Enterobacteriaceae In Intensive Care Unit Research Articles

425. Spread of Carbapenem-resistant Enterobacteriaceae in Intensive Care Unit and effective preventative strategies: Agent-based model study

Abstract Background Carbaepenem-resistant Enterbacteriaceae (CRE) could propagate through person-to-person contacts such as contaminated hands of staff, contamination of the environment, or the use of contaminated medical equipment by spreading carbapenemase encoded in plasmid and cause healthcare associated infections (HAIs). Critically ill patients in a compact space of Intensive care unit (ICU) are at significantly high risk of CRE infection, which should be protected by effective infection control strategies. Agent-based model (ABM) has been employed to examine the spread of infectious organisms and estimate the impact of intervention as it reflects behaviors of heterogeneous individuals. We aimed to create an ABM reflecting the medical ICU and identify preventative strategies to reduce CRE infection in the ICU. Methods The blueprint of the medical ICU in a tertiary hospital in Republic of Korea was obtained. Researchers had a meeting with the head staffs to get information about healthcare workers (HCWs), patients, and the spatial unit. In this unit, HCWs visiting a patient in ICU are required to wash their hands and wear personal protective equipment. We did a survey to collect data of the routes and the handwashing rates of HCWs. An ABM was made using Python’s Mesa library which simulates the situation in the ICU and the status of CRE. Figure 1.(A) Blueprint of ICU in Severance Hospital, (B) Simulated ICU in agent-based modelFigure 2.Dynamics between agents and environment Results Medical ICU consists of two units, and each unit holds fifteen beds. Five nurses work in each unit and six doctors and three technicians take rounds daily, contacting patients in the ICU. The dynamics among agents and environment were constructed.. Parameters were set up from the real world data or the clinical studies. At any given moment, there are about 2.5 patients infected with CRE, and transmission probability and isolation factors were calibrated according to this target. Interventions were enhanced environment cleansing, handwashing of HCWs, and prompt isolation of infected patients through tests and actions. We found those interventions effectively reduced HAIs, and combining effects lead to better results. Figure 3.Parameters and variables in agend-based modelFigure 4.Healthcare associated infections in study periods according to (A) interval of clensing environment, (B) handwashing of HCWs, (C) isolation of infected patients, (D) combined of environmental cleansing and patient isolation Conclusion Increasing handwashing rates, environment cleansing, and prompt isolation of infected patients have drastic effects of reducing HAIs caused by CRE in this model, and bundle approach should be considered to prevent the spread of CRE. Disclosures All Authors: No reported disclosures.

Combination Therapy with Aminoglycoside in Bacteremiasdue to ESBL-Producing Enterobacteriaceae in ICU.

Objectives: Evaluation of the efficacy of empirical aminoglycoside in critically ill patients with bloodstream infections caused by extended-spectrum β-lactamase producing Enterobacteriaceae (ESBL-E BSI). Methods: Patients treated between 2011 and 2018 for ESBL-E BSI in the ICU of six French hospitals were included in a retrospective observational cohort study. The primary endpoint was mortality on day 30. Results: Among 307 patients, 169 (55%) were treated with empirical aminoglycoside. Death rate was 40% (43% with vs. 39% without aminoglycoside, p = 0.55). Factors independently associated with death were age ≥70 years (OR: 2.67; 95% CI: 1.09–6.54, p = 0.03), history of transplantation (OR 5.2; 95% CI: 1.4–19.35, p = 0.01), hospital acquired infection (OR 8.67; 95% CI: 1.74–43.08, p = 0.008), vasoactive drugs >48 h after BSI onset (OR 3.61; 95% CI: 1.62–8.02, p = 0.001), occurrence of acute respiratory distress syndrome (OR 2.42; 95% CI: 1.14–5.16, p = 0.02), or acute renal failure (OR 2.49; 95% CI: 1.14–5.47, p = 0.02). Antibiotherapy appropriateness was more frequent in the aminoglycoside group (91.7% vs. 77%, p = 0.001). Rate of renal impairment was similar in both groups (21% vs. 24%, p = 0.59). Conclusions: In intensive care unit (ICU) patients with ESBL-E BSI, empirical treatment with aminoglycoside was frequent. It demonstrated no impact on mortality, despite increasing treatment appropriateness.

