Ep29: Drug Interactions and Deprescribing
Ep29: Drug Interactions and Deprescribing
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Adverse drug events cause about five per cent of admissions to a public hospital, although some studies suggest the figure could be as high as 15 per cent. That makes at least half a million patients in Australia and 55,000 in New Zealand every year.
Drug-drug interactions make up about a fifth of these adverse events. They have become more frequent over the decades, as more medications reach the market. More than half of people over the age of 75 are on five or more prescriptions—a state referred to as polypharmacy.
This episode examines some of the systems that have led to current rates of polypharmacy, and some strategies for deprescribing. We also discuss Professor Richard Day’s recent review of drug interactions from the Internal Medicine Journal, and highlight the combinations physicians should be most concerned about.
Guests: Professor Richard Day FRACP (St Vincent’s Hospital, UNSW), Professor Sarah Hilmer FRACP (Royal North Shore Hospital, University of Sydney).
Extended podcast: Case study of drug interactions, azothiprene interaction with allopurinol interactions, methotrexate interaction with trimethoprim/ sulfamethoxasole, electronic alert systems, systemic barriers to and observational research in support of desprescribing [RACP]
Life-threatening drug interactions: what the physician needs to know [Internal Medicine Journal]
Polypharmacy in older people: when should you deprescribe? [Medicine Today]
Reducing inappropriate polypharmacy: the process of deprescribing [JAMA Internal Medicine]
Prevalence of potential and clinically relevant statin-drug interactions in frail and robust older inpatients [Drugs & Aging]
Perpetrators of pharmacokinetic drug–drug interactions arising from altered cytochrome P450 activity: a criteria-based assessment [British Journal of Pharmacology]
A drug burden index to define the functional burden of medications in older people [Archives of Internal Medicine]
STOPP/START criteria for potentially inappropriate prescribing in older people: version 2 [Age & Ageing]
Stockley's Drug Interactions [Pharmaceutical Press]
Drug Interactions Analysis and Management [Hansten and Horn]
Drug Interaction Tools
The Australian Medicines Handbook [AMH]
HIV Drug Interaction Checker [University of Liverpool]
MIMS Online Drug Interaction Module [MIMS Australia]
Home Medicines Review [6CPA]
Beers Criteria Medication Review [The American Geriatrics Society]
Produced by Mic Cavazzini. Music courtesy of Daddy Scrabble (“Flying Pea”, “Cherry Blossom”), Doctor Turtle (“Manly Nunn Steps Out”), and Scott Holmes (“Chasing Shadows”). Photo by iStock. Executive producer Anne Fredrickson.
Editorial feedback for this episode was provided by RACP Fellows Dr Paul Jauncey, Dr Marion Leighton, Dr Rebecca Grainger, Dr Alan Ngo, Dr Phillipa Wormald and Dr Michael Herd.
RICHARD DAY: We say that adverse drug events, we can avoid about half. It’s a big ticket item that causes a lot of morbidity. It costs a lot of money so we really should be doing better.
MIC CAVAZZINI: Adverse drug events cause about 5 per cent of admissions to hospital, although some studies put the number much higher. That makes at least half a million patients in Australia and 55,000 in New Zealand every year. Rheumatologist and clinical pharmacologist Richard Day of St Vincent’s Hospital, Sydney:
RICHARD DAY: Yeah, it’s a big number and you’re not safe when you get into hospital. So the rate sort of adverse drug reaction there again, 5 to 15 percent. But about a fifth of those are drug interactions.
MIC CAVAZZINI: Drug interactions become more likely in ageing patients who develop multiple conditions. Polypharmacy is the term given when five or more medications have been prescribed to a single patient, and it’s far from uncommon.
SARAH HILMER: Yeah, look in Australia, polypharmacy is the norm for older people. Amongst older Australians in the community aged 75 years or older, about half are exposed to five or more medicines and about a fifth are exposed to 10 or more, which we call hyper-polypharmacy.
MIC CAVAZZINI: That’s geriatrician Sarah Hilmer of the Royal North Shore Hospital, and professor at the University of Sydney.
SARAH HILMER: For older people in hospital, the numbers are much higher. Nearly all older people in hospital are on five or more medicines. And five or more is the number of drugs that’s been associated with adverse outcomes in older people. It seems like once you get to your fifth drug, that’s when you’re more likely to fall over, that’s when you’re more likely to get confused, become frail, die.
