scholarly journals Longitudinal surveillance of outpatient β-lactam antimicrobial use in Canada, 1995 to 2010

2014 ◽  
Vol 25 (2) ◽  
pp. 107-112 ◽  
Author(s):  
Shiona K Glass-Kaastra ◽  
Rita Finley ◽  
Jim Hutchinson ◽  
David M Patrick ◽  
Karl Weiss ◽  
...  
Keyword(s):  
Antimicrobial Resistance ◽  
Broad Spectrum ◽  
Population Data ◽  
Time Frame ◽  
Repeated Measurements ◽  
Antimicrobial Use ◽  
Defined Daily Doses ◽  
Canadian Provinces ◽  
Statistics Canada ◽  
Over Time

INTRODUCTION: β-lactam antimicrobials are the most commonly prescribed group of antimicrobials in Canada, and are categorized by the WHO as critically and highly important antimicrobials for human medicine. Because antimicrobial use is commonly associated with the development of antimicrobial resistance, monitoring the volume and patterns of use of these agents is highly important.OBJECTIVE: To assess the use of penicillin and cephalosporin antimicrobials within Canadian provinces over the 1995 to 2010 time frame according to two metrics: prescriptions per 1000 inhabitant-days and the average defined daily doses dispensed per prescription.METHODS: Antimicrobial prescribing data were acquired from the Canadian Integrated Program for Antimicrobial Resistance Surveillance and the Canadian Committee for Antimicrobial Resistance, and population data were obtained from Statistics Canada. The two measures developed were used to produce linear mixed models to assess differences among provinces and over time for the broad-spectrum penicillin and cephalosporin groups, while accounting for repeated measurements at the provincial level.RESULTS: Significant differences among provinces were found, as well as significant changes in use over time. A >28% reduction in broad-spectrum penicillin prescribing occurred in each province from 1995 to 2010, and a >18% reduction in cephalosporin prescribing occurred in all provinces from 1995 to 2010, with the exception of Manitoba, where cephalosporin prescribing increased by 18%.DISCUSSION: Significant reductions in the use of these important drugs were observed across Canada from 1995 to 2010. Newfoundland and Labrador and Quebec emerged as divergent from the remaining provinces, with high and low use, respectively.

scholarly journals Longitudinal Surveillance of Outpatient Quinolone Antimicrobial Use in Canada

2014 ◽  
Vol 25 (2) ◽  
pp. 99-102 ◽  
Author(s):  
Shiona K Glass-Kaastra ◽  
Rita Finley ◽  
Jim Hutchinson ◽  
David M Patrick ◽  
Karl Weiss ◽  
...  
Keyword(s):  
Antimicrobial Resistance ◽  
Treatment Guidelines ◽  
Repeated Measurements ◽  
Antimicrobial Use ◽  
Patterns Of Use ◽  
Defined Daily Doses ◽  
Appropriate Treatment ◽  
Canadian Provinces ◽  
Health Canada ◽  
Over Time

INTRODUCTION: Because antimicrobial use is commonly associated with the development of antimicrobial resistance, monitoring the volume and patterns of use of these agents is important.OBJECTIVE: To assess the use of quinolone antimicrobials within Canadian provinces over time.METHODS: Antimicrobial prescribing data collected by IMS Health Canada were acquired from the Canadian Integrated Program for Antimicrobial Resistance Surveillance and the Canadian Committee for Antimicrobial Resistance, and were used to calculate two yearly metrics: prescriptions per 1000 inhabitant-days and the mean defined daily doses (DDDs) per prescription. These measures were used to produce linear mixed models to assess differences among provinces and over time, while accounting for repeated measurements.RESULTS: The quinolone class of antimicrobials is used similarly among Canadian provinces. Year-to-year increases in quinolone prescribing occurred from 1995 to 2010, with a levelling off in the latter years. Year-to-year decreases in the DDDs per prescription were found to be significant from 2000 to 2010.DISCUSSION: Although the overall use of antimicrobials differs significantly among Canadian provinces, the use of the quinolone class does not vary at the provincial level. Results suggest that prescribing of ciprofloxacin may be a potential target for antimicrobial stewardship programs; however, decreases in the average DDDs per prescription suggest continued uptake of appropriate treatment guidelines.

