scholarly journals An ST131 clade and a Phylogroup A clade bearing a novel Escherichia coli O-antigen cluster predominate among bloodstream E. coli isolates from southwest Nigeria hospitals

2021 ◽  
Author(s):  
Ayorinde O. Afolayan ◽  
Aaron O. Aboderin ◽  
Anderson O. Oaikhena ◽  
Erkison Ewomazino Odih ◽  
Veronica O. Ogunleye ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
High Risk ◽  
Antimicrobial Resistance ◽  
Bloodstream Infections ◽  
Whole Genome ◽  
Southwestern Nigeria ◽  
Common Cause ◽  
E Coli ◽  
Factors Associated ◽  
Southwest Nigeria

Escherichia coli bloodstream infections are typically attributed to a limited number of lineages that carry virulence factors associated with invasion and, in recent years, are increasingly multiply antimicrobial resistant. In Nigeria, E. coli is a common cause of bloodstream infections but the identity of circulating clones is largely unknown and surveillance of their antimicrobial resistance has been limited. We verified, susceptibility-tested and whole genome-sequenced 68 bloodstream E. coli isolates recovered between 2016 and 2018 at three sentinel sites in southwestern Nigeria. Resistance to antimicrobials commonly used in Nigeria was high, reaching 100 % (n = 67) for trimethoprim, 92.5 % (n = 62) for ampicillin, 79.1 % (n = 53) for ciprofloxacin, and 55.2 % (n = 37) for aminoglycosides. All the isolates were susceptible to carbapenems and colistin. The strain set included isolates from globally disseminated high-risk clones including those belonging to ST12 (n=2), ST131 (n=12), and ST648 (n = 4). Twenty-three (33.82%) of the isolates clustered within two clades. The first of these consisted of ST131 strains, comprised of O16:H5 and O25:H4 sub-lineages. The second was an ST10-ST167 complex clade comprised of strains carrying capsular genes that may have originated in Klebsiella. We additionally determined that four ST90 strains from one sentinel represented a retrospectively detected outbreak. Our data demonstrate that a broad repertoire of invasive E. coli isolates cause bloodstream infections in southwest Nigeria. In addition to pandemic lineages, particularly ST131, these include a previously undescribed lineage. Genomic surveillance is valuable for tracking these and other clones and for outbreak identification.

scholarly journals Genomic evolution of antimicrobial resistance in Escherichia coli

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Pimlapas Leekitcharoenphon ◽  
Markus Hans Kristofer Johansson ◽  
Patrick Munk ◽  
Burkhard Malorny ◽  
Magdalena Skarżyńska ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Antimicrobial Resistance ◽  
Virulence Genes ◽  
Mobile Genetic Elements ◽  
Whole Genome ◽  
Sequencing Analysis ◽  
Metagenomic Sequencing ◽  
Fecal Samples ◽  
E Coli ◽  
Genetic Elements

AbstractThe emergence of antimicrobial resistance (AMR) is one of the biggest health threats globally. In addition, the use of antimicrobial drugs in humans and livestock is considered an important driver of antimicrobial resistance. The commensal microbiota, and especially the intestinal microbiota, has been shown to have an important role in the emergence of AMR. Mobile genetic elements (MGEs) also play a central role in facilitating the acquisition and spread of AMR genes. We isolated Escherichia coli (n = 627) from fecal samples in respectively 25 poultry, 28 swine, and 15 veal calf herds from 6 European countries to investigate the phylogeny of E. coli at country, animal host and farm levels. Furthermore, we examine the evolution of AMR in E. coli genomes including an association with virulence genes, plasmids and MGEs. We compared the abundance metrics retrieved from metagenomic sequencing and whole genome sequenced of E. coli isolates from the same fecal samples and farms. The E. coli isolates in this study indicated no clonality or clustering based on country of origin and genetic markers; AMR, and MGEs. Nonetheless, mobile genetic elements play a role in the acquisition of AMR and virulence genes. Additionally, an abundance of AMR was agreeable between metagenomic and whole genome sequencing analysis for several AMR classes in poultry fecal samples suggesting that metagenomics could be used as an indicator for surveillance of AMR in E. coli isolates and vice versa.