And that may be partly because of the reason why you’re prescribed those five drugs, it may also just be a red flag and the more drugs you’re on, the more likely you are to be on a high-risk drug. But it seems in controlled studies, where you’ve controlled as well as you can in observational data, that it’s more than that. So older people are more susceptible to adverse drug reactions and drug interactions—firstly because they take more drugs, secondly because they don’t clear them as well in the first place and thirdly because their end organs and their overall body is less resilient.
MIC CAVAZZINI: You’re listening to Pomegranate Health—a podcast for physicians of the RACP. I’m Mic Cavazzini, and in today’s show we talk about the dangers of polypharmacy and strategies for deprescribing.
Professor Day authored a review about the most common life-threatening drug interactions in May’s Internal Medicine Journal. He begins with some of the reasons there’s been a three to fivefold rise in polypharmacy in the last two decades.
RICHARD DAY: Yeah, I think it’s really interesting because for each of the particular conditions, as the evidence accrues about what should be done, it often includes more than one drug. So for example, if you have a heart attack there are three or four drugs that are part of the guidelines that one should prescribe. Now, if you happen to have diabetes, well there’s a few more. And if you happen to have hypotension a few more again, and it’s unusual for any guideline to present what to do when you’ve got comorbidities.
MIC CAVAZZINI: And Sarah, how does the prescribing cascade fit into this?
SARAH HILMER: Yeah, the prescribing cascade is something that we always look for in geriatric medicine when we’re doing a medication review. The prescribing cascade is when you use one medication to treat the side effects of another without realising that you’re doing it. And a good example of that is if someone is taking thiazide then they’re more likely to be taking a gout medicine. If someone is taking metoclopramide, they’d more than likely be taking an anti-Parkinson’s medicine. If someone takes a cholinesterase inhibitor, then they’re more likely to be prescribed an anticholinergic for urinary incontinence.
MIC CAVAZZINI: And can you paint a bit of a picture of the number of different prescribers that a geriatric patient might have?
SARAH HILMER: Depends very much on the patient, but if you think that on average, every decade over 60 you pick up one chronic disease, then a person in their 80’s usually has about three and for each of those they will have a sub-specialist, they will also have their GP they may well have another GP who covers when their GP is not there. And they’ll have the geriatrician who may or may not see them in the community. And so it’s really quite the norm to have four or five different prescribers and it’s quite hard to stay on top of knowing what those four or five different prescribers are doing.
MIC CAVAZZINI: Now there are different types of drug-drug interactions. Can you start by describing the difference between pharmacodynamic from pharmacokinetic interactions?
RICHARD DAY: Probably the commonest are what we call pharmacodynamic interactions. So that’s when two drugs do roughly the same thing. So for example they both cause CNS depression.
More challenging in a lot of ways is the pharmacokinetic interactions. So that’s removal of the drug from the body and its absorption. Other drugs might slow down the process of elimination and the reverse can happen, where you can actually speed up the process of elimination. So if you increase the removal, that means loss of effect and if you block the removal that means too much effect.
Now, if it’s a critical drug, the difference between too much and too little isn’t much. Probably the biggest area is in metabolism in the liver.
MIC CAVAZZINI: Yeah, we’ll get into the complex metabolic pathways later, but there’s also some very simple interactions in the gut, aren’t there? The example of iron supplements and absorption.
RICHARD DAY: Yeah, it’s very important that people understand that the absorption can be affected by binding agents like cholestyramine or iron preparations, and a good general rule is to separate critical drugs from those type of agents. One of the important things is that people that take the iron preparations you mightn’t know about it, because the patient’s actually purchase them themselves or some other practitioners prescribe them. So that’s one thing.
The other thing you can do is you can change the pH with some very effective agents like proton pump inhibitors. Now that can affect the absorption of a number of drugs, for example, some of the new kinase inhibitors used to treat cancer won’t be absorbed if the pH is headed towards neutral. You can also effect through the same mechanism, using antacids.
MIC CAVAZZINI: Sarah, can you explain the physiological changes older patients that put them at greater risk of adverse drug reactions?
