Contact Precautions: An Ongoing Quest for Definitive Guidance and Policy

By Kelly M. Pyrek

As we know, contact precautions (CP) are a standard method for preventing patient-to-patient transmission of multiple drug-resistant organisms (MDROs) in hospital settings. CPs are recommended by the Centers for Disease Control and Prevention (CDC) as an intervention to control spread of MDROs and consist of the use of gowns and gloves for all staff who have contact with the patient or patient’s environment, as well as housing patients in a single room or a room shared with other patients on CPs.

Gottenborg and Barron (2016) remind us that there are three indications for the use of contact precautions:
1. Presence of epidemiologically important multidrug-resistant microorganisms
2. Spore-forming organisms such as Clostridium difficile
3. Excessive wound drainage, bodily discharges or fecal incontinence

Gottenborg and Barron (2016) note that "it is thought that contact precautions can help halt the chain of transmission, as patients placed in a private room and healthcare workers' strict adherence to hand hygiene and donning of isolation gowns and gloves can help prevent unintended contact with the patient’s environment. And when leaving the isolation room, it is essential for healthcare workers to properly remove personal protective equipment (PPE) -- first the gown, followed by the gloves, with care to limit contact with the exposed surface, followed by the performance of hand hygiene (with soap-and-water handwashing for C. difficile)."

As Marra, et al. (2017) note, "Contact precautions were first recommended by the CDC in 1970, at a time when there was minimal surveillance for healthcare-associated infections (HAIs), few single-bed hospital rooms, very poor compliance with hand hygiene, no use of alcohol-based handrubs, no chlorhexidine bathing to decolonize patients, and no enhanced technology for environmental disinfection. Over the ensuing decades, more knowledge has been acquired about strategic approaches to infection prevention.
Morgan (2009) acknowledges that "Isolation has long been employed to control the spread of infectious diseases. During epidemics, it has been applied for short durations to many patients. Prior to the availability of effective therapy for mycobacterial disease, isolation was often used for years, as exemplified by tuberculosis sanitariums and leper colonies. With these forms of isolation, however, came social stigmatization and limited access to medical care. More recently, Blood and Body Fluid Precautions, introduced in the 1980s, in response to the HIV epidemic, were associated with social stigmatization of patients until they were replaced by Universal Precautions. Beginning in the 1960s, isolation was employed for longer duration within hospitals, first for protective isolation of severely immunocompromised patients and later to prevent cross-transmission from patients with MDROs, principally methicillin-resistant Staphylococcus aureus (MRSA). Reports of psychologic stress and anxiety in patients in isolation appeared soon after the development of protective isolation."

At the center of the debate is the effectiveness of gowns and gloves to prevent the transmission of pathogenic MDROs. The 20-site Benefits of Universal Glove and Gown (BUGG) study conducted by Harris, et al. (2017) found that wearing gloves and gowns for all patient contacts in the intensive care unit (ICU) reduced acquisition rates of MRSA. The researchers found that across 40 simulated replications for each factorial design point and intervention site, approximately 44 percent of the decrease in MRSA acquisition rates was due to universal glove and gown use, 38.1 percent of the decrease was due to improvement in hand hygiene compliance on exiting patient rooms, and 14.5 percent of the decrease was due to the reduction in healthcare worker/patient contact rates. The authors concluded that using mathematical modelling, the decrease in MRSA acquisition in the BUGG study was found to be due primarily to the barrier effects of gowns and gloves, followed by improved hand hygiene and lower healthcare worker/patient contact rates.

As Harris, et al. (2017) note, "As it is likely that the mandatory universal gown and glove policy drove the higher hand hygiene compliance and reduced HCW/patient contacts, the BUGG bundle is an effective intervention in the MRSA prevention armamentarium. The authors believe that certain ICUs would benefit from the use of universal glove and gown policies for all patients."

Two colleagues who are professors of epidemiology and public health at the University of Maryland School of Medicine have enjoyed a spirited dialogue about CPs and while they disagree on some points, they share the united view that following the global evidence when it is appropriate at the local level and when resources allow, is a prudent course of action. Anthony Harris, MD, MPH, and Daniel Morgan, MD, MS, who conduct clinical work in the Veterans Administration system, have "a similar understanding of the literature but different interpretations," says Morgan.