scholarly journals Provincial and Temporal Variation in Macrolide and Lincosamide Antimicrobial Use by Outpatients in Canada, 1995 to 2010

2014 ◽  
Vol 25 (2) ◽  
pp. 103-106 ◽  
Author(s):  
Shiona K Glass-Kaastra ◽  
Rita Finley ◽  
Jim Hutchinson ◽  
David M Patrick ◽  
Karl Weiss ◽  
...  
Keyword(s):  
Mixed Models ◽  
Repeated Measures ◽  
Secular Trend ◽  
Time Frame ◽  
Antimicrobial Use ◽  
Patterns Of Use ◽  
Defined Daily Doses ◽  
The Mean ◽  
Canadian Provinces ◽  
Over Time

INTRODUCTION: Because antimicrobial use is commonly associated with the development of antimicrobial resistance, monitoring the volume and patterns of use of these agents is very important.OBJECTIVE: To assess the use of macrolide and lincosamide (ML) antimicrobials within Canadian provinces over time, and to compare use rates with those reported by European countries.METHODS: Antimicrobial prescribing data were used to develop two yearly metrics: prescriptions per 1000 inhabitant-days (PrIDs) and the mean defined daily doses (DDDs) per prescription, which were then used to build linear mixed models to assess differences among provinces over time.RESULTS: After accounting for repeated measures over time, prescribing rates (PrIDs) varied significantly according to province and year (P<0.001). However, little change occurred within each province over the time frame studied; from 1995 to 2010, each province had a PrID change <0.01. Quebec and British Columbia had significantly lower prescribing rates than all other provinces. No overall secular trend was apparent. In contrast, the DDDs per prescription did not vary significantly according to province, but showed a significant year-to-year increase.DISCUSSION: ML prescribing varied among provinces in Canada between 1995 and 2010, but remained relatively stable within each province. The average DDDs per ML prescription did not vary according to province, but increased linearly over time. These increases are likely to indicate that fewer prescriptions are being written for children over time, a practice supported by good antimicrobial stewardship principles.

scholarly journals Longitudinal Surveillance of Outpatient Tetracycline, Sulfonamide-Trimethoprim and ‘Other’ Antimicrobial Use in Canada, 1995 to 2010

2014 ◽  
Vol 25 (2) ◽  
pp. 113-117 ◽  
Author(s):  
Shiona K Glass-Kaastra ◽  
Rita Finley ◽  
Jim Hutchinson ◽  
David M Patrick ◽  
Karl Weiss ◽  
...  
Keyword(s):  
Prince Edward Island ◽  
Antimicrobial Agents ◽  
Repeated Measurements ◽  
The Other ◽  
Antimicrobial Use ◽  
Defined Daily Dose ◽  
Defined Daily Doses ◽  
Canadian Provinces ◽  
Tract Infections ◽  
Over Time

INTRODUCTION: Monitoring the volume and patterns of use of antimicrobial agents is important in light of antimicrobial resistance.OBJECTIVE: To assess the use of three antimicrobial groups – tetracycline, sulfonamide-trimethoprim and ‘other’ antimicrobials – within Canadian provinces over time.METHODS: Prescription counts from 1995 to 2010 were acquired for the tetracycline and sulfonamide-trimethoprim groups of antimicrobials, and from 2001 to 2010 for the ‘other’ antimicrobial group. Linear mixed models were produced to assess differences among provinces and over time while accounting for repeated measurements. Prescription rate, defined daily dose per 1000 inhabitant-days and defined daily doses per prescription measures for the year 2009 were also compared with those reported by participating European Union countries to determine where Canadian provinces rank in terms of antimicrobial use among these countries.RESULTS: Prescribing of all three groups varied according to province and over time. Tetracycline and sulfonamide-trimethoprim group prescribing were significantly reduced over the study period, by 36% and 61%, respectively. Prescribing of the ‘other’ antimicrobial group increased in all provinces from 2001 to 2010 with the exception of Prince Edward Island, although by varying amounts (10% to 61% increases).DISCUSSION: The overall use of antimicrobials in Canada has dropped from 1995 to 2010, and the tetracycline and sulfonamide-trimethoprim groups have contributed to this decline. The use of the ‘other’ antimicrobials has increased, however. These results may suggest that switches are being made among these groups, particularly among the antimicrobials used to treat urinary tract infections.