SARAH HILMER: Older people are at highest risk. Firstly as we get older, we get changes in our body composition, what we call sarcopenic obesity. So we lose muscle, that’s sarcopenia and we get relatively more fat. And that has implications particularly for the volume of distribution of drugs, so a water soluble drug like gentamicin or a low molecular weight heparin would actually have a smaller distribution for the patient’s overall weight, so you’d need a smaller loading dose. And it’s partly also because you get age-related decline in your renal function, so your kidneys aren’t working as well in the first place.
The good thing about renal clearance is you can measure it, so you can actually adjust your maintenance dose of renally-cleared drugs using creatinine clearance. You do have to always be careful not to just use the serum creatinine as an estimate of a person’s renal clearance because obviously as you have less muscle, so you have less creatinine to clear. And therefore a person can have a relatively normal serum creatinine, but a very impaired creatinine clearance when they’re old. And when it comes to hepatic clearance, There’s about a 50per cent reduction in hepatic blood flow as you get older and there’s a reduction in enzyme clearance. Your liver does not work as well as you get old.
MIC CAVAZZINI: Most of the clearance of medications in the liver and gut occurs by oxidative metabolism. The cytochrome P450 enzymes convert drugs into products that can be eliminated more easily. Unfortunately, many drugs also disturb the function of these enzymes. One example is clarithromyocin, a commonly used macrolide antibiotic. Its inhibitory effect on cytochromes can result in dangerously high concentrations some potent subject drugs. Richard Day explains.
RICHARD DAY: So that’s a very good example because it does also inhibit cytochrome P450s, 3A4 and 3A5. Now, they metabolise some very important drugs—drugs used in transplantation and also cancer drugs and also some of the newer anticoagulants. So you can see the situation where someone’s maybe had a transplant, in the community, he goes to the GP, he has an infection, he’s started on antibiotic—and the drug that’s actually suppressing the rejection, its removal is inhibited. Now that can be very serious because people are over immune-suppressed with a risk of infections and so on.
MIC CAVAZZINI: In the paper you write that macrolides also inhibit warfarin metabolism by the cytochromeP450 pathway. So that would elevate concentrations, and increase the risk of bleeding?
RICHARD DAY: Yeah, warfarin would be a good example. It’s really—the difference between too much and too little isn’t much, so if you increase the removal that means loss of effect, and if you block the removal, that means too much effect, so either bleeding or clotting, which is catastrophic.
Amiodarone, which is a widely used antiarrhythmic drug, again, a very important interaction where you can increase the effect of warfarin significantly. Now, the opposite can happen with other antibiotics that actually induce the metabolism, so rifampicin you might be using for staphylococcal infection will induce metabolism. And any of the drugs used to treat seizures, at least the old ones phenytoin and carbamazepine,
I think the thing with warfarin is it’s one of the biggest drugs for serious adverse drug reactions. If you’re starting and stopping anything, just expect an interaction, number one. Number two, you need to be monitoring more often, otherwise it’s too risky.
MIC CAVAZZINI: And amiodarone itself has a narrow therapeutic window and is also sensitive to changes in P450 function. What are the consequences there when you’re trying to control arrhythmia?
RICHARD DAY: Amiodarone is one type 3 anti-arrhythmic, metabolised by this cytochrome P450 system. And either concentrations that are too low or too high are bad—the arrhythmia gets out of control or, in fact, you know, there’s very significant toxicity with amiodarone, the lungs, the skin and the heart. So inducers and inhibitors of cytochrome P450 are big issues.
I think there’s also in the HIV group of drugs interacting with amiodarone and you’ve got to just look that up, I’ll have to look it up because I’ve forgotten the one which does the inhibiting. But my HIV therapeutic colleagues shake in their boots when amiodarone is mentioned.
And HIV I think is a great example because now we’ve got big cohorts of people who are maintained very well on combination therapy who are now developing coronary artery disease, diabetes, depression, intermittent infections, being treated by lots more people, different doctors, polypharmacy, drugs that are through the cytochrome P450 system—so potential for mayhem unless you’re very careful.
SARAH HILMER: Yeah, certainly in geriatrics the kinase inhibitors are proving to be quite a challenge. Things like ibrutinib which people take for chronic lymphocytic leukaemia, and can take for quite a long time, have a lot of drug interactions and then they have side effects like an increased risk of atrial fibrillation, and then the drugs that you want to prescribe for the atrial fibrillation will interact with the ibrutinib. And it’s a really complex cycle and I think as a geriatrician or general physician or a GP who’s looking at the whole picture, it’s really hard to stay on top of these new drugs. But we have to remember that just because it’s a sub-specialist drug, it doesn’t mean that it doesn’t interact with all the other drugs that we’re using and someone’s got to look at all of them and think about it.
