection.

Access Microbiol 2020 31;2(1):acmi000074. Epub 2019 Oct 31.

Department of Medical Microbiology, Radboud University Medical Centre, Nijmegen, The Netherlands.

belongs to the complex (MTBC). It can cause pulmonary and extrapulmonary tuberculosis in humans. Compared to , which is the most prevalent subspecies of the MTBC, infection has a different etiology. Moreover, establishing the diagnosis with conventional bacteriology can be difficult. We will illustrate this with a case of an extrapulmonary tuberculosis of the hip caused by in an immunocompetent patient in The Netherlands.
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http://dx.doi.org/10.1099/acmi.0.000074DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7525059PMC
October 2019

Epidemiology of nontuberculous mycobacterial pulmonary disease in Europe and Japan by Delphi estimation.

Respir Med 2020 11 21;173:106164. Epub 2020 Sep 21.

Radboud Center for Infectious Diseases, Department of Medical Microbiology, Radboud University Medical Center, Nijmegen, the Netherlands. Electronic address:

Background: Nontuberculous mycobacterial pulmonary disease (NTM-PD) is an emerging opportunistic infection, but basic epidemiological data are lacking in most regions. We have investigated epidemiology and diagnostic and treatment practices in five EU countries (United Kingdom, Spain, Italy, France, Germany; EU5) and Japan.

Study Design: and methods: Annual prevalence in each country was established using a 2-round Delphi method in combination with a regional prevalence-estimation model that incorporated data obtained from a blinded physician screening survey (3154 physicians) and a real-world NTM-PD treating-physician/patient-chart observational study (619 physicians - 1429 patient charts).

Results: The annual prevalence of NTM-PD was estimated at 6.2/100,000 in the EU5 and 24.9/100,000 in Japan. Overall prevalence between the EU5 was comparable, while differences in regional prevalence were found to be pronounced in France and The United Kingdom. Regional differences were also found in Japan, with the majority of cases in Chubu and Kanto regions.

Conclusion: This new methodology for obtaining often missing regional-level epidemiological data reveals dramatic variations in NTM-PD annual prevalence and helps pinpoint areas that may merit special preventative and treatment focus.
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http://dx.doi.org/10.1016/j.rmed.2020.106164DOI Listing
November 2020

Management of Drug Toxicity in Mycobacterium avium Complex Pulmonary Disease: An Expert Panel Survey.

Clin Infect Dis 2021 07;73(1):e256-e259

Division of Pulmonary and Critical Care Medicine, Seoul National University College of Medicine, Seoul, South Korea.

Adverse events are frequent in nontuberculous mycobacteria pulmonary disease treatment, but evidence to support their management is scarce. An expert panel survey on management of adverse events shows consistent opinions on management of hepatoxicity, ocular toxicity, ototoxicity, tinnitus, and gastrointestinal upset. These opinions can provide assistance in individual patient management decisions.
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http://dx.doi.org/10.1093/cid/ciaa1361DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8491833PMC
July 2021

Treatment of Nontuberculous Mycobacterial Pulmonary Disease: An Official ATS/ERS/ESCMID/IDSA Clinical Practice Guideline.

Clin Infect Dis 2020 08;71(4):905-913

Divisions of Infectious Diseases, Schools of Public Health and Medicine, Oregon Health and Science University, Portland, Oregon, USA.

Nontuberculous mycobacteria (NTM) represent over 190 species and subspecies, some of which can produce disease in humans of all ages and can affect both pulmonary and extrapulmonary sites. This guideline focuses on pulmonary disease in adults (without cystic fibrosis or human immunodeficiency virus infection) caused by the most common NTM pathogens such as Mycobacterium avium complex, Mycobacterium kansasii, and Mycobacterium xenopi among the slowly growing NTM and Mycobacterium abscessus among the rapidly growing NTM. A panel of experts was carefully selected by leading international respiratory medicine and infectious diseases societies (ATS, ERS, ESCMID, IDSA) and included specialists in pulmonary medicine, infectious diseases and clinical microbiology, laboratory medicine, and patient advocacy. Systematic reviews were conducted around each of 22 PICO (Population, Intervention, Comparator, Outcome) questions and the recommendations were formulated, written, and graded using the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) approach. Thirty-one evidence-based recommendations about treatment of NTM pulmonary disease are provided. This guideline is intended for use by healthcare professionals who care for patients with NTM pulmonary disease, including specialists in infectious diseases and pulmonary diseases.
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http://dx.doi.org/10.1093/cid/ciaa1125DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7768745PMC
August 2020

What is the role of the EUCAST reference method for MIC testing of the Mycobacterium tuberculosis complex?

Clin Microbiol Infect 2020 Nov 6;26(11):1453-1455. Epub 2020 Aug 6.

APHP-GHU Nord site Bichat, Service de Mycobactériologie Spécialisée et de Référence, Laboratoire Associé du Centre National de Référence des Mycobactéries et de la Résistance des Mycobactéries aux Antituberculeux (CNR-MyRMA), Paris, France; Université de Paris, INSERM, IAME UMR1137, Paris, France. Electronic address:

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http://dx.doi.org/10.1016/j.cmi.2020.07.037DOI Listing
November 2020

Treatment of nontuberculous mycobacterial pulmonary disease: an official ATS/ERS/ESCMID/IDSA clinical practice guideline.

Eur Respir J 2020 07 7;56(1). Epub 2020 Jul 7.

Divisions of Infectious Diseases, Schools of Public Health and Medicine, Oregon Health and Science University, Portland, OR, USA.