scholarly journals Variation in Outpatient Oral Antimicrobial Use Patterns among Canadian Provinces, 2000 to 2010

2014 ◽  
Vol 25 (2) ◽  
pp. 95-98 ◽  
Author(s):  
Shiona K Glass-Kaastra ◽  
Rita Finley ◽  
Jim Hutchinson ◽  
David M Patrick ◽  
Karl Weiss ◽  
...  
Keyword(s):  
Drug Level ◽  
Antibiotic Use ◽  
Repeated Measurements ◽  
Antimicrobial Use ◽  
Antimicrobial Drugs ◽  
Defined Daily Doses ◽  
The Mean ◽  
Canadian Provinces ◽  
The Individual ◽  
Over Time

BACKGROUND: The volume and patterns of antimicrobial drug use are key variables to consider when developing guidelines for prescribing, and programs to address stewardship and combat the increasing prevalence of antimicrobial resistant pathogens. Because drug programs are regulated at the provincial level, there is an expectation that antibiotic use may vary among provinces.OBJECTIVE: To assess these potential differences according to province and time.METHODS: Provincial antimicrobial prescribing data at the individual drug level were acquired from the Canadian Integrated Program for Antimicrobial Resistance Surveillance for 2000 to 2010. Data were used to calculate two yearly metrics: prescriptions per 1000 inhabitant-days and the average defined daily doses per prescription. The proportion of liquid oral prescriptions of total prescriptions was also calculated as a proxy measure for the proportion of prescriptions given to children versus adults. To assess the significance of provincial antimicrobial use, linear mixed models were developed for each metric, accounting for repeated measurements over time.RESULTS: Significant differences among provinces were found, as well as significant changes in use over time. Newfoundland and Labrador was found to have significantly higher prescribing rates than all other provinces (P<0.001) in 2010, as well as the mean of all other provinces (P<0.001). In contrast, Quebec exhibited significantly lower prescribing than all other provinces (P<0.001 for all provinces except British Columbia, where P=0.024) and the mean of all other provinces (P<0.001).DISCUSSION/CONCLUSION: Reports of reductions in antimicrobial use at the Canadian level are promising, especially prescribing to children; however, care must be taken to avoid the pitfall of the ecological fallacy. Reductions are not consistent among the provinces or among the classes of antimicrobial drugs dispensed in Canada.

scholarly journals Effects of the cefazolin shortage on the sales, cost, and appropriate use of other antimicrobials

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Ryuji Koizumi ◽  
Yoshiki Kusama ◽  
Yusuke Asai ◽  
Gu Yoshiaki ◽  
Yuichi Muraki ◽  
...  
Keyword(s):  
Antimicrobial Resistance ◽  
Prediction Model ◽  
Broad Spectrum ◽  
Early Recognition ◽  
Antimicrobial Use ◽  
Appropriate Use ◽  
Sales Data ◽  
Defined Daily Doses ◽  
Before And After ◽  
Appropriate Antimicrobial Use

Abstract Background Shortages of antimicrobials lead to treatment failures, increase medical costs, and accelerate the development of antimicrobial resistance. We evaluated the effects of the serious cefazolin shortage in 2019 in Japan on the sales, costs, and appropriate use of other antimicrobials. Methods We evaluated monthly defined daily doses/1000 inhabitants/day (DID) values of antimicrobial sales from January 2016 to December 2019 using wholesaler’s sales databases. Using 2016–2018 sales data, we generated a prediction model of DID in 2019 under the assumption that the cefazolin shortage did not occur. We then compared the predicted DID and actual DID. Cefazolin, government-recommended alternatives, and government-not-recommended broad-spectrum alternatives were assessed. Antimicrobial groups according to the AWaRe classification were also assessed to evaluate the effect on appropriate antimicrobial use. In addition, we evaluated changes in costs between 9 months before and after the cefazolin shortage. Results DID values of total antimicrobials increased sharply 1 month before the decrease in cefazolin. Actual DIDs were higher than predicted DIDs for ceftriaxone, flomoxef, clindamycin, cefotiam, piperacillin/tazobactam, and meropenem. Actual DID values were higher than the predicted DID values in the Watch group. The costs of antimicrobials between pre- and post- cefazolin shortage were unchanged. Conclusion The cefazolin shortage brought confusion to the antimicrobial market and led to a setback in the appropriate use of antimicrobials. Early recognition and structures for prompt reactions to antimicrobial shortages are needed. Moreover, development of a system to secure the supply of essential antimicrobials is required.