scholarly journals Extraintestinal pathogenic Escherichia coli in Saudi Arabia: A review of antimicrobial resistance and molecular epidemiology

2020 ◽  
Vol 19 (2) ◽  
pp. 447-453
Author(s):  
Abdulaziz Alqasim
Keyword(s):  
Escherichia Coli ◽  
Saudi Arabia ◽  
Antimicrobial Resistance ◽  
Molecular Epidemiology ◽  
Bloodstream Infections ◽  
Epidemiological Studies ◽  
Colistin Resistance ◽  
E Coli ◽  
Extended Spectrum ◽  
Pathogenic Escherichia Coli

Extra-intestinal pathogenic Escherichia coli (ExPEC) is commonly associated with causing urinary tract and bloodstream infections. Over the past two decades, the antimicrobial resistance of ExPEC has increasingly been reported [1]. Given that Saudi Arabia annually hosts mass religious events, such as Hajj, this review investigated several aspects of antimicrobial resistance of ExPEC in this country including the current prevalence of resistance and molecular epidemiology of ExPEC isolates. Generally, the overall prevalence of antibiotic resistance of ExPEC in Saudi Arabia is on increase. The current emergence of colistin resistance in ExPEC represents a major challenge to public health. Local molecular epidemiological studies have shown the dominance of E. coli sequence type 131 (E. coli ST131) over other major ExPEC STs. This is an important observation given that this clone has been associated with high multidrug resistance and extended-spectrum β-lactamases carriage. To reduce the burden of this resistance in the future, it would be crucial to avoid uncontrolled use of antibiotics in either clinical settings or animal food industry. Keywords: Extra-intestinal pathogenic Escherichia coli, Antimicrobial resistance, ST131, Saudi Arabia, Colistin resistance, Extended-spectrum β-lactamases

scholarly journals Escherichia coliSequence Type 410 Is Causing New International High-Risk Clones

mSphere ◽  
2018 ◽  
Vol 3 (4) ◽  
pp. e00337-18 ◽  
Author(s):  
Louise Roer ◽  
Søren Overballe-Petersen ◽  
Frank Hansen ◽  
Kristian Schønning ◽  
Mikala Wang ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
High Risk ◽  
Antimicrobial Resistance ◽  
Sequence Type ◽  
Recurrent Infections ◽  
Content Type ◽  
E Coli ◽  
The Past ◽  
Carbapenemase Gene ◽  
Globally Distributed

ABSTRACTEscherichia colisequence type 410 (ST410) has been reported worldwide as an extraintestinal pathogen associated with resistance to fluoroquinolones, third-generation cephalosporins, and carbapenems. In the present study, we investigated national epidemiology of ST410E. coliisolates from Danish patients. Furthermore,E. coliST410 was investigated in a global context to provide further insight into the acquisition of the carbapenemase genesblaOXA-181andblaNDM-5of this successful lineage. From 127 whole-genome-sequenced isolates, we reconstructed an evolutionary framework ofE. coliST410 which portrays the antimicrobial-resistant clades B2/H24R, B3/H24Rx, and B4/H24RxC. The B2/H24R and B3/H24Rx clades emerged around 1987, concurrently with the C1/H30R and C2/H30Rx clades inE. coliST131. B3/H24Rx appears to have evolved by the acquisition of the extended-spectrum β-lactamase (ESBL)-encoding geneblaCTX-M-15and an IncFII plasmid, encoding IncFIA and IncFIB. Around 2003, the carbapenem-resistant clade B4/H24RxC emerged when ST410 acquired an IncX3 plasmid carrying ablaOXA-181carbapenemase gene. Around 2014, the clade B4/H24RxC acquired a second carbapenemase gene,blaNDM-5, on a conserved IncFII plasmid. From an epidemiological investigation of 49E. coliST410 isolates from Danish patients, we identified five possible regional outbreaks, of which one outbreak involved nine patients withblaOXA-181- andblaNDM-5-carrying B4/H24RxC isolates. The accumulated multidrug resistance inE. coliST410 over the past two decades, together with its proven potential of transmission between patients, poses a high risk in clinical settings, and thus,E. coliST410 should be considered a lineage with emerging “high-risk” clones, which should be monitored closely in the future.IMPORTANCEExtraintestinal pathogenicEscherichia coli(ExPEC) is the main cause of urinary tract infections and septicemia. Significant attention has been given to the ExPEC sequence type ST131, which has been categorized as a “high-risk” clone. High-risk clones are globally distributed clones associated with various antimicrobial resistance determinants, ease of transmission, persistence in hosts, and effective transmission between hosts. The high-risk clones have enhanced pathogenicity and cause severe and/or recurrent infections. We show that clones of theE. coliST410 lineage persist and/or cause recurrent infections in humans, including bloodstream infections. We found evidence of ST410 being a highly resistant globally distributed lineage, capable of patient-to-patient transmission causing hospital outbreaks. Our analysis suggests that the ST410 lineage should be classified with the potential to cause new high-risk clones. Thus, with the clonal expansion over the past decades and increased antimicrobial resistance to last-resort treatment options, ST410 needs to be monitored prospectively.

