scholarly journals Systemic Infection Facilitates Transmission of Pseudomonas aeruginosa

2019 ◽  
Author(s):  
Kelly E. R. Bachta ◽  
Jonathan P. Allen ◽  
Bettina H. Cheung ◽  
Cheng-Hsun Chiu ◽  
Alan R. Hauser
Keyword(s):  
Health Care ◽  
Pseudomonas Aeruginosa ◽  
Mouse Model ◽  
Virulence Factors ◽  
Systemic Infection ◽  
Bloodstream Infections ◽  
Hospitalized Patients ◽  
Dead End ◽  
Health Care Associated Infections ◽  
A Priority

ABSTRACTHealth care-associated infections such as Pseudomonas aeruginosa (PA) bacteremia pose a major clinical risk for hospitalized patients, and efforts to limit them are a priority. The fitness pressures accounting for PA virulence factors that facilitate bloodstream infections are unclear, as these infections are presumed to be a “dead-end” and have no impact on transmission. Here, we used a mouse model to show that PA spreads from the bloodstream to the gallbladder, where it replicates to extremely high numbers. Bacteria in the gallbladder then seed the intestines and feces, leading to transmission to uninfected cage-mate mice. The findings demonstrate that the gallbladder is critical for spread of PA from the bloodstream to the feces during bacteremia, a process that promotes transmission.

scholarly journals Three-year study of health care-associated infections in a Turkish pediatric ward

2014 ◽  
Vol 8 (11) ◽  
pp. 1415-1420 ◽  
Author(s):  
Canan Kuzdan ◽  
Ahmet Soysal ◽  
Gulcan Çulha ◽  
Gulsen Altinkanat ◽  
Guner Soyletir ◽  
...  
Keyword(s):  
Health Care ◽  
Bloodstream Infections ◽  
Blood Stream ◽  
Hospitalized Patients ◽  
University Hospital ◽  
Pediatric Ward ◽  
Control Programmes ◽  
Resistance Patterns ◽  
Health Care Associated Infections ◽  
Tract Infections

Introduction: Health care-associated infections (HCAIs) can cause an increase in morbidity, mortality and costs, especially in developing countries. As information on the epidemiology of HCAIs in pediatric patientsinTurkey is limited, we decided to study the annual incidence and antibiotic resistance patterns in our pediatric ward at Marmara University Hospital. Methodology: All hospitalized patients in the pediatric ward were assessed with regard to HCAIs betweenJanuary 1, 2008 and December 31, 2010. Data was prospectively collected according to standard protocols of the National Nosocomial Infections Surveillance System (NosoLINE). Results: A total of 16.5% of all hospitalized patients developed HCAIs in the three years studied. The most frequent HCAIs were urinary tract infections (UTI) (29.3%), bloodstream infections (27%) and pneumonias (21%). While the most frequent agent isolatedfrom UTI was Escherichia coli (26%), the most common agent in blood stream infections was Staphylococcus epidermidis (30.4%). Vancomycin resistance was found in 73.3% of all Enterococcus faecium strains. Extended-spectrum β-lactamase was detected in 58.3% of Klebsiella pneumoniae and E. coli isolates. Conclusions: Continual HCAI surveillance is important to determineits rate. Knowledge of the HCAI incidence can influence people’s use of broad-spectrum antibiotics and encourage antibiotic rotation. Moreover, the knowledge of HCAI incidence may support the infection control programmes, including education and isolation methods which ultimately may help to reducethe rate of the HCAIs.

Health Care–Associated Infections

2012 ◽  
pp. 458-463
Author(s):  
Rodney L Thompson ◽  
Priya Sampathkumar
Keyword(s):  
Health Care ◽  
Home Health Care ◽  
Bloodstream Infections ◽  
Surgical Site Infections ◽  
Infectious Complications ◽  
Health Care Associated Infections ◽  
Health Care Associated Infection ◽  
Tract Infections ◽  
And Control ◽  
And Training

Health care–associated infection (HAI) is an infection that occurs in hospitals, nursing homes, clinics, or home health care programs. Infection control departments have been constituted to prevent and control infectious complications in health care settings. Prevention and control require combinations of education and training, procedures and policies, surveillance and reporting, and interventions that include isolation and teamwork. Common HAIs (nosocomial infections) include urinary tract infections, surgical site infections, bloodstream infections, and ventilator-associated pneumonia. Diagnosis and treatment of each type of infection are reviewed.