2170. Xpert Carba-R Assay on Flagged Blood Culture Samples: Clinical Utility in Intensive Care Unit Patients with Gram-Negative Bacteremia

BackgroundRapid molecular diagnostics that predict carbapenem resistance (CR) well before the availability of routine drug sensitivity testing (DST) can serve as an antimicrobial stewardship tool in the context of high rates of carbapenem-resistant enterobacteriaceae (CRE).MethodsA retrospective observational study of patients more than 18 years of age on whom Xpert Carba-R (FDA approved for rectal swab specimen) was done on Gram-negative bacteria (GNB) flagged blood culture samples, in a tertiary care Indian intensive care unit between January 2015 and November 2018.ResultsThe study included 160 patients who had a median (Sequential Organ Failure Assessment) SOFA score of 16. A total of 164 GNB were isolated with 4 patients having polymicrobial bacteremia. Klebsiella pneumoniae and Escherichia coli were the predominant isolates (Figure 1). Carba-R was positive in 58/164 (35.36%) samples (Figure 2) and 73/161 isolates (45.34%) were CR (after excluding intrinsic CR organisms) on routine DST. The distribution of CR genes overall was: OXA-48 like (29/58–50%), followed by NDM (19/58–32.7%), followed by OXA-48 and NDM co-expression (9/58–15.51%) and in individual groups as in Figure 3. The sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, positive predictive value (PPV) and negative predictive value (NPV) of Carba-R vs. routine DST were 90.74%, 93.15%, 13.25, 0.10, 83.58% and 96.31% for enterobacteriaceae (Figure 4). The median time to obtaining the Carba-R report was 30 hours 34 minutes vs. 74 hours and 20 minutes for carbapenem resistance on routine DST. Based on the Carba-R report, 9.72% of patients had escalation of antibiotics (e.g., colistin) to cover CR organisms and 27.08% had de-escalation from CR cover that had already been started.ConclusionXpert Carba-R serves as a rapid diagnostic tool for CR Gram-negative bacteremia, particularly hospital-acquired enterobacteriaceae in intensive care units with a high CRE prevalence. It assists in initiating early appropriate therapy and early institution of infection control measures in these patients, as well as in de-escalation of colistin in patients without carbapenem resistance. We recommend that clinicians consider routinely utilizing this test in this setting. Disclosures All authors: No reported disclosures.

Carbapenemase producing Enterobacteriaceae in intensive care units in Ecuador: Results from a multicenter study

IntroductionCarbapenemase-producing Enterobacteriaceae (CPE) are of global concern due to the growing number of patients who acquire them and their association with high mortality rates. Although there are some reports of endemicity in developing countries, little is known about this microorganism, and Ecuador is not an exception. Subsequently, our objective was to clinically and molecularly characterize carbapenemase producing-Enterobacteriaceae in intensive care units (ICUs) in Guayaquil, Ecuador. MethodsTo determine CPE colonization, we obtained perineal and inguinal swabs from patients admitted to seven intensive-care adult units in Guayaquil-Ecuador between February and April 2016. The Centers for Disease Control and Prevention (CDC) laboratory protocol and chromogenic agar were used to process the cultures. Polymerase chain reaction was used to confirm carbapenemase production. Genotypic analysis was performed by Multilocus Sequence Typing (MLST) and pulsed-field electrophoresis (PFEG). Demographic and clinical data were obtained from the electronic charts and patient’s relatives. ResultsSix hundred seventy-seven patients were included in the study, of whom 255 were colonized/infected by CPE. The CPE prevalence was 37.67%. Previous use of antimicrobials, use of invasive procedures and being burned at admission were associated with CPE. The most frequent infection was found after a surgical procedure. Klebsiella pneumoniae (n=249) was the predominant microorganism harbouring blaKPC, followed by Enterobactercloacae (n=8), Klebsiella aerogenes (n=4), Escherichia coli (n=4) and Klebsiella oxytoca (n=1). NDM was present in Proteus mirabilis. The strains were distributed in 19 sequence types (ST), and 10 were not reported previously in Ecuador. ST 258 was the sequence type isolated most frequently. ConclusionThis study shows a high prevalence of CPE in ICUs, particularly K. pneumoniae blaKPC ST 258. The identification of KPC alleles may help to understand the routes of dissemination and control spread within ICUs in Guayaquil, Ecuador.