scholarly journals Genomic surveillance of Escherichia coli and Klebsiella spp. in hospital sink drains and patients

2020 ◽  
Vol 6 (7) ◽  
Author(s):  
Bede Constantinides ◽  
Kevin K. Chau ◽  
T. Phuong Quan ◽  
Gillian Rodger ◽  
Monique I. Andersson ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Antimicrobial Resistance ◽  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Type Species ◽  
Whole Genome ◽  
Content Type ◽  
E Coli ◽  
Link Type ◽  
Antimicrobial Resistance Genes

Escherichia coli and Klebsiella spp. are important human pathogens that cause a wide spectrum of clinical disease. In healthcare settings, sinks and other wastewater sites have been shown to be reservoirs of antimicrobial-resistant E. coli and Klebsiella spp., particularly in the context of outbreaks of resistant strains amongst patients. Without focusing exclusively on resistance markers or a clinical outbreak, we demonstrate that many hospital sink drains are abundantly and persistently colonized with diverse populations of E. coli , Klebsiella pneumoniae and Klebsiella oxytoca , including both antimicrobial-resistant and susceptible strains. Using whole-genome sequencing of 439 isolates, we show that environmental bacterial populations are largely structured by ward and sink, with only a handful of lineages, such as E. coli ST635, being widely distributed, suggesting different prevailing ecologies, which may vary as a result of different inputs and selection pressures. Whole-genome sequencing of 46 contemporaneous patient isolates identified one (2 %; 95 % CI 0.05–11 %) E. coli urine infection-associated isolate with high similarity to a prior sink isolate, suggesting that sinks may contribute to up to 10 % of infections caused by these organisms in patients on the ward over the same timeframe. Using metagenomics from 20 sink-timepoints, we show that sinks also harbour many clinically relevant antimicrobial resistance genes including bla CTX-M, bla SHV and mcr, and may act as niches for the exchange and amplification of these genes. Our study reinforces the potential role of sinks in contributing to Enterobacterales infection and antimicrobial resistance in hospital patients, something that could be amenable to intervention. This article contains data hosted by Microreact.

Genetic diversity of enteroaggregative Escherichia coli

2020 ◽  
Vol 65 (11) ◽  
pp. 707-711
Author(s):  
M. A. Makarova ◽  
L. A. Kaftyreva
Keyword(s):  
Escherichia Coli ◽  
Genetic Diversity ◽  
High Risk ◽  
Urine Samples ◽  
Whole Genome ◽  
Epidemic Spread ◽  
E Coli ◽  
Genes Encoding ◽  
Stool Samples ◽  
O Antigens