scholarly journals Pseudomonas aeruginosaAlters Its Transcriptome Related to Carbon Metabolism and Virulence as a Possible Survival Strategy in Blood from Trauma Patients

mSystems ◽  
2019 ◽  
Vol 4 (4) ◽  
Author(s):  
Moamen M. Elmassry ◽  
Nithya S. Mudaliar ◽  
Kameswara Rao Kottapalli ◽  
Sharmila Dissanaike ◽  
John A. Griswold ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Healthy Volunteers ◽  
Carbon Metabolism ◽  
Systemic Infection ◽  
Bloodstream Infections ◽  
Trauma Patients ◽  
Type Vi Secretion System ◽  
Content Type ◽  
Causative Agents ◽  
Induced Changes

ABSTRACTTrauma patients (TPs) are highly susceptible to infections, which often lead to sepsis. Among the numerous causative agents,Pseudomonas aeruginosais especially important, asP. aeruginosasepsis is often fatal. Understanding the mechanism of its pathogenesis in bloodstream infections is imperative; however, this mechanism has not been previously described. To examine the effect of trauma-induced changes in blood on the expression ofP. aeruginosagenes, we grew strain UCBPP-PA14 (PA14) in blood samples from eight TPs and seven healthy volunteers (HVs). Compared with its growth in blood from HVs, the growth of PA14 in blood from TPs significantly altered the expression of 285 genes. Genes whose expression was significantly increased were related to carbon metabolism, especially malonate utilization and mannitol uptake, and efflux of heavy metals. Genes whose expression was significantly reduced included genes of the type VI secretion system, genes related to uptake and metabolism of amino acids, and genes related to biosynthesis and transport of the siderophores pyoverdine and pyochelin. These results suggest that during systemic infection in trauma patients, and to adapt to the trauma-induced changes in blood,P. aeruginosaadjusts positively and negatively the expression of numerous genes related to carbon metabolism and virulence, respectively.IMPORTANCEWhile a considerable body of knowledge regarding sepsis in trauma patients is available, the potential influence of trauma-induced changes in the blood of these patients on the pathogenesis ofPseudomonas aeruginosais basically an unexplored area. Rather than using standard laboratory media, we grewP. aeruginosain whole blood from either healthy volunteers or trauma patients. The specific changes in theP. aeruginosatranscriptome in response to growth in blood from trauma patients reflect the adaptation of this organism to the bloodstream environment. This knowledge is vital for understanding the strategies this pathogen uses to adapt and survive within the host during systemic infection. Such information will help researchers and clinicians to develop new approaches for treatment of sepsis caused byP. aeruginosain trauma patients, especially in terms of recognizing the effects of specific therapies (e.g., iron, zinc, or mannitol) on the organism. Further, this information can most likely be extrapolated to all patients withP. aeruginosasepticemia.

Experimental studies of the pathogenesis of infections due to Pseudomonas aeruginosa: extracellular protease and elastase as in vivo virulence factors

1979 ◽  
Vol 25 (5) ◽  
pp. 593-599 ◽  
Author(s):  
Ian Alan Holder ◽  
Constantine G. Haidaris
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Mouse Model ◽  
Proteolytic Activity ◽  
Virulence Factors ◽  
Proteolytic Enzyme ◽  
Experimental Studies ◽  
Toxin Production ◽  
Significant Delay ◽  
Lethal Injection

The effects on mortality of supplemental injections of protease and elastase were determined in burned mice infected with non-lethal inocula of a toxin-producing but non-proteolytic- enzyme-producing strain of Pseudomonas aeruginosa. When a variety of solutions containing proteolytic enzyme were injected under these conditions, the mortality increased significantly. This did not occur when organisms other than P. aeruginosa were used. Injections of the enzyme solutions alone were non-lethal. Injection of a solution of α2-macroglobulin, which was shown to inhibit proteolytic activity, together with a proteolytic enzyme – toxin producing strain of P. aeruginosa caused a significant delay in mortality when compared with controls. It was concluded that protease, elastase, and toxin production were necessary for P. aeruginosa to express full virulence in the burned mouse model.