"The real issue around CPs boils down to how big are the pros and what are the cons, with the only remaining con being in the costs," says Harris, who rejects the claim that CPs lead to more adverse events for patients. "Dan and I did a study together, a randomized controlled trial (BUGG), the highest level of evidence, which clearly showed that CPs did not lead to more adverse events, so we agree on that. There are also some of Dan’s studies that show CPs do not lead to more anxiety and depression, and he would agree with that."

Harris continues, "Dan and I summarize the facts the same way. Where we disagree is, I think the pros far outweigh the costs/cons, and he thinks the pros are not as strong and he thinks the annoyance factor of contact precautions for healthcare workers is exceedingly high. Ironically, we share some of the same points and the reason I think it's good for him to express the con side, is that there are some people out there (in contrast to Dan) who are so against CPs that they don't present the data fairly. As an example, you would never have a cardiology-related RTCT show that lipid-lowering agents were needed for myocardial infarction, and then have a researcher who thought, 'Well, the cost of these lipid-lowering agents are really expensive so I'm going to write a paper that says these agents are not needed because the observational non-randomized study showed they had no benefit.' No one would tolerate that. Yet it seems like in the literature around CPs, the people who are against it are cherry-picking the poorer studies to support their argument. The data about CPs not leading to more adverse events is very clear and yet people are still claiming that contact precautions lead to more adverse events."

Morgan alludes to the interpretation challenge: "The goal is to not over-reach and over-extrapolate from the research, too, as I think that is often the difference between two people who disagree on a clinical intervention," he says. "It can be a matter of thinking, 'They say it should work, so let's do it until we are proven wrong,' versus 'Let's do what we know, taking into consideration what evidence would lead us to think an intervention works, and if it changes, then let's do whatever is recommended.'"

Guidelines, especially those that are aging in place, can be subverted to scenarios at the institutional level, such as in the cases of outbreaks or any other situation driven by patient characteristics.

"Guidelines are generally helpful for infection control, but many recommendations we have are based upon relatively low-quality evidence," says Morgan, "and the CDC guidelines that people refer to for CPs, haven't been reissued since they first came out in 2007. I think HICPAC would have a harder time endorsing CPs because it has new criteria for grading the quality of the evidence. Local concerns are, of course, critical in this discussion. For example, if I have an outbreak of MRSA in my hospital, and I wasn't using CPs, I would probably start using them just because I know there is a big problem I need to address. If I don't know if CPs work or not and I don't have a problem such as an outbreak, I'd be less inclined to use CPs, assuming I was able to make those decisions."

Morgan continues, "That old expression, 'the road to hell is paved with good intentions,' fits CPs, as in healthcare, we do a lot of things that may be of low value, as the literature is unclear if there is a benefit to it, but at least you are doing something. Theoretically, a lot of interventions should work, but as it turns out, they don't."

Morgan alludes to the additional tasks that CPs place on healthcare personnel. "One thing that we do know about CPs is they do seem to be burdensome to healthcare workers and probably to patients also, and they do result in fewer healthcare personnel visits, about 20 percent less time with patients. And there isn't any strong proof that CPs work. At best, hospitals must use a lot of PPE to prevent a single transmission, so I think CPs are of low value. I think it’s more helpful to spend additional time in the clinical area to see how often CPs are being used, and how they may complicate patient flow and bed-related issues for the facility. If those appear to be issues, and if the institution perceives that there are strong negatives to the use of CPs, then it's smart to think about how to scale CPs back to where they would be used less frequently."

As the hospital epidemiologist for the Maryland VA health system, Morgan explains that he implements current national guidance, and that the VA is on the assertive end of the CPs spectrum. "Within the VA we use active surveillance culturing for all patients who come into any facility, long-term care or acute care, and then we place people on CPs within acute care so long as they are positive from either surveillance or clinical culture. In LTC facilities, we place people on a modified form of CPs. We are the only place I know of that routinely does that in LTC is the VA, so it’s an aggressive approach."