scholarly journals Effects of the cefazolin shortage on the sales, cost, and appropriate use of other antimicrobials

2021 ◽  
Author(s):  
Ryuji KOIZUMI ◽  
Yoshiki KUSAMA ◽  
Yusuke ASAI ◽  
Yoshiaki GU ◽  
Yuichi MURAKI ◽  
...  
Keyword(s):  
Antimicrobial Resistance ◽  
Prediction Model ◽  
Broad Spectrum ◽  
Early Recognition ◽  
Antimicrobial Use ◽  
Appropriate Use ◽  
Sales Data ◽  
Defined Daily Doses ◽  
Before And After ◽  
Appropriate Antimicrobial Use

Abstract Background Shortages of antimicrobials lead to treatment failures, increase medical costs, and accelerate the development of antimicrobial resistance. We evaluated the effects of the serious cefazolin shortage in 2019 in Japan on the sales, costs, and appropriate use of other antimicrobials. Methods We evaluated monthly defined daily doses/1,000 inhabitants/day (DID) values of antimicrobial sales from January 2016 to December 2019 using wholesaler’s sales databases. Using 2016–2018 sales data, we generated a prediction model of DID in 2019 under the assumption that the cefazolin shortage did not occur. We then compared the predicted DID and actual DID. Cefazolin, government-recommended alternatives, and non-government-recommended broad-spectrum alternatives were assessed. Antimicrobial groups according to the AWaRe classification were also assessed to evaluate the effect on appropriate antimicrobial use. In addition, we evaluated changes in costs between 9 months before and after the cefazolin shortage. Results DID values of total antimicrobials increased sharply 1 month before the decrease in cefazolin. Actual DIDs were higher than predicted DIDs for ceftriaxone, flomoxef, clindamycin, cefotiam, piperacillin/tazobactam, and meropenem. Actual DID values were higher than the predicted DID values in the Watch group. The costs of antimicrobials between pre- and post- cefazolin shortage were unchanged. Conclusion The cefazolin shortage brought confusion to the antimicrobial market and led to a setback in the appropriate use of antimicrobials. Early recognition and structures for prompt reactions to antimicrobial shortages are needed. Moreover, development of a system to secure the supply of essential antimicrobials is required.

scholarly journals Evaluation of the impact of antimicrobial use protocols in PRRS virus infected swine on phenotypic antimicrobial resistance patterns

2021 ◽  
Author(s):  
Carissa A. Odland ◽  
Roy Edler ◽  
Noelle R. Noyes ◽  
Scott A. Dee ◽  
Joel Nerem ◽  
...  
Keyword(s):  
Antimicrobial Resistance ◽  
Longitudinal Studies ◽  
Bacterial Infections ◽  
Population Level ◽  
Control Group ◽  
Antimicrobial Use ◽  
Treatment Groups ◽  
Resistance Patterns ◽  
The Impact ◽  
Over Time

A longitudinal study was conducted to assess the impact of different antimicrobial exposures of nursery-phase pigs on patterns of phenotypic antimicrobial resistance in fecal indicator organisms throughout the growing phase. Based on practical approaches used to treat moderate to severe PRRSV-associated secondary bacterial infections, two antimicrobial protocols of differing intensity of exposure [44.1 and 181.5 animal-treatment days per 1000 animal days at risk (ATD)] were compared with a control group with minimal antimicrobial exposure (2.1 ATD). Litter-matched pigs (n = 108) with no prior antimicrobial exposure were assigned randomly to the treatment groups. Pen fecal samples were collected nine times during the wean-to-finish period and cultured for Escherichia coli and Enterococcus spp. Antimicrobial susceptibility testing was conducted using NARMS gram-negative and gram-positive antibiotic panels. Despite up to 65-fold difference in ATD, few and modest differences were observed between groups and over time. Resistant patterns at marketing overall remained similar to those observed at weaning, prior to any antimicrobial exposures. Those differences observed could not readily be reconciled with the patterns of antimicrobial exposure. Resistance of E. coli to streptomycin was higher in the group exposed to 44.1 ATD, but no aminoglycosides were used. In all instances where resistance differed between time points, the higher resistance occurred early in the trial prior to any antimicrobial exposures. These minimal impacts on AMR despite substantially different antimicrobial exposures point to the lack of understanding of the drivers of AMR at the population level and the likely importance of factors other than antimicrobial exposure. IMPORTANCE Despite a recognized need for more longitudinal studies to assess the effects of antimicrobial use on resistance in food animals, they remain sparse in the literature, and most longitudinal studies of pigs have been observational. The current experimental study had the advantages of greater control of potential confounding, precise measurement of antimicrobial exposures which varied markedly between groups and tracking of pigs until market age. Overall, resistance patterns were remarkably stable between the treatment groups over time, and the differences observed could not be readily reconciled with the antimicrobial exposures, indicating the likely importance of other determinants of AMR at the population level.