scholarly journals Development and Application of a Core Genome Multilocus Sequence Typing Scheme for the Health Care-Associated Pathogen Pseudomonas aeruginosa

2020 ◽  
Vol 58 (9) ◽  
Author(s):  
Richard A. Stanton ◽  
Gillian McAllister ◽  
Jonathan B. Daniels ◽  
Erin Breaker ◽  
Nicholas Vlachos ◽  
...  
Keyword(s):  
Health Care ◽  
Pseudomonas Aeruginosa ◽  
Multilocus Sequence Typing ◽  
Core Genome ◽  
Health Care Environment ◽  
Content Type ◽  
Health Care Associated Infections ◽  
Opportunistic Human Pathogen ◽  
The Stability ◽  
Core Genes

ABSTRACT Pseudomonas aeruginosa is an opportunistic human pathogen that frequently causes health care-associated infections (HAIs). Due to its metabolic diversity and ability to form biofilms, this Gram-negative nonfermenting bacterium can persist in the health care environment, which can lead to prolonged HAI outbreaks. We describe the creation of a core genome multilocus sequence typing (cgMLST) scheme to provide a stable platform for the rapid comparison of P. aeruginosa isolates using whole-genome sequencing (WGS) data. We used a diverse set of 58 complete P. aeruginosa genomes to curate a set of 4,440 core genes found in each isolate, representing ∼64% of the average genome size. We then expanded the alleles for each gene using 1,991 contig-level genome sequences. The scheme was used to analyze genomes from four historical HAI outbreaks to compare the phylogenies generated using cgMLST to those of other means (traditional MLST, pulsed-field gel electrophoresis [PFGE], and single-nucleotide variant [SNV] analysis). The cgMLST scheme provides sufficient resolution for analyzing individual outbreaks, as well as the stability for comparisons across a variety of isolates encountered in surveillance studies, making it a valuable tool for the rapid analysis of P. aeruginosa genomes.

scholarly journals Benefit of Having Multiple ampD Genes for Acquiring β-Lactam Resistance without Losing Fitness and Virulence in Pseudomonas aeruginosa

2008 ◽  
Vol 52 (10) ◽  
pp. 3694-3700 ◽  
Author(s):  
Bartolomé Moya ◽  
Carlos Juan ◽  
Sebastián Albertí ◽  
José L. Pérez ◽  
Antonio Oliver
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Mouse Model ◽  
Resistance Mechanism ◽  
Systemic Infection ◽  
Triple Mutant ◽  
Biological Cost ◽  
Sequential Inactivation ◽  
High Level ◽  
Insight Into

ABSTRACT The inactivation of ampD in Pseudomonas aeruginosa leads to a partially derepressed phenotype, characterized by a moderately high level basal ampC expression that is still further inducible, due to the presence of two additional ampD genes in this species (ampDh2 and ampDh3). The sequential inactivation of the three ampD genes was shown to lead to a stepwise upregulation of ampC expression, reaching full derepression in the triple mutant. To gain insight into the biological role of P. aeruginosa AmpD multiplicity, we determined the effects of the inactivation of the ampD genes on fitness and virulence. We show that, in contrast to what was previously documented for Salmonella spp., the inactivation of ampD in P. aeruginosa does not affect fitness or virulence in a mouse model of systemic infection. This lack of effect was demonstrated to be dependent on the presence of the additional ampD genes (ampDh2 and ampDh3), since the double and the triple ampD mutants completely lost their biological competitiveness and virulence; full ampC derepression and disruption of the AmpD peptidoglycan recycling system itself are both found to cause a major biological cost. Furthermore, among the ampD genes, ampDh3 is found to be the most relevant for virulence in P. aeruginosa. Therefore, as a consequence of the presence of additional ampD genes, partial ampC derepression mediated by ampD inactivation confers a biologically efficient resistance mechanism on P. aeruginosa.

scholarly journals Analysis of Cuorum Sensing-Dependent Virulence Factors and Drug Resistance in Pseudomonas Aeruginosa Strains