Studied 74 E. coli strains isolated from stool samples (60) and urine samples (14) of patients examined for clinical indications. Molecular methods included: PCR with electrophoretic detection of genes associated with diarrheal E. coli pathogroup EAgEC (aggR, aaf, aap, aatA, pet, ast, aai) and ExPEC pathogroup UPEC (pap, sfa, afa, kpsMT II, iutA, hlyA, cnf), MLST typing, whole genome sequencing. Strains isolated from stool samples were significantly more likely (88.3%, p > 0.05) to be typical EAgECaggR+ compared to atypical EAgECaggR-. Strains isolated from urine samples, significant differences between typical and atypical EAgEC were not detected (p > 0.05). Genes associated with ExPEC were present in all strains isolated from urine samples and in 45 strains (75%) isolated from stool samples. Coproisolates belonged to 10 serogroups and 13 serovars: O3:H2, O11:H10, O16:H48, O51:H30, O55:H21, O73:H18, O73:H33, O86:H2, O86:H10, O92:H33, O140:H2, O159:H10. Two strains had unique nucleotide sequences of genes encoding O-antigens that were missing from the SerotypeFinder database. 80% of EAgEC isolated from feces and urine was characterized by an enteroaggregative/uropathogenic genotype (EAgEC/UPEC). Most of the strains isolated from urine belonged to the virulent clone of high-risk epidemic spread ST 38 associated with hybrid strains of UPEC / EAgEC.

scholarly journals Three cases of mcr-1-positive colistin-resistant Escherichia coli bloodstream infections in Italy, August 2016 to January 2017

2017 ◽  
Vol 22 (16) ◽  
Author(s):  
Marta Corbella ◽  
Bianca Mariani ◽  
Carolina Ferrari ◽  
Francesco Comandatore ◽  
Erika Scaltriti ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Multidrug Resistance ◽  
Whole Genome Sequencing ◽  
Bloodstream Infection ◽  
Genome Sequencing ◽  
Bloodstream Infections ◽  
Tertiary Hospital ◽  
Whole Genome ◽  
E Coli ◽  
Sequence Types

We describe three cases of bloodstream infection caused by colistin-resistant Escherichia coli in patients in a tertiary hospital in Italy, between August 2016 and January 2017. Whole genome sequencing detected the mcr-1 gene in three isolated strains belonging to different sequence types (STs). This occurrence of three cases with mcr-1-positive E. coli belonging to different STs in six months suggests a widespread problem in settings where high multidrug resistance is endemic such as in Italy.

scholarly journals Socioeconomic factors associated with antimicrobial resistance of Pseudomonas aeruginosa, Staphylococcus aureus, and Escherichia coli in Chilean hospitals (2008–2017)

2020 ◽  
Vol 44 ◽  
pp. 1
Author(s):  
Kasim Allel ◽  
Patricia García ◽  
Jaime Labarca ◽  
José M. Munita ◽  
Magdalena Rendic ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Staphylococcus Aureus ◽  
Pseudomonas Aeruginosa ◽  
Antimicrobial Resistance ◽  
Socioeconomic Factors ◽  
Resistance Rate ◽  
Public Hospitals ◽  
Socioeconomic Indicators ◽  
E Coli ◽  
Factors Associated

Objective. To identify socioeconomic factors associated with antimicrobial resistance of Pseudomonas aeruginosa, Staphylococcus aureus, and Escherichia coli in Chilean hospitals (2008–2017). Methods. We reviewed the scientific literature on socioeconomic factors associated with the emergence and dissemination of antimicrobial resistance. Using multivariate regression, we tested findings from the literature drawing from a longitudinal dataset on antimicrobial resistance from 41 major private and public hospitals and a nationally representative household survey in Chile (2008–2017). We estimated resistance rates for three priority antibiotic–bacterium pairs, as defined by the Organisation for Economic Co-operation and Development; i.e., imipenem and meropenem resistant P. aeruginosa, cloxacillin resistant S. aureus, and cefotaxime and ciprofloxacin resistant E. coli. Results. Evidence from the literature review suggests poverty and material deprivation are important risk factors for the emergence and transmission of antimicrobial resistance. Most studies found that worse socioeconomic indicators were associated with higher rates of antimicrobial resistance. Our analysis showed an overall antimicrobial resistance rate of 32.5%, with the highest rates for S. aureus (40.6%) and the lowest for E. coli (25.7%). We found a small but consistent negative association between socioeconomic factors (income, education, and occupation) and overall antimicrobial resistance in univariate (p < 0.01) and multivariate analyses (p < 0.01), driven by resistant P. aeruginosa and S. aureus. Conclusion. Socioeconomic factors beyond health care and hospital settings may affect the emergence and dissemination of antimicrobial resistance. Preventing and controlling antimicrobial resistance requires efforts above and beyond reducing antibiotic consumption.