"The reason why I am more in favor of CPs is, we need more data," he says. "Until Dan and I finish the universal glove and gown study for additional outcomes -- we are finishing research into the question of do CPs have an effect on C. difficile and resistant Gram-negatives -- we won't be certain. I think if those results are negative, similar to the BUGG study VRE results, then I think you could make an argument that we should be peeling CPs back. However, our study did show that there was a 40 percent decrease in MRSA acquisition in the ICU, with universal gloving and gowning, and that 20 percent of those patients can get a subsequent clinical culture infection -- to me that is as large as the effect of CHG bathing, and no one would argue that we shouldn't be doing CHG bathing in the ICU. I would not remove CPs in the ICU because in that setting we know that the patients, if they become colonized with resistant bacteria, they get infected with it about 20 or 30 percent of the time on the same admission. We know that those patients' outcomes are poor, and we know in the ICU, when you interact with a patient who is colonized with resistant bacteria, you pick up that bacteria on your gloves and gowns 15 percent to 25 percent of the time. So, for me, that data supports CPs in the ICU setting, and that it's unwise to remove CPs in the ICU setting."

Harris continues, "I think where Dan and I are in strong agreement is that in facilities such as nursing homes, where the people are residents, or I think in ambulatory clinics where there is much less data of the benefit of CPs, I think if I was trying to save money, that's the areas where I would remove CPs. These are lower-risk patients with fewer potential breaches to their barriers -- they are not intubated, they don't have a central line -- so I think the lower-risk patient is the patient for whom I would remove CPs."

He adds, "Some of the studies suggesting that 'my situation is different, meaning I'm not in an outbreak, I removed CPs and I saw no difference,' are underpowered and you could actually be doing harm to your patients but you wouldn't know it. For example, I could remove CPs in my ICU, and I think it would be the wrong thing to do, but if I just looked at CLABSI, CAUTI and VAP rates, I wouldn't see a statistically significant difference in a year; however, if I looked over a longer period, I think that you would see a difference. People insist we should be getting to zero infections, and now ironically people are arguing, 'Well, if I remove CPs it's not cost effective because I will only be having a couple additional infections.' It's clear that if you remove CPs, you're not going to have any more infections -- to me it doesn't make any sense. If you walk out with resistant bacteria on your gloves and gown 20 percent of the time, and we know hand hygiene compliance is not sufficient to prevent the transmission, then I don't see how people argue that you are not doing some harm by using fewer CPs. The question is, can you achieve a sweet spot of saving a little bit of money, decreasing the annoyance of putting on the gloves and gowns, and not causing more patient harm."

Harris says CPs-related policy comes down to costs. "It ties into what monetary resources you have," he says, adding, "Personally, in infection control I think we spend way too little money; people have no problem spending money on orphan drugs or robotic surgery with no improved outcomes, and yet the cost of contact precautions is not an astronomical dollar amount."

Harris and Morgan are currently conducting research that they hope can definitively add to the existing dialogue about the value of CPs. "As much as I am in favor of CPs, Dan and I are doing research to help guide people who are trying to move away from it in a more logical fashion," he says. "We have NIH and CDC grants to try to predict which patients transmit the bacteria more to the gloves and gowns, which healthcare worker interactions lead to more pick-up of bacteria, and potentially which organisms lead to more infections. We think hospitals can find that sweet spot better, saying 'Hey, I'm a hospital that wants to save $200,000 on CPs, but here are the locations and/or types of patients where I still should use them and here are the type of patients or locations where maybe it's fine not to use CPs.' To be honest, I'd like to combine Dan's and my thoughts to the extent that you would have patients you wouldn't use CPs on and then you could potentially have patients for which you would not only use CPs but for which you would hopefully do more infection control interventions. So, if I had a nurse who was going to touch a patient with MRSA in a wound, not only do I want that nurse to wear gloves and a gown, I want our next intervention added to that approach. Or if I found that touching the patient was a key issue, maybe we need to do more CHG bathing or more skin decontamination in certain patients. What upsets me is that some institutions have heeded the advice of underpowered studies showing that facilities are fine not using CPs anywhere in their facilities. I think that is dangerous."

Harris adds, "I want more money and more infection control interventions but I want to adopt the ones that are more evidence-based. So, do I envision in five years' time having a hospital where for certain patients we do more decolonization, more active surveillance, and more CPs? Yes, in a certain subset I think that is where we need to go; but do we need to do all those for everyone? No, probably not."