2021 ◽  
pp. 46-51
Author(s):  
José José de Jesús Alba-Romero ◽  
Pablo Ruiz-Flores ◽  
Graciela Castro-Escarpulli ◽  
Sandra Isabel Hernández-González ◽  
Aurora Martínez-Romero ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Drug Resistance ◽  
Antibiotic Resistance ◽  
Risk Factor ◽  
Virulence Factors ◽  
Virulence Factor ◽  
Protein Analysis ◽  
Hospitalized Patients ◽  
Clinical Samples ◽  
Beta Lactamase

The objective was to analyze the virulence factors dependent on Cuorum Sensing and drug resistance in strains of Pseudomonas aeruginosa. Virulence factors such as pyocyanin, beta-lactamase, biofilm, and antibiotic resistance were determined in 95 strains of P. aeruginosa isolated from hospitalized patients. Genus and species were identified by protein analysis by MALDI-TOF. 100% of the strains were resistant to at least one drug and the highest proportion was 32 strains resistant to 4 drugs and 5 resistant PAM strains. In the analysis of virulence factors, 98.8% produce at least one virulence factor and 48.9% are beta-lactamase producers. Therefore, it is concluded that P. aeruginosa strains isolated from clinical samples constitute a risk factor for hospitalized patients.

scholarly journals Virulence factors genes and drug resistance in Pseudomonas aeruginosa strains derived from different forms of community and healthcare associated infections

2018 ◽  
Vol 72 ◽  
pp. 751-759 ◽  
Author(s):  
Monika Pobiega ◽  
Agnieszka Chmielarczyk ◽  
Joanna Kozioł ◽  
Monika Pomorska-Wesolowska ◽  
Grzegorz Ziolkowski ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Virulence Factors ◽  
Simultaneous Detection ◽  
Bloodstream Infections ◽  
Effector Proteins ◽  
Diffusion Method ◽  
Virulence Determinants ◽  
Chronic Infections ◽  
Hospitalised Patients ◽  
Tract Infections

Background: The pathogenesis of Pseudomonas aeruginosa (PA) infection is multifactorial and depends mainly on two types of virulence determinants: virulence factors involved in acute infections and membrane bound factors, and virulence factors involved in chronic infections. The aim of this laboratory-based study was to analyse the resistance and virulence of PA strains isolated from different types of infections in hospitalised and non-hospitalised patients in Southern Poland. Material/Methods: Non-repetitive samples from urinary tract infections (UTI), bloodstream infections (BSI) and pneumonia (PNU) were collected. Isolates were screened for the presence of virulence factors by PCR method. Antimicrobial susceptibility testing was performed using disc diffusion method. Metallo-beta-lactamases (MBLs) were detected using an imipenem-EDTA double-disc synergy test. Results: There were 232 specimens collected: UTI-152, PNU-69, BSI-11. Fifty-one (22%) strains were classified as multidrug resistant (MDR), 23 (10%) as extensively-drug resistant (XDR). MDR/XDR strains were more frequently isolated from pneumonia (OR = 2.28). The prevalence values for the genes of effector proteins were 82.8% for exoS, 89% for exoY, and 24% for exoU. The simultaneous detection of four effector proteins was confirmed in 10.4% of the strains. pilB was more prevalent in isolates from the elderly (p=0.013). lasB occurred more frequently in PNU (p=0.048). Three of the genes were more prevalent in isolates from patients hospitalised in ICU (lasB (p=0.017), aprA (p=0.022), phzS (p=0.039)). Conclusions: Understanding the contribution of selected virulence genes to the outcome of an infection may be important for the therapeutic management of patients infected with PA. Simultaneous detection of virulence factors and antimicrobial resistance might be particularly useful because both are clinically important during an infection.

scholarly journals EFEKTIFITAS MANDI CHLORHEXIDINE GLUCONATE TERHADAP PENURUNAN ANGKA KEJADIAN HAIs: LITERATURE REVIEW

2020 ◽  
Vol 4 (2) ◽  
pp. 1
Author(s):  
Tia Atnawanty ◽  
Sri Yona ◽  
Riri Maria
Keyword(s):  
Health Care ◽  
Literature Review ◽  
Bloodstream Infections ◽  
Chlorhexidine Gluconate ◽  
Cost Of Care ◽  
Healthcare Associated Infections ◽  
Chlorhexidine Bathing ◽  
Health Care Associated Infections ◽  
Healthcare Associated ◽  
The Cost