Universal or targeted approach to prevent the transmission of extended-spectrum beta-lactamase-producing Enterobacteriaceae in intensive care units: a cost-effectiveness analysis

ObjectiveSeveral control strategies have been used to limit the transmission of multidrug-resistant organisms in hospitals. However, their implementation is expensive and effectiveness of interventions for the control of extended-spectrum beta-lactamase-producing...

Infection Using ERCP Endoscopes

© 2016 by the AGA Institute 0016-5085/$36.00 http://dx.doi.org/10.1053/j.gastro.2016.05.040 Ttion during endoscopic retrograde cholangiopancreatography (ERCP) continues to evolve. The occurrence of carbapenem-resistant Enterobacteriaceae infections after ERCP reached the awareness of the medical community in 2014 when the Centers for Disease Control and Prevention (CDC) published the findings of their investigation of a suburban Chicago case cluster. In early 2015, reports of similar outbreaks at several major medical centers across the United States prompted the US Food and Drug Administration (FDA) to issue safety alerts and convene an FDA expert panel; there was intense media attention and both the CDC and industry provided guidance regarding steps for ensuring safe clinical care in the absence of definitive solutions. In 2016, the release of a US Senate committee investigative report culminated in a closely coordinated FDA and industry recall of duodenoscopes for refurbishment and replacement of suspect parts, among other related actions. Despite progress in our awareness and understanding of the problem, the currently proposed solutions remain cumbersome and unproven. Endoscope cleaning and reprocessing technologies and practices progressed greatly in the latter part of the 20th century, culminating in enduring standards for high-level disinfection (HLD). In the Spaulding classification for reprocessing of durable medical devices, endoscopes are designated as “semicritical” devices that make contact with mucous membranes and thus are suitable for HLD. Transmission of infection by flexible endoscopes has historically been ascribed to inconsistent practice of manual cleaning and HLD. Outbreaks of Pseudomonas aeruginosa after ERCP using side-viewing duodenoscopes dating to the 1980s were noted to occur particularly in the first patient of the day after overnight storage and shortly after reprocessing. This problem was largely eliminated with adoption of complete channel drying by alcohol flushing and forced air perfusion after HLD. Clinical infections occasionally follow the use of ERCP in patients with preexisting chronic colonization of bacteria (owing to obstructing pathology, abnormal anatomy, indwelling prostheses, or prior interventions). The recent occurrences of interpatient transmission via the duodenoscope only became evident when infections with newly recognized, highly resistant species prompted point source investigations using sophisticated bacterial typing to determine their origin. A recent single-center study using universal culturing of reprocessed endoscopes demonstrated that 2% of patient-ready instruments harbored persistent enteric pathogens. Thus, we now realize that contaminated endoscopes can transmit some antibioticsensitive, as well as highly resistant cases, of post-ERCP cholangitis. Furthermore, the unusual resistant cases can result in chronic colonization of the gastrointestinal tract, with delayed infectious complications weeks to months later in unrelated organ systems. Infectious cross-contamination also occurs from other hospital or institutional sources, as demonstrated in outbreaks of carbapenem-resistant Enterobacteriaceae in intensive care units and chronic nursing facilities. The frequency of transmission through the environment, however, is generally far lower than for iatrogenic exposure and investigations strongly suggest that the endoscope is the transmission source in most outbreaks of post-ERCP multidrug-resistant infections. The recent report of the Senate’s Health, Education, Labor, and Pensions Committee thoroughly outlines the breadth of the problem and potential regulatory and industry factors contributing to the delay in response to the risk of duodenoscope transmission of infection (Table 1).

Active surveillance of carbapenem-resistant Enterobacteriaceae in intensive care units: Is it cost-effective in a nonendemic region?