"The trend seems to be that hospitals are not using CPs for MRSA or VRE, but at a slow rate of discontinuation," Morgan says. "Every month or so I hear about a new hospital that is no longer using CPs and I think that trend will continue. However, I think it would be very interesting for the CDC to sponsor a study that would attempt to look at CPs across a large group of hospitals and I know there has been some discussion of that -- but it's seen as a politically thorny issue because if it is a negative study, it will mean that people stopped using CPs and it's really just the true believers. I think the true believers are concerned about a study that could potentially be negative and so in the absence of that, there will be an ongoing debate and institutions will stop CPs because it is burdensome."

In January, the Society for Healthcare Epidemiology of America (SHEA) issued expert guidance advising hospitals on determining when they can safely discontinue CPs for patients with multidrug-resistant bacteria. The framework addresses how long hospital staff should use these safety protocols to reduce the spread of potentially deadly organisms within the hospital, in most cases ranging from one to three negative cultures prior to discontinuation. The guidance also outlines the use of molecular testing that is guiding these care decisions.

"Because of the virulent nature of multidrug-resistant infections and C. difficile infections, hospitals should consider establishing policies on the duration of CPs to safely care for patients and prevent spread of these bacteria," says David Banach, MD, MPH, hospital epidemiologist at University of Connecticut Health Center. "Unfortunately, current guidelines on CPs are incomplete in describing how long these protocols should be maintained. We outlined expert advice for hospitals to consider in developing institutional policies to more effectively use CPs to safely care for patients."

The SHEA Guidelines Committee developed the recommendations based on available evidence, theoretical rationale, practical considerations, a survey of SHEA members, author opinion, and consideration of potential harm, where applicable. The recommendations for duration of CPs, are specific to key multidrug-resistant organisms such as MRSA, VRE and Carbapenem-resistant Enterobacteriaceae (CRE), as well as Clostridium difficile. Per the guidance document, hospital personnel should weigh how much time has elapsed since the last positive culture to determine if contact transmission is likely. The guidance also advises on patient characteristics that could determine the duration of care. For C. difficile infections, the recommendation is to continue CPs for at least 48 hours after the resolution of diarrhea and consider extending if CDI rates are elevated despite infection prevention and control measures. SHEA says insufficient evidence exists to make a formal recommendation on whether patients with CDI be placed on CPs if readmitted to the hospital. The recommendations state that any guidance should be overseen and revisited by infection prevention and control leadership, especially in outbreak situations.

The authors note that hospitals should carefully assess their institutional risks, priorities, and resources prior to adopting a new policy on the duration of contact precautions, as well as weigh the cost and feasibility of implementation.
"The expert guidance paper was designed to fill a gap, as there is not much evidence as to when you can remove CPs," Morgan says. "Despite the CDC recommending three cultures, we knew there is significant variation from one institution to another. The guidance suggests how you can use CPs a bit less often but it's fairly labor intensive to culture someone three times before you remove MRSA CPs. So, I think the guidance helps people operationalize CPs for organisms other than MRSA, but it probably won't create a huge change in practice in most hospitals."

The SHEA guidance emphasizes using patient characteristics to guide the use of CPs and Morgan notes, "I always applaud people being thoughtful about how they determine the need for infection prevention and control interventions for their facilities. I do think CPs probably if they work, they work better when they are applied to the highest-risk patients, which is probably some combination of how much organism they have as well as what their co-morbidities are. For instance, if a patient has a large open wound -- and we know people shed a lot of bacteria -- and they need help with activities of daily living, there is going to be a lot of contact between healthcare workers and that patient, and CPs could be helpful."

A word about active surveillance is warranted. In the mid-2000s, mandatory screening for MRSA propelled the debate about the need for CPs into another dimension. Peterson and Diekema (2010) engaged in a point-counterpoint discussion of whether U.S. healthcare institutions should aggressively deploy programs to control MRSA. Peterson asserted that the policy hinged on three critical questions: "Is the burden of MRSA disease sufficiently high so that human effort and financial resources should be directed toward this problem? If the answer is yes, then the second question is this: How do the policymakers in a healthcare organization decide whether MRSA is a problem for its patients? The last question, then, involves implementation: what type of MRSA control program is likely to reduce disease cost effectively?"