INTISARI : Latar Belakang: Insiden Health-care Associated Infections (HAIs) atau infeksi yang berhubungan dengan pelayanan kesehatan di dunia semakin meningkat sehingga menyebabkan morbiditas, mortalitas, dan biaya tinggi bagi rumah sakit. Klorheksidin glukonat sebagai antiseptik dengan aktivitas antimikroba spektrum luas telah ditunjukkan dalam beberapa penelitian sebagaiABSTRAKLatar belakang: Penyakit infeksi di fasilitas kesehatan atau disebut juga Healthcare Associated Infections (HAIs) menjadi masalah besar yang masuk ke rumah sakit karena dapat meningkatkan angka morbiditas (kesakitan), angka mortalitas (kematian) dan menambah biaya perawatan yang besar bagi rumah sakit. Chlorhexidine gluconate sebagai antiseptik dengan aktivitas antimikroba spektrum luas merupakan komponen penting dalam pencegahan infeksi. Rutinitas mandi harian di perawatan kritis dan intensif dan mandi sebelum operasi dengan sabun Chlorhexidine gluconatetelah menurunkan infeksi aliran darah, infeksi daerah operasi dan akuisi organisme patogen berbahaya dan resisten yang terdapat di rumah sakit. Namun karena belum konsistennya hasil penelitian terkait hal ini, akibatnya mandi Chlorhexidine belum dilakukan secara universal sebagai prosedur tetap dan masih menyisakan sampai sekarang. Kajian literatur ini bertujuan untuk menilai efektifitas mandi Chlorhexidine gluconate terhadap penurunan kejadian infeksi yang berkaitan dengan kesehatan dan mikroorganisme penyebabnya.Metode: Penulis melakukan pencarian literatur dengan mengumpulkan beberapa artikel terindeks yang berhubungan dengan topik yang diangkat menggunakan database seperti Clinical key, Elsevier, ProQuest , dan ScienceDirect dengan kata kunci chlorhexidine gluconate, chlorhexidine bathing, health care related infeksi .Hasil: Dari 3871 artikel umum, dilakukan penyaringan menjadi 269 artikel yang terkait, dikumpulkan sebanyak 16 artikel yang sesuai dengan topik dan 8 artikel yang sesuai kriteria sebagai bahan kajian literatur.Kesimpulan: Penulis menyimpulkan bahwa mandi dengan Chlorhexidine gluconate secara rutin penerapan “ bundles ” pencegahan dapat menurunkan prevalensi mikroorganisme berbahaya termasuk kuman patogen yang resisten terhadap antimikroba, namun efektifitas biaya, integritas kulit dan resistensi tetap harus. Kata kunci: chlorhexidine gluconate, mandi chlorhexidine, infeksi terkait perawatan kesehatan ABSTRAKLatar Belakang: Infectious diseases in health facilities also known as Healthcare Associated Infections (HAIs) are major problem facing hospitals because they can increase morbidity rates (pain), mortality rates (deaths) and increase the cost of care for hospitals. Chlorhexidine gluconate as an antiseptic with broad spectrum antimicrobial activity is an important component in infection prevention. Daily bathing routine in critical or intensive care and pre-surgery showers with Chlorhexidine soap have reduced bloodstream infections, surgical area infections and the acquisition of harmful and resistant pathogenic organisms found in hospitals. However, due to the inconsistency of research results related to this matter, as a result chlorhexidine bathing has not been done universally as a permanent procedure and still leaves debate until now. This literature review aims to assess the effectiveness of chlorhexidine gluconate baths in reducing the incidence of infections related to health services and their causative microorganisms. Metode: Penulis melakukan pencarian dengan mengumpulkan beberapa artikel terindeks yang berhubungan dengan topik yang diangkat dari beberapa database seperti Clinical keys, Elsevier, ProQuest dan ScienceDirect dengan kata kunci chlorhexidine gluconate, chlorhexidine bathing, perawatan kesehatan terkait infeksi .Hasil: Dari 3871 artikel umum yang disaring menjadi 269 artikel terkait, didapatkan sebanyak 16 artikel yang sesuai dengan topik dan 8 artikel yang memenuhi kriteria sebagai bahan studi literatur.Kesimpulan: Penulis menyimpulkan bahwa mandi dengan klorheksidin glukonat secara rutin dengan aplikasi “bundel” pencegahan infeksi dapat menurunkan prevalensi mikroorganisme berbahaya termasuk patogen resisten antimikroba, namun pertimbangan efektivitas biaya, integritas kulit, dan resistensi tetap harus diperhatikan. Kata kunci: klorheksidin glukonat, mandi klorheksidin, infeksi terkait perawatan kesehatankomponen tant dalam pencegahan infeksi di unit perawatan pasien. Salah satunya dengan rutinitas mandi sehari-hari di ruang perawatan kritis / intensif dan mandi sebelum operasi dengan sabun klorheksidin telah mengurangi infeksi aliran darah, infeksi area operasi dan didapatnya organisme patogen berbahaya dan resisten yang terdapat di rumah sakit. Namun karena ketidakkonsistenan hasil penelitian terkait hal tersebut, akibatnya mandi klorheksidin belum dilakukan secara universal sebagai prosedur permanen dan masih menyisakan perdebatan hingga saat ini. Tinjauan pustaka ini bertujuan untuk menilai keefektifan mandi klorheksidin glukonat dalam mengurangi kejadian infeksi yang berkaitan dengan layanan kesehatan dan mikroorganisme penyebabnya.Metode: Metode yang digunakan adalah penelusuran literatur baik nasional maupun internasional yang dilakukan dengan menggunakan database Clinical keys, Elsevier, ProQuest, dan lain-lain.Hasil: Dari hasil pencarian diperoleh sebanyak 22 artikel terkait yang dijadikan studi literatur.Kesimpulan: Penulis menyimpulkan bahwa mandi dengan klorheksidin glukonat secara rutin dengan aplikasi “bundel” pencegahan infeksi dapat menurunkan prevalensi mikroorganisme berbahaya termasuk patogen resisten antimikroba, namun pertimbangan efektivitas biaya, integritas kulit, dan resistensi tetap harus diperhatikan.