scholarly journals Identification of Risk Factors Associated with Resistant Escherichia coli Isolates from Poultry Farms in the East Coast of Peninsular Malaysia: A Cross Sectional Study

Antibiotics ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 117
Author(s):  
Sharifo Ali Elmi ◽  
David Simons ◽  
Linzy Elton ◽  
Najmul Haider ◽  
Muzamil Mahdi Abdel Hamid ◽  
...  
Keyword(s):  
Risk Factors ◽  
Escherichia Coli ◽  
Antimicrobial Resistance ◽  
East Coast ◽  
Tap Water ◽  
Peninsular Malaysia ◽  
E Coli ◽  
Factors Associated ◽  
Poultry Farms ◽  
Resistance Patterns

Antimicrobial resistance is of concern to global health security worldwide. We aimed to identify the prevalence, resistance patterns, and risk factors associated with Escherichia coli (E. coli) resistance from poultry farms in Kelantan, Terengganu, and Pahang states of east coast peninsular Malaysia. Between 8 February 2019 and 23 February 2020, a total of 371 samples (cloacal swabs = 259; faecal = 84; Sewage = 14, Tap water = 14) were collected. Characteristics of the sampled farms including management type, biosecurity, and history of disease were obtained using semi-structured questionnaire. Presumptive E. coli isolates were identified based on colony morphology with subsequent biochemical and PCR confirmation. Susceptibility of isolates was tested against a panel of 12 antimicrobials and interpreted alongside risk factor data obtained from the surveys. We isolated 717 E. coli samples from poultry and environmental samples. Our findings revealed that cloacal (17.8%, 46/259), faecal (22.6%, 19/84), sewage (14.3%, 2/14) and tap water (7.1%, 1/14) were significantly (p < 0.003) resistant to at least three classes of antimicrobials. Resistance to tetracycline class were predominantly observed in faecal samples (69%, 58/84), followed by cloacal (64.1%, 166/259), sewage (35.7%, 5/14), and tap water (7.1%, 1/84), respectively. Sewage water (OR = 7.22, 95% CI = 0.95–151.21) had significant association with antimicrobial resistance (AMR) acquisition. Multivariate regression analysis identified that the risk factors including sewage samples (OR = 7.43, 95% CI = 0.96–156.87) and farm size are leading drivers of E. coli antimicrobial resistance in the participating states of east coast peninsular Malaysia. We observed that the resistance patterns of E. coli isolates against 12 panel antimicrobials are generally similar in all selected states of east coast peninsular Malaysia. The highest prevalence of resistance was recorded in tetracycline (91.2%), oxytetracycline (89.1%), sulfamethoxazole/trimethoprim (73.1%), doxycycline (63%), and sulfamethoxazole (63%). A close association between different risk factors and the high prevalence of antimicrobial-resistant E. coli strains reflects increased exposure to resistant bacteria and suggests a concern over rising misuse of veterinary antimicrobials that may contribute to the future threat of emergence of multidrug-resistant pathogen isolates. Public health interventions to limit antimicrobial resistance need to be tailored to local poultry farm practices that affect bacterial transmission.

scholarly journals Multiple and High-Risk Clones of Extended-Spectrum Cephalosporin-Resistant and blaNDM-5-Harbouring Uropathogenic Escherichia coli from Cats and Dogs in Thailand

Antibiotics ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 1374
Author(s):  
Naiyaphat Nittayasut ◽  
Jitrapa Yindee ◽  
Pongthai Boonkham ◽  
Teerapong Yata ◽  
Nipattra Suanpairintr ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
High Risk ◽  
Antimicrobial Resistance ◽  
Resistance Genes ◽  
Multidrug Resistant ◽  
Integrase Gene ◽  
E Coli ◽  
Extended Spectrum ◽  
Antimicrobial Resistance Genes ◽  
Tract Infections