RICHARD DAY: Exactly, Exactly.
MIC CAVAZZINI: And of course always in the press are statins. I think it might have been in your paper, Richard. You say that around 10 per cent of older patients prescribed statins and admitted to a teaching hospital, were discovered to have potentially clinically significant drug interactions with these ubiquitous medicines.
RICHARD DAY: Yeah so look—
SARAH HILMER: That was my paper. You might have cited it.
RICHARD DAY: I hope so!
MIC CAVAZZINI: Maybe I’ll let you answer that one.
SARAH HILMER: No, Ric can answer it.
RICHARD DAY: Yeah so, look, firstly adverse reactions with statins are common, I suppose the biggest one is muscle pain, also liver function test abnormalities. But there also is metabolism by this cytochrome P450 system. So they’re subject to inhibition and higher concentrations, so greater risk of these adverse effects. Now, in the group of statins, some are more prone to these interactions than others, so simvastatin for example is prone, whereas rosuvastatin would be much less likely to be associated with the problem.
The other thing is, there’s things called transporters that are linked very closely to the cytochrome P450 system and p-glycoprotein is the transporter which transports across membranes but particularly from the circulation into the gut. So blocking that can lead to very high concentrations of drug and it’s very much like increasing the dose, as if you double the dose or triple the dosing.
SARAH HILMER: Yeah, I’ve seen some terrible cases of digoxin toxicity when people have started on a macrolide, a chest infection in winter and suddenly they block their p-glycoprotein and wound up with digoxin toxicity and also dabigatran and bleeding.
MIC CAVAZZINI: Of the most prescribed drugs in Australia, statins take first and third place. But the ACE inhibitor perindopril is number two, and another four drugs targeting the angiotensin system make it to the top ten. When prescribing these it’s important to consider pharmacodynamic effects as well as homeostasis of salts in the blood serum.
SARAH HILMER: So look, ACE inhibitors are commonly used with other drugs that also lower blood pressure. If you think about a person who’s got heart failure or is just after having a myocardial infarction, they’ll most likely be prescribed an ACE inhibitor as well as a beta-blocker as part of their guideline-recommended therapy, which would then predispose the person to hypotension or postural hypotension and potentially, falls.
The other interaction that we worry about with ACE inhibitors is interactions with other drugs that can impair your renal function. And we talk about the triple whammy which is when you’re on an ACE inhibitor and a diuretic and a non-steroidal anti-inflammatory drug. And the combination of those three has a very good chance of causing renal impairment and those three are very commonly used together. Diuretics are commonly used for heart failure and non-steroidal anti-inflammatory drugs are readily available over the counter and people will take them not necessarily discussing it with their doctor, they’ll go from having two drugs that put their renal function on the edge, to having the triple whammy.
Another one that I often see with ACE inhibitors is spironolactone, again as part of the heart failure guidelines. And you’ve got to be very careful to monitor potassium in that situation because both drugs will increase potassium and again, in older people with borderline renal function in the first place, you can wind up with dangerous hypokalaemia very easily. And the other drug that’s commonly prescribed with ACE inhibitors is trimethoprim. Trimethoprim is an antibiotic commonly used for urinary tract infection and it can cause a type 4 renal tubular acidosis and high potassium.
MIC CAVAZZINI: And Richard, you also mention in the paper that ace inhibitors can lead to lithium toxicity in patients being treated for bipolar disorder?
RICHARD DAY: Yeah, that’s very common. It’s very dramatic, people turn up confused, they’re twitching, people are red in the face, their blood pressure might be labile, tachycardic. It looks in a lot of ways perhaps like an infection or some sort of systemic illness, very unpleasant. And one of the common interactions is with a diuretic that started with a thiazide. Anything that interrupts the sodium economy in the body because sodium and lithium exchange, so that changes the potential difference across nerve and muscle membranes, making them more excitable. And the remedy is to get rid of the lithium by flushing it out with sodium essentially.