Impact of Different Methods of Feedback to Clinicians After Postprescription Antimicrobial Review Based on the Centers for Disease Control and Prevention's 12 Steps to Prevent Antimicrobial Resistance Among Hospitalized Adults

2007 ◽  
Vol 28 (6) ◽  
pp. 641-646 ◽  
Author(s):  
Sara E. Cosgrove ◽  
Alpa Patel ◽  
Xiaoyan Song ◽  
Robert E. Miller ◽  
Kathleen Speck ◽  
...  
Keyword(s):  
Antimicrobial Resistance ◽  
Disease Control ◽  
Broad Spectrum ◽  
Antimicrobial Therapy ◽  
Detection System ◽  
Tertiary Care ◽  
Clinical Event ◽  
Antimicrobial Use ◽  
12 Steps ◽  
Centers For Disease Control

Objectives.To evaluate (1) the framework of the 12 Steps to Prevent Antimicrobial Resistance Among Hospitalized Adults that is part of the Centers for Disease Control and Prevention (CDC) Campaign to Prevent Antimicrobial Resistance in Healthcare Settings, with regard to steps addressing antimicrobial use; and (2) methods of feedback to clinicians regarding antimicrobial use after postprescription review.Design.Prospective intervention to identify and modify inappropriate antimicrobial therapy.Setting.A 1,000-bed, tertiary care teaching hospital.Patients.Inpatients in selected medicine and surgery units receiving broad-spectrum antimicrobials for 48-72 hours.Interventions.We created a computer-based clinical-event detection system that automatically identified inpatients taking broad-spectrum and “reserve” antimicrobials for 48-72 hours. Although prior approval was required for initial administration of broad-spectrum and reserve antimicrobials, once approval was obtained, therapy with the antimicrobials could be continued indefinitely at the discretion of the treating clinician. Therapy that was ongoing at 48-72 hours was reviewed by an infectious diseases pharmacist or physician, and when indicated feedback was provided to clinicians to modify or discontinue therapy. Feedback was provided via a direct telephone call, a note on the front of the medical record, or text message sent to the clinician's pager. The acceptance rate of feedback was recorded and recommendations were categorized according to the 12 steps recommended by the CDC.Results.Interventions were recommended for 334 (30%) of 1,104 courses of antimicrobial therapy reviewed. A total of 87% of interventions fit into one of the CDC's 12 steps of prevention: 39% into step 3 (“target the pathogen”), 1% into step 4 (“access experts”), 3% into steps 7 and 8 (“treat infection, not colonization or contamination”), 18% into step 9 (“say ‘no’ to vancomycin”), and 26% into step 10 (“stop treatment when no infection”). The rate of compliance with recommendations to improve antimicrobial use was 72%. No differences in compliance were seen with the different methods of feedback.Conclusions.Nearly one-third of antimicrobial courses did not follow the CDC's recommended 12 steps for prevention of antimicrobial resistance. Clinicians demonstrated high compliance with following suggestions made after postprescription review, suggesting that it is a useful approach to decreasing and improving antimicrobial use among inpatients.

scholarly journals Informing Stewardship Measures in Canadian Food Animal Species through Integrated Reporting of Antimicrobial Use and Antimicrobial Resistance Surveillance Data—Part II, Application