Nontuberculous mycobacteria (NTM) represent over 190 species and subspecies, some of which can produce disease in humans of all ages and can affect both pulmonary and extrapulmonary sites. This guideline focuses on pulmonary disease in adults (without cystic fibrosis or human immunodeficiency virus infection) caused by the most common NTM pathogens such as complex, , and among the slowly growing NTM and among the rapidly growing NTM. A panel of experts was carefully selected by leading international respiratory medicine and infectious diseases societies (ATS, ERS, ESCMID, IDSA) and included specialists in pulmonary medicine, infectious diseases and clinical microbiology, laboratory medicine, and patient advocacy. Systematic reviews were conducted around each of 22 PICO (Population, Intervention, Comparator, Outcome) questions and the recommendations were formulated, written, and graded using the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) approach. Thirty-one evidence-based recommendations about treatment of NTM pulmonary disease are provided. This guideline is intended for use by healthcare professionals who care for patients with NTM pulmonary disease, including specialists in infectious diseases and pulmonary diseases.
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http://dx.doi.org/10.1183/13993003.00535-2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8375621PMC
July 2020

Treatment of Nontuberculous Mycobacterial Pulmonary Disease: An Official ATS/ERS/ESCMID/IDSA Clinical Practice Guideline.

Clin Infect Dis 2020 08;71(4):e1-e36

Divisions of Infectious Diseases, Schools of Public Health and Medicine, Oregon Health and Science University, Portland, Oregon, USA.

Nontuberculous mycobacteria (NTM) represent over 190 species and subspecies, some of which can produce disease in humans of all ages and can affect both pulmonary and extrapulmonary sites. This guideline focuses on pulmonary disease in adults (without cystic fibrosis or human immunodeficiency virus infection) caused by the most common NTM pathogens such as Mycobacterium avium complex, Mycobacterium kansasii, and Mycobacterium xenopi among the slowly growing NTM and Mycobacterium abscessus among the rapidly growing NTM. A panel of experts was carefully selected by leading international respiratory medicine and infectious diseases societies (ATS, ERS, ESCMID, IDSA) and included specialists in pulmonary medicine, infectious diseases and clinical microbiology, laboratory medicine, and patient advocacy. Systematic reviews were conducted around each of 22 PICO (Population, Intervention, Comparator, Outcome) questions and the recommendations were formulated, written, and graded using the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) approach. Thirty-one evidence-based recommendations about treatment of NTM pulmonary disease are provided. This guideline is intended for use by healthcare professionals who care for patients with NTM pulmonary disease, including specialists in infectious diseases and pulmonary diseases.
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http://dx.doi.org/10.1093/cid/ciaa241DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7768748PMC
August 2020

Recovery of aerobic gram-negative bacteria from the Copan Eswab transport system after long-term storage.

Diagn Microbiol Infect Dis 2020 Sep 6;98(1):115100. Epub 2020 Jun 6.

Radboudumc Center for Infectious Diseases, Department of Medical Microbiology, Radboud university medical center, Nijmegen, The Netherlands. Electronic address:

We evaluated the Copan Eswab transport system for the quantitative recovery of Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa after 1, 2, 3, 5, and 7 days of storage at room and refrigerator temperatures, and 7 and 30 days of storage at -80 °C and -20 °C using mono- and polymicrobial samples. The study was based on Clinical and Laboratory Standards Institute (CLSI) M40-A2 standard procedures on the quality control of microbiological transport systems. Eswab met the CLSI standards at room and refrigerator temperatures for all (combinations of) bacterial strains tested. At room temperature, after 24 h, bacterial growth was observed. At -80 °C, bacterial viability was maintained in monomicrobial samples; however, in polymicrobial samples, P. aeruginosa recovery was compromised. Storage at -20 °C was unsuitable. We conclude that specimens collected using Eswab should be transported to the laboratory as soon as possible. If transport or processing is delayed, specimens should preferably be stored at refrigerator temperatures.
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http://dx.doi.org/10.1016/j.diagmicrobio.2020.115100DOI Listing
September 2020

BCG Vaccination in Humans Elicits Trained Immunity via the Hematopoietic Progenitor Compartment.

Cell Host Microbe 2020 08 15;28(2):322-334.e5. Epub 2020 Jun 15.

Quantitative Systems Biology, Life & Medical Sciences Institute, University of Bonn, 53115 Bonn, Germany; Single Cell Genomics and Epigenomics Unit at the German Center for Neurodegenerative Diseases and the University of Bonn, 53175 Bonn, Germany. Electronic address:

Induction of trained immunity by Bacille-Calmette-Guérin (BCG) vaccination mediates beneficial heterologous effects, but the mechanisms underlying its persistence and magnitude remain elusive. In this study, we show that BCG vaccination in healthy human volunteers induces a persistent transcriptional program connected to myeloid cell development and function within the hematopoietic stem and progenitor cell (HSPC) compartment in the bone marrow. We identify hepatic nuclear factor (HNF) family members 1a and b as crucial regulators of this transcriptional shift. These findings are corroborated by higher granulocyte numbers in BCG-vaccinated infants, HNF1 SNP variants that correlate with trained immunity, and elevated serum concentrations of the HNF1 target alpha-1 antitrypsin. Additionally, transcriptomic HSPC remodeling was epigenetically conveyed to peripheral CD14 monocytes, displaying an activated transcriptional signature three months after BCG vaccination. Taken together, transcriptomic, epigenomic, and functional reprogramming of HSPCs and peripheral monocytes is a hallmark of BCG-induced trained immunity in humans.
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http://dx.doi.org/10.1016/j.chom.2020.05.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7295478PMC
August 2020
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