MIC CAVAZZINI: And another condition that’s often comorbid with aging and heart disease is depression and SSRIs are, of course, a useful drug in its treatment, but there are many other drugs that non-specifically block serotonin reuptake. What are some of these drugs?
RICHARD DAY: Yeah, so this is a big issue, so the serotonin syndrome from minor manifestations to really very dramatic and troublesome ones. So the serotonin reuptake inhibitors like sertraline or citalopram or escitalopram can cause this in their own right. But if you actually combine drugs that have that same effect—as examples, there’s a very commonly used opioid analgesic called tramadol which has a component that inhibits reuptake of serotonin.
There’s also, of course, St John’s wort. We haven’t talked about complimentary medicines much, but it’s a serotonin reuptake inhibitor and it’s commonly taken. So it’s not unusual to find out later when someone turns up twitching in the ED department with their blood pressure going up and down or tachycardic with clonus, that in fact there’s been more than one drug. And it’s important to be aware of what the serotonin syndrome is actually like. I’ve had people who’ve had clonus for weeks after taking, you know, one or two of these things, occasionally with drugs of abuse like ecstasy on top of an antidepressant like sertraline.
MIC CAVAZZINI: Well, drugs of abuse or recreational drugs or even complimentary medicines are not something that patients will often talk about with the prescriber. Have you got an approach for bringing that up, Sarah?
SARAH HILMER: I always explicitly ask. I try to ask in a non-judgmental way, I explain why it’s important that I understand what they’re taking and that it might interact with their other drugs, or partly explain how their health is at the moment. And the gold standard really is to get a pharmacist to go out to their house and do a home medicines review and actually have a look around and get them to show you exactly what they’re taking. You know at clinics we say, “Come in and bring all your medicines in a brown bag, anything you take,” and we usually get a range of complimentary medicines.
Older people, on average, 50 percent of them take at least one complementary medicine. Of those people who take a complimentary medicine, they take an average of three and they’re usually the things that are related to aging which modern medicine hasn’t really made big gains in yet. Things like ginkgo biloba in the hope that it might help your memory or various antioxidant vitamins in the hope that it might help your aging. And so I always ask and I explain why I need to know and generally I find out, I think.
MIC CAVAZZINI: You can keep informed about dangerous drug interactions through numerous online resources, which we've linked to on our website. A few example are the Australian Medicines Handbook, MIMS Online and the Drug Burden Index.
But it’s good practice in patients already taking more than five drugs to review them carefully. Sarah Hilmer outlines a strategy for deprescribing, and consideration of non-pharmacological solutions:
SARAH HILMER: Yeah, look, we try very hard to get patients down to their top four or five and the first step is to look at what their problems are and what their goals are and to see how you can align those. And then—people do this in different ways, some people imagine that they’re starting from scratch and say “OK, well if this patient has these five comorbidities and his main goal is to maintain their physical and cognitive function, which five drugs could I use to achieve that?” The other strategy is to start with what they’re on and look at each drug and say, “Is there still a valid indication for this, is there evidence of toxicity?” Weigh up the risk benefit for each drug and then work out whether those drugs are going to be in the top five or not.
The important thing is to make sure that you explain to the patient that you are doing this to help them achieve their goals, you’re not doing this because you’ve given up on them, because they’re not worth treating, because you don’t want to spend money on their drugs, you are doing this to help them achieve whatever their goal may be.
Sometimes that is about optimizing the treatment of one particular disease that is actually the thing that is their rate-limiting step for example, if you had stage four heart failure and bad arthritis and you also had macular degeneration, it may well be that you’ve got everything in place to manage getting around with your arthritis, and your house is set up for your impaired vision, but the thing that is actually stopping you from getting out of bed and going to sit out in the sun is your shortness of breath. And in that case, there would be good justification for doing what you could to treat the heart failure. However, if the treatment of the heart failure then made you incontinent or made you so dizzy that you feel over and you couldn’t get outside anyway, then there would really be no point.
MIC CAVAZZINI: The point about functional outcomes I could imagine in the case of incontinence for example, that you might be able to avoid pharmacological treatment using pads or something else?
SARAH HILMER: Continence is a great example. The drugs we use for incontinence are generally quite toxic to older people and are not terribly effective. For urge incontinence, which is the incontinence you get when you can’t get to the toilet in time, the main drug class that we use are the anticholinergics. And on average they reduce your episodes of going to the toilet by one or two per day, that brings down from an average of 12 to 10, it doesn’t make a huge difference to your lifestyle.