Carbapenem-resistant Enterobacteriaceae (CRE) cause significant morbidity and mortality in intensive care unit (ICU) settings. We examined potential cost-effectiveness of active CRE surveillance at ICUs in a nonendemic region from the perspective of a Hong Kong health care provider. A decision analytic model was designed to simulate outcomes of active CRE surveillance in ICUs. Outcome measures included CRE-associated direct medical cost, infection rate, mortality rate, quality-adjusted life year (QALY) loss, and incremental cost per QALY saved by active surveillance. Model inputs were derived from the literature. Sensitivity analyses evaluated the influence of uncertainty of model variables. In base-case analysis, the surveillance group was more costly ($1,260 vs $1,256) with lower CRE infection rate (5.670% vs 5.902%), CRE-associated mortality rate (2.139% vs 2.455%), and CRE-associated QALY loss (0.3335 vs 0.3827) than the control group. Incremental cost per QALY saved of active surveillance was $81 per QALY saved. One-way sensitivity analyses found base-case results to be robust to a variety of model inputs. In 10,000 Monte Carlo simulations, the surveillance group was the preferred option 99.98% of time. Active CRE surveillance in ICUs appears to be highly cost-effective to reduce CRE infection rate, mortality rate, and QALY loss in a low CRE burden region.

Antimicrobial resistance and resistance mechanisms of Enterobacteriaceae in ICU and non-ICU wards in Europe and North America: SMART 2011-2013.

Intensive care units (ICUs) are often described as hotbeds of antimicrobial resistance, with high rates of extended-spectrum β-lactamase (ESBL)-producing and multidrug-resistant (MDR) Enterobacteriaceae. Data from the SMART study were used to examine differences between the susceptibility of Enterobacteriaceae from ICU and non-ICU wards in Europe and North America. In total, 21,470 Enterobacteriaceae isolates from intra-abdominal and urinary tract infections were collected at 90 sites in 20 European and North American countries in 2011-2013. Susceptibility and ESBL phenotypes were determined using the CLSI broth microdilution method and breakpoints. Susceptibility was lower and ESBL and MDR rates were higher in ICUs, with much greater ICU/non-ICU differences in Europe than North America. Susceptibility was lower and ESBL and MDR rates were higher in Europe than in North America in both patient locations. Resistance among Enterobacteriaceae in Europe was largely driven by Klebsiella pneumoniae, which had high rates of ESBLs (41.2% in ICUs; mostly CTX-M) and carbapenemases (13.2%; mostly KPC and OXA). For all Enterobacteriaceae combined, only ertapenem and amikacin inhibited >90% of isolates in ICUs in both regions. In North America, ertapenem, imipenem and amikacin inhibited >90% of K. pneumoniae from ICUs, whereas in Europe only amikacin did. ESBL and MDR rates varied considerably within Europe. Antimicrobial resistance was higher in Europe than North America, especially in ICUs. Further surveillance at the country, hospital and even patient ward level, and investigation of reasons for these findings, would be useful for the development of effective strategies to reduce antimicrobial resistance in ICUs.

Assessment of five screening strategies for optimal detection of carriers of third-generation cephalosporin-resistant Enterobacteriaceae in intensive care units using daily sampling

There is no consensus on optimal screening procedures for multidrug-resistant Enterobacteriaceae (MDRE) in intensive care units (ICUs). Therefore, we assessed five strategies for the detection of extended-spectrum beta-lactamase (ESBL) and high-level expressed AmpC cephalosporinase (HL-CASE) producers. During a 3-month period, a rectal screening swab sample was collected daily from every ICU patient, from the first 24 h to the last day of ICU stay. Samples were plated on MDRE-selective media. Bacteria were identified using MALDI-TOF mass spectrometry and antibiograms were performed using disk diffusion. MDREs were isolated from 682/2348 (29.0%) screening samples collected from 93/269 (34.6%) patients. Incidences of patients with ESBL and HL-CASE producers were 17.8 and 19.3 per 100 admissions, respectively. In 48/93 patients, MDRE carriage was intermittent. Compared with systematic screening at admission, systematic screening at discharge did not significantly increase the rate of MDRE detection among the 93 patients (62% vs. 70%). In contrast, screening at admission and discharge, screening at admission and weekly thereafter, and screening at admission and weekly thereafter and at discharge significantly increased MDRE detection (77%, p 0.02; 76%, p 0.01; 86%, p <0.001, respectively). The difference in MDRE detection between these strategies relies essentially on the levels of detection of patients with HL-CASE producers. The most reasonable strategy would be to collect two samples, one at admission and one at discharge, which would detect 87.5% of the ESBL strains, 67.3% of the HL-CASE strains and 77.4% of all MDRE strains. This study should facilitate decision-making concerning the most suitable screening policy for MDRE detection in a given ICU setting.