Resistance to extended-spectrum cephalosporins (ESC) and carbapenems in Escherichia coli (E. coli), increasingly identified in small animals, indicates a crisis of an antimicrobial resistance situation in veterinary medicine and public health. This study aimed to characterise the genetic features of ESC-resistant E. coli isolated from cats and dogs with urinary tract infections in Thailand. Of 72 ESC-resistant E. coli isolated from diagnostic samples (2016–2018), blaCTX-M including group 1 (CTX-M-55, -15 and -173) and group 9 (CTX-M-14, -27, -65 and -90) variants were detected in 47 isolates (65.28%) using PCR and DNA sequencing. Additional antimicrobial resistance genes, including plasmid-mediated AmpC (CIT and DHA), blaNDM-5, mcr-3, mph(A) and aac(6′)-Ib-cr, were detected in these isolates. Using a broth microdilution assay, all the strains exhibited multidrug-resistant phenotypes. The phylogroups were F (36.11%), A (20.83%), B1 (19.44%), B2 (19.44%) and D (4.17%), with several virulence genes, plasmid replicons and an integrase gene. The DNA fingerprinting using a repetitive extragenic palindromic sequence-PCR presented clonal relationships within phylogroups. Multiple human-associated, high-risk ExPEC clones associated with multidrug resistance, including sequence type (ST) 38, ST131, ST224, ST167, ST354, ST410, ST617 and ST648, were identified, suggesting clonal dissemination. Dogs and cats are a potential reservoir of ESC-resistant E. coli and significant antimicrobial resistance genes.

scholarly journals Increasing incidence and antimicrobial resistance in Escherichia coli bloodstream infections: a multinational population-based cohort study

2021 ◽  
Vol 10 (1) ◽  
Author(s):  
Melissa C. MacKinnon ◽  
Scott A. McEwen ◽  
David L. Pearl ◽  
Outi Lyytikäinen ◽  
Gunnar Jacobsson ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Incidence Rate ◽  
Bloodstream Infections ◽  
Generation Cephalosporin ◽  
Population Based ◽  
Incidence Rates ◽  
Third Generation ◽  
Common Cause ◽  
E Coli ◽  
Cephalosporin Resistance

Abstract Background Escherichia coli is an important pathogen in humans and is the most common cause of bacterial bloodstream infections (BSIs). The objectives of our study were to determine factors associated with E. coli BSI incidence rate and third-generation cephalosporin resistance in a multinational population-based cohort. Methods We included all incident E. coli BSIs (2014–2018) from national (Finland) and regional (Australia [Canberra], Sweden [Skaraborg], and Canada [Calgary, Sherbrooke, and western interior]) surveillance. Incidence rates were directly age and sex standardized to the European Union 28-country 2018 population. Multivariable negative binomial and logistic regression models estimated factors significantly associated with E. coli BSI incidence rate and third-generation cephalosporin resistance, respectively. The explanatory variables considered for inclusion in both models were year (2014–2018), region (six areas), age (< 70-years-old and ≥ 70-years-old), and sex (female and male). Results We identified 31,889 E. coli BSIs from 40.7 million person-years of surveillance. Overall and third-generation cephalosporin-resistant standardized rates were 87.1 and 6.6 cases/100,000 person-years, respectively, and increased 14.0% and 40.1% over the five-year study. Overall, 7.8% (2483/31889) of E. coli BSIs were third-generation cephalosporin-resistant. Calgary, Canberra, Sherbrooke, and western interior had significantly lower E. coli BSI rates compared to Finland. The significant association between age and E. coli BSI rate varied with sex. Calgary, Canberra, and western interior had significantly greater odds of third-generation cephalosporin-resistant E. coli BSIs compared to Finland. Compared to 2014, the odds of third-generation cephalosporin-resistant E. coli BSIs were significantly increased in 2016, 2017, and 2018. The significant association between age and the odds of having a third-generation cephalosporin-resistant E. coli BSI varied with sex. Conclusions Increases in overall and third-generation cephalosporin-resistant standardized E. coli BSI rates were clinically important. Overall, E. coli BSI incidence rates were 40–104% greater than previous investigations from the same study areas. Region, sex, and age are important variables when analyzing E. coli BSI rates and third-generation cephalosporin resistance in E. coli BSIs. Considering E. coli is the most common cause of BSIs, this increasing burden and evolving third-generation cephalosporin resistance will have an important impact on human health, especially in aging populations.

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