But the drugs themselves, being anticholinergic, give you dry mouth, they give you constipation, they make you confused, they give you blurred vision, so yeah, we often suggest things like timed toileting. Particularly if someone is living in residential aged care, it’s been well established that if you just take someone to the toilet every couple of hours you can keep them dry. Or continence pads and continence aids. They’re also—for the more highly functioning people with good cognition, there are various bladder training exercises and things that you can do which, again, are about as effective as the drugs and not nearly as toxic.
MIC CAVAZZINI: You’re saying in your review that treating or preventing a specific disease in a very elderly person may alter the cause of death without substantially impacting on life expectancy. Can you elaborate on this?
SARAH HILMER: Well, once you get to a certain age and you’ve got a lot of different chronic diseases going on at the same time and frailty, we could talk about the concept of competing morbidity. And the idea is that even if you really optimize the treatment of one of the diseases, then one of the other ones will probably catch up with you. And a number of preventative medicines will take at least two years to have any difference. And if a person’s life expectancy is less than two years, then clearly there’s not a lot of point in taking the medicine, you’re getting the side effect and there’s no evidence at all that you would ever get any benefit.
And the other really important thing is to monitor closely after you start deprescribing. You also have to remember that when you withdraw a drug, you can basically reverse an existing drug interaction and Ric touched on that a bit with the warfarin. If you stop something that was inhibiting cytochrome P450, then you’ve got to bear in mind that now cytochrome P450 will be working better and it might actually affect the clearance of some of your other remaining drugs and so that’s one of the things that you have to monitor for.
MIC CAVAZZINI: One of my editorial committee talked about this culture where clinicians are so caught up in the importance of their area of specialty and the disease that they’re treating can act quite single-mindedly to cure that particular problem, is this something you see, Ric?
RICHARD DAY: Yes, absolutely. We we’re taught to be physicians first and -ologists second, but it’s the hardest lesson to get across. All of us have an obligation as physicians to do a simple check on what people are taking. It does require time and some expertise , and people haven’t got time and maybe not the expertise. Well, I think that’s a big area that physicians can lead on. We’re the main prescribers or main influencers of prescribers. Because general practice of course is writing most of the prescriptions, but a lot of them start by the sub-specialists for these particular patients and people, once started—look, stopping your own prescriptions are hard enough, but someone else’s is even a tougher one.
SARAH HILMER: As one of my really very respected colleagues put it, we don’t like to mess with other people’s drugs. We see ourselves as specialists in one area and other people are specialists in other areas and we don’t really like to mess with what they’re doing. But if we do recognize a potential drug-drug interaction, then, yeah we shouldn’t ignore it. We need to talk to the other sub-specialist about it. Talk to the GP about it, make sure the patient knows and I think as specialists, one of the things we need to bear in mind is that when we give our advice back to GPs, we need to almost give permission to adjust the treatment as appropriate as the patient’s condition changes because a lot of the time when patients get very old and very frail, they don’t get out to see their sub-specialist anymore and the advice that was given when they were in great shape when they were 75, may no longer apply at 85 when they’ve picked up a couple of more comorbidities with drug-drug and drug-disease interactions.
MIC CAVAZZINI: Many thanks to Sarah Hilmer and Richard Day for joining us on this episode of Pomegranate Health. The views expressed are their own, and may not represent those of the Royal Australasian College of Physicians.
If you want to hear parts of this interview that couldn’t be squeezed into the story, visit our website at racp.edu.au/pomcast. Feel free to keep the discussion going in the comments section. And sign up to our email alert service, if you’re not already subscribed via a podcasting app. At the website you’ll also find a link to Professor Day’s IMJ review about life-threatening drug interactions, and Professor Hilmer’s publications on deprescribing.
We’ve also provided list of other medical podcasts recommended by our listeners. BroomeDocs shares tips and experiences for the rural generalist. PEM Currents out of Cincinnati Children’s hospital covers the latest practice and technology in paediatric emergency. And KeyLIME from the Canadian Royal College of Surgeons and Physicians discusses important publications in the field of medical education.
Please check back in mid-October for our next story on the mental health of doctors. I’m
Mic Cavazzini, thanks for listening.