Vigilancia de infecciones asociadas a la atención en salud, resistencia bacteriana y consumo de antibióticos en hospitales de alta complejidad, Colombia, 2011

Introduction: Preventing healthcare associated infections, especially for resistant microorganisms, is a priority. In Colombia, the surveillance of such events was started through a national pilot study.Objective: To describe the epidemiology of device-associated infections, bacterial resistance and antibiotic consumption patterns in institutions with intensive care units (ICU), 2011.Materials and methods: Descriptive observational study in 10 health institutions from three Colombian provinces: Antioquia, Valle del Cauca, and Bogotá. Surveillance protocols were designed and implemented by trained health professionals in each hospital. A web tool was designed for data reporting and analysis. Infection rates, device-use percentages and antibiotics defined daily dose (DDD) were calculated. Bacterial resistance phenotypes and profiles were reported and analyzed using Whonet 5.6.Results: The most common event was bloodstream infection (rate &gt; 4.8/1000 catheter-days) followed by ventilator-associated pneumonia (VAP) and catheter-related urinary tract infection, showing a wide variability among institutions. A high consumption of meropenem in the ICU (DDD 22.5/100 beds-day) was observed, as well as a high carbapenem resistance (&gt; 11.6%) and a high frequency of third generation cephalosporins resistance (&gt; 25.6%) in Enterobacteriaceae in ICUs and hospitalization wards. The percentage of methicillin-resistant Staphylococcus aureus was higher in hospitalization wards (34.3%).Conclusions: This is the first experience in measuring these events in Colombia. It is necessary to implement a national surveillance system aimed at guiding governmental and institutional actions oriented to infection prevention and control, to resistance management and to the promotion of antibiotics rational use, along with a follow-up and monitoring process.

Surveillance of healthcare associated infections, bacterial resistance and antibiotic consumption in high-complexity hospitals in Colombia, 2011

Preventing healthcare associated infections, especially for resistant microorganisms, is a priority. In Colombia, the surveillance of such events was started through a national pilot study. To describe the epidemiology of device-associated infections, bacterial resistance and antibiotic consumption patterns in institutions with intensive care units (ICU), 2011. Descriptive observational study in 10 health institutions from three Colombian provinces: Antioquia, Valle del Cauca, and Bogotá. Surveillance protocols were designed and implemented by trained health professionals in each hospital. A web tool was designed for data reporting and analysis. Infection rates, device-use percentages and antibiotics defined daily dose (DDD) were calculated. Bacterial resistance phenotypes and profiles were reported and analyzed using Whonet 5.6. The most common event was bloodstream infection (rate > 4.8/1000 catheter-days) followed by ventilator-associated pneumonia (VAP) and catheter-related urinary tract infection, showing a wide variability among institutions. A high consumption of meropenem in the ICU (DDD 22.5/100 beds-day) was observed, as well as a high carbapenem resistance (> 11.6%) and a high frequency of third generation cephalosporins resistance (> 25.6%) in Enterobacteriaceae in ICUs and hospitalization wards. The percentage of methicillin-resistant Staphylococcus aureus was higher in hospitalization wards (34.3%). This is the first experience in measuring these events in Colombia. It is necessary to implement a national surveillance system aimed at guiding governmental and institutional actions oriented to infection prevention and control, to resistance management and to the promotion of antibiotics rational use, along with a follow-up and monitoring process.

Clinical investigation for infections caused by Enterobacteriaceae in intensive care unit of Anhui, China

Clinical investigation for infections caused by Enterobacteriaceae in intensive care unit of Anhui, China

Nationwide surveillance of antimicrobial resistance among Enterobacteriaceae in intensive care units in Taiwan