The Effects of Chlorhexidine Dressing on Health Care-Associated Infection in Hospitalized Patients: A Meta-Analysis

2019 ◽  
Author(s):  
Hou-Xing WANG ◽  
Shu-Yuan XIE ◽  
Hao WANG ◽  
Hao-Kai CHU
Keyword(s):  
Health Care ◽  
English Language ◽  
Meta Analysis ◽  
Bloodstream Infections ◽  
Hospitalized Patients ◽  
Cochrane Library ◽  
Control Group ◽  
Forest Plot ◽  
Catheter Colonization ◽  
Health Care Associated Infection

Background: To assess the effects of chlorhexidine dressing on health care-associated infection in hospitalized patients. Methods: We searched for English-language published randomized controlled trials (RCTs) in Cochrane Library, EMBASE and PubMed between January 1998 and January 2018. We used meta-analysis to calculate the risk ratios (RRs) and 95% confidence intervals (CIs) of the data, and using the I2 assessment to summarize the heterogeneity of RCTs and the funnel plot and Egger regression test to evaluate publication bias. Results: A total of 13 RCTs were included in our meta-analysis, including 7555 patients and 11,931 catheters. The effects of chlorhexidine dressing on the incidence of catheter-related bloodstream infections (CRBSIs) were reported in 13 RCTs, and the incidence of CRBSIs were 1.3% (80/6160) in the chlorhexidine group and 2.5% (145/5771) in the control group. We used a forest plot to determine the risk ratio (RR) of chlorhexidine dressing on the incidence of CRBSIs, and our results showed that chlorhexidine dressing significantly reduced the incidence of CRBSIs (RR 0.55, 95% CI 0.39-0.77, P<0.001). Moreover, we also analyzed the effects of chlorhexidine dressing on the incidence of catheter colonization and catheter-related infections (CRIs), and our forest plot results showed that chlorhexidine dressing significantly reduced the incidence of catheter colonization (RR 0.52, 95% CI 0.40-0.67, P<0.001) and the incidence of CRIs (RR 0.43, 95% CI 0.28-0.66, P<0.001) in hospitalized patients. Conclusion: The use of chlorhexidine dressings for hospitalized patients significantly reduce the incidence of CRBSIs, catheter colonization and CRIs.

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