"I think we jumped the gun on mandatory surveillance, as the level of evidence wasn't high enough that you should force people to do it," Harris says, "and I think we then suffer this backlash that to be honest, is transferred over to CPs. It seems as if in infection control, we swing the pendulum one way too far or the other, to the point where we are either doing no active surveillance or we are culturing everyone. I feel it's the same way with CPs -- we have said previously that CPs are great, but now we are saying CPs are horrible, and there is likely a sweet spot of both active surveillance and CPs that should be guided by the literature that then dictates practice. I think hospitals should have some flexibility as to where that sweet spot is, based on their resistance profile, the acuity of the patient, and similar factors."

"The use of decolonization of the nares, whether with mupirocin or povidone iodine or something else, probably is beneficial if someone is at relatively high risk of having an infection," Morgan notes, "so if you can target patients before they have open heart surgery or a hip or knee replacement, I think nasal decolonization is probably a valuable intervention. We know that if you decolonize people it is temporary, as flora tend to recover; so it's probably not something you'd want to do very broadly, but it probably does work pretty well if you can figure out ways to implement it among a narrow patient population."
Let's examine what the literature says about CPs. Marra, et al. (2017) declare, "Despite the widespread use of CPs, there is little evidence to support effectiveness in the prevention of methicillin-resistant Staphylococcus aureus (MRSA) or vancomycin-resistant enterococci (VRE) infections in endemic settings. In addition, questions have been raised regarding the impact of CPs on care delivery and patient safety."

Amid questions about the benefit of CPs, Kullar, et al. (2016) evaluated the effectiveness and adverse outcomes associated with CPs for prevention of MRSA transmission. Their review showed that CPs reduced MRSA transmission in epidemic settings and in instances with high compliance, but a decrease in infection rates was not shown. The researchers pointed out that the unintended consequences of CPs include decreased healthcare provider (HCP) time spent with patients, low HCP compliance, decreased perceptions of comfort from patients, and greater likelihood of patient complaints and negative psychologic implications.

Kullar, et al. (2016) point out that the effectiveness of CPs as a method to stem the spread of MDROs has been well documented in epidemic outbreaks. Jernigan et al. described the benefits of CPs during a seven-month outbreak of MRSA in a neonatal intensive care unit (ICU) and described a 16-fold reduction in transmission due to implementation of CPs. Kullar, et al. (2016) emphasize that although there may be a reduction in transmission in an outbreak situation because of implementation of CPs, this may not stand true in a non-outbreak endemic setting. In the Harris et al. cluster randomized trial, the primary composite outcome of reducing MRSA or VRE acquisition was not met; however, a secondary outcome of reduction in MRSA acquisition in the intervention arm was achieved. Consistent with prior studies, a decrease in HCP room entry was noted in the intervention group by 20 percent. Of note, the authors suggest that fewer visits may benefit patients and may have been associated with their reduced MRSA transmission rates. Kullar, et al. (2016) underscore that due in part to weekly feedback on compliance, the investigators achieved 85 percent to 95 percent compliance with admission and discharge screening and CPs and state, "This may not be applicable to real-world ICUs, where compliance rates have been reported as low as 20 percent. Overall, this study provides convincing data that the use of CPs can reduce the transmission of MRSA and raises interesting questions regarding whether CPs should be tailored to specific organisms or circumstances in the non-outbreak setting."

Regarding the issue of healthcare workers not spending enough time with patients placed under CPs, Evans, et al. found no statistical difference noted in patients’ recollection of encounters between the isolated and non-isolated groups. However, non-isolated patients reported greater comfort with nursing staff than their isolated counterparts. Morgan et al. found that CPs influenced the actions of healthcare personnel (HCP), with patients under CPs having 36.4 percent fewer visits from HCP and 17.7 percent less direct patient contact time with HCP. The frequency of visitors was also impacted by CPs, with 23 percent fewer visitors for patients on CPs. Notably, HCP were 15.8 percent more likely to perform hand hygiene when exiting isolated patients’ rooms.

Regarding these two key issues relating to CPs, Kullar, et al. (2016) concluded that "In endemic settings, there are few data to support routine use of CPs to control the spread of MRSA. Education should be performed in hospitals to improve patients’ perception of care and understanding of CPs when implemented and HCP adherence to good hand hygiene and standard precautions practices." They add, … because there remains a gap in the evidence supporting the direct benefit of CPs in preventing the spread of MRSA in non-outbreak, endemic settings, infection prevention programs should assess the incidence and prevalence for MRSA in their community and institution and balance the risk of transmission with the possible adverse effects of isolation. Authors have suggested that preparing patients in CPs emotionally by explaining the reasoning for the isolation, before isolation, may help decrease their overall anxiety. Therefore, we recommend that education measures should be put in place to improve both patients’ and HCP perceptions of care and understanding of CPs. Assuring HCP adherence to good hand hygiene practices and the use of standard precautions for all patients should be at the forefront of all infection prevention program plans, with the use of gowns and gloves reserved in instances (e.g., infected wounds that cannot be contained) that pose a high risk for transmission of MRSA."