To determine the antimicrobial resistance profiles among clinical isolates of Enterobacteriaceae in Taiwanese intensive care units (ICUs), a national surveillance of antibiotic resistance among important Enterobacteriaceae was conducted from September 2005 through November 2005 at the ICUs of ten major teaching hospitals in Taiwan. A total of 574 Enterobacteriaceae isolates recovered from various clinical samples of our ICU patients were submitted for in vitro test. Minimum inhibitory concentrations (MICs) of these isolates to 18 antimicrobial agents were determined by the broth microdilution method. The prevalences of Enterobacteriaceae isolates with phenotypic extended-spectrum beta-lactamase (ESBL) production were 26% in Klebsiella pneumoniae, 16% in Serratia marcescens, 14% in Escherichia coli, and 13% in Proteus mirabilis, in which a significantly rising prevalence of ESBL production among K. pneumoniae was noted (p = 0.002) when compared with a previous Taiwanese survey in 2000. Heterogeneous resistance to various fluoroquinolones was found among our Enterobacteriaceae isolates, except for Enterobacter cloacae. Emergence of ertapenem-resistant isolates of E. coli, K. pneumoniae, E. cloacae, and S. marcescens was noted. Gradually increasing rates of drug-resistant Enterobacteriaceae were noted in Taiwanese ICUs. Periodic surveillance of the evolutionary trend of antimicrobial resistance among ICU isolates is crucial for starting appropriately empirical antimicrobial therapy in the future.

Unnoticed Spread of Integron-Carrying Enterobacteriaceae in Intensive Care Units

Integrons are strongly associated with multidrug resistance in Enterobacteriaceae. Little is known about the natural history of integron-associated resistance in hospitals during nonoutbreak periods. The prevalence of integrons and the incidence of cross-transmission and horizontal gene transfer in Enterobacteriaceae with reduced susceptibility to cephalosporins (ERSC) were determined for 2 intensive care units (ICUs). Microbiological surveillance using rectal swab samples obtained 2 times per week and genotyping using amplified fragment-length polymorphism (AFLP) were used to determine colonization with and genetic relatedness of ERSC. IntI1 integrase polymerase chain reaction (PCR), conserved-segment PCR, restriction fragment-length polymorphism, and DNA sequencing were used to determine the prevalence and contents of integrons. Of 457 patients, 121 patients were colonized with ERSC, and 174 isolates underwent AFLP and PCR. In 34 isolates obtained from 31 patients, 11 different integrons were identified; these integrons encoded resistance to streptomycin/spectinomycin, gentamicin/tobramycin/kanamycin, chloramphenicol, and trimethoprim. Integrons could be divided into 7 clusters of > or =2 isolates each. Compared with isolates that were negative for integrons, isolates that were positive for integrons were associated with resistance to piperacillin, cephalosporins, aminoglycosides, and quinolones. Acquisition rates of integron-carrying ERSC were 10 cases per 1000 patient-days in the first ICU and 8 cases per 1000 patient-days in the second ICU, with most cases (26 of 34) being acquired during the ICU stay. Nineteen episodes resulted from cross-transmission. In addition, 2 cases of interspecies transfer and 1 case of intraspecies transfer of integrons were recorded. Younger age was independently associated with acquisition of integron-carrying ERSC (hazard ratio, 0.953; 95% confidence interval, 0.926-0.987). Surveillance, genotyping, and integron analysis identified previously unnoticed outbreaks of integron-carrying ERSC. Cross-transmission appeared to be the dominant route of transmission. Therefore, barrier precautions are necessary to prevent further spread.

Control of Enterobacteriaceae Producing Extended-Spectrum Beta-Lactamase in Intensive Care Units: Rectal Screening May Not Be Needed in Non-Epidemic Situations

To evaluate the usefulness of screening cultures in the control of extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae in intensive care units (ICUs). A 4-year retrospective study. Two adult ICUs of a university-affiliated public hospital in France. A total of 7,777 specimens were analyzed and 28 (0.97%) of 2,883 screened patients had a positive result on a screening test, among the 3,678 admitted patients. Thirteen of these 28 patients were only carriers; 4 were carriers and then were colonized or infected 2, 2, 3, and 8 days later, respectively; and 11 were colonized or infected before a screening test was positive. Cluster analysis showed that the occurrence of ESBL-producing Enterobacteriaceae cross-transmission within both ICUs was limited to 9 cases. Thus, most cases (19 of 28) were probably imported. Surveillance cultures failed to detect 9 of the 19 cases. The low prevalence of ESBL-producing Enterobacteriaceae carriers on admission (0.45%) and the relative ineffectiveness of our screening test to detect imported cases suggest that systematic detection of ESBL-producing Enterobacteriaceae in ICU patients is not cost-effective and that the use of clinical cultures may be sufficient to control ESBL-producing Enterobacteriaceae in non-epidemic situations.