Pathogens ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 1491
Author(s):  
Agnes Agunos ◽  
Sheryl P. Gow ◽  
Anne E. Deckert ◽  
David F. Léger
Keyword(s):  
Antimicrobial Resistance ◽  
Animal Health ◽  
Surveillance Data ◽  
Integrated Analysis ◽  
Antimicrobial Use ◽  
Integrated Reporting ◽  
Farm Level ◽  
Antimicrobial Resistance Surveillance ◽  
Defined Daily Doses ◽  
The Impact

Using the methodology developed for integrated analysis and reporting of antimicrobial use (AMU) and antimicrobial resistance (AMR) data, farm-level surveillance data were synthesized and integrated to assess trends and explore potential AMU and AMR associations. Data from broiler chicken flocks (n = 656), grower–finisher pig herds (n = 462) and turkey flocks (n = 339) surveyed by the Canadian Integrated Program for Antimicrobial Resistance Surveillance (CIPARS) at the farm-level (2015–2019) were used. The analyses showed a reduction in mean flock/herd level number of defined daily doses using Canadian standards (nDDDvetCA) adjusted for kg animal biomass that coincided with the decline in % resistance in the three species. This was noted in most AMU-AMR pairs studied except for ciprofloxacin resistant Campylobacter where resistance continued to be detected (moderate to high levels) despite limited fluoroquinolone use. Noteworthy was the significantly negative association between the nDDDvetCA/kg animal biomass and susceptible Escherichia coli (multispecies data), an early indication that AMU stewardship actions are having an impact. However, an increase in the reporting of diseases in recent years was observed. This study highlighted the value of collecting high-resolution AMU surveillance data with animal health context at the farm-level to understand AMR trends, enable data integration and measure the impact of AMU stewardship actions.

scholarly journals How the COVID-19 Pandemic Affected Antimicrobial Prescribing Practices at a Tertiary-Care Healthcare System in Detroit, Michigan

2021 ◽  
Vol 1 (S1) ◽  
pp. s37-s38
Author(s):  
Angela Beatriz Cruz ◽  
Jennifer LeRose ◽  
Avnish Sandhu ◽  
Teena Chopra
Keyword(s):  
Broad Spectrum ◽  
Treatment Guidelines ◽  
Tertiary Care ◽  
Antibiotic Use ◽  
Modern Medicine ◽  
Antimicrobial Use ◽  
Prescribing Practices ◽  
Primary Object ◽  
Antibiotics Use ◽  
Over Time

Background: Inappropriate antimicrobial use continues to threaten modern medicine. The ongoing pandemic likely exacerbated this problem because COVID-19 presents similarly to bacterial pneumonia, confusion exists regarding treatment guidelines, and testing turnaround times (TATs) are slow. Our primary object was to quantify antimicrobial use changes during the pandemic to rates before the crisis. A subanalysis within the COVID-19 cohort was completed based on SARS-CoV-2 status. Methods: The pre–COVID-19 period was January–May 2019 and the COVID-19 period was January–May 2020. Subanalyses were used to explore differences in antibiotics use between persons not under investigation (non-PUIs), SARS-CoV-2–negative PUIs, and SARS-CoV-2–positive PUIs. Non-PUI patients were those without respiratory symptoms and/or fever. The χ2 and Wilcoxon signed rank-sum tests were used for analysis. Results: During the 2019 and 2020 study periods, 7,909 and 7,283 patients received >1 antimicrobial, respectively (Figure 1). Overall, antibiotic therapy per 1,000 patient days increased from 633.1 before COVID-19 to 678.5 during COVID-19, a 7.2% increase (Table 1). Notably, broad-spectrum respiratory antibiotics demonstrated a significant increase between pre–COVID-19 and COVID-19 cohorts (p < 0.001). Of the 7,283 patients within the COVID-19 cohort, 34.7% (n = 2,532) were PUI and 13.8% (n = 1,002) of these patients tested SARS-CoV-2 positive. Again, broad-spectrum respiratory antibiotics use was significantly increased for COVID-19 patients (p < 0.001). Of note, the proportion of patients receiving respiratory antibiotics steadily decreased over time (R2 = 0.99). Conclusions: There was a significant increase in antibiotic use during the COVID-19 pandemic. Encouragingly, antimicrobial use decreased over time, likely due to (1) faster TATs, (2) real-time education to clinicians and subsequent de-escalation of unnecessary antimicrobials, and (3) development of treatment guidelines as new research emerged.Funding: NoDisclosures: None

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