In their review of the literature on the impact of discontinuing contact precautions in the acute-care setting, Marra, et al. (2017) used 14 studies meeting inclusion criteria and found that six studies discontinued CPs for MRSA and VRE; three studies for MRSA only; two studies for VRE only; two studies for extended-spectrum β-lactamase–producing Escherichia coli; and one study for Clostridium difficile infection. When study results were pooled, there was a trend toward reduction of MRSA infection after discontinuing CPs and a statistically significant reduction in VRE infection. Nine studies reported compliance with an alternative intervention, such as hand hygiene compliance interventions, bare-below-the-elbows, or chlorhexidine bathing.

As Marra, et al. (2017) observe, "Three recent systematic reviews on the effectiveness of CPs have also concluded there were no high-quality data to support the use of CPs for endemic MRSA or VRE, and raised concern that there may be patient harm and unintended consequences." The investigators concluded that discontinuation of CPs for MRSA and VRE has not been associated with increased infection rates. The researchers note, "These results are limited by the design of the studies included in our review and meta-analysis, and are not applicable to epidemic (outbreak) situations. Nor are there sufficient studies to evaluate the impact of discontinuing CPs for resistant Gram-negative pathogens or C difficile. We think discontinuation of CPs (as currently practiced) for MRSA and VRE can be safely accomplished, particularly in hospitals with a strong horizontal infection prevention strategy, including high levels of compliance with hand hygiene."

References:

Banach DB, Bearman G, Barnden M, Hanrahan JA, Leekha S, Morgan DJ, Murthy R, Munoz-Prince LS, Sullivan KV, Popovich KJ and Weimken TL. Duration of Contact Precautions for Acute-Care Settings. Published online Jan. 11, 2018.

Gottenborg EW and Barron MS. Source: Isolation Precautions in the Inpatient Setting. Hosp Med Clin 5 (2016) 30-42.

Harris AD, Morgan DJ, Pineles L, Perencevich EN and Barnese SL. Deconstructing the relative benefits of a universal glove and gown intervention on MRSA acquisition. J Hosp Infect. Vol. 96, No. 1. Pp 49-53. May 2017.

Harris AD, Pineles L, Belton B, Johnson JK, Shardell M, Loeb M, Newhouse R, Dembry L, Braun B, Perencevich EN, Hall KK, Morgan DJ and the Benefits of Universal Glove and Gown (BUGG) Investigators. Universal glove and gown use and acquisition of antibiotic-resistant bacteria in the ICU: a randomized trial. JAMA 2013;310(15):1571-80.

Kullar R, Vassallo A, Turkel S, Chopra T, Kaye KS and Dhar S. State of the science review: Degowning the controversies of contact precautions for methicillin-resistant Staphylococcus aureus: A review. American Journal of Infection Control. 44 (2016) 97-103.

Marra AR, Edmond MB, Schweizer ML, Ryan GW and Diekema DJ. Discontinuing contact precautions for multidrug-resistant organisms: A systematic literature review and meta-analysis. Am J Infect Control. 2017.

Morgan DJ, Diekema DJ, Sepkowitz K and Perencevich EN. Adverse outcomes associated with contact precautions: A review of the literature. Am J Infect Control 2009;37:85-93.

Peterson L Diekema D. Point-Counterpoint: To Screen or Not to Screen for Methicillin-Resistant Staphylococcus aureus. J. Clin. Microbiol. Vol. 48, No. 3. 683-689. March 2010. Accessed at: http://jcm.asm.org/content/48/3/683.full

Siegel JD, Rhinehart E, Jackson M, Chiarello L, and the Healthcare Infection Control Practices Advisory Committee, 2007 guideline for isolation precautions: preventing transmission of infectious agents in healthcare settings, June 2007. Atlanta, GA: Centers for Disease control and prevention.