Brian F. Mandell, MD, PhD

In no way do I minimize the value of the imprimatur of FDA approval stating a drug, after appropriate preclinical and clinical studies, is deemed safe and effective. Whatever the agency’s shortcomings, the story of thalidomide (a drug never approved by the FDA) gives credence to the value of having a robust approval process. Arguments will likely continue forever as to whether the agency errs on the side of being too permissive or too restrictive in its approval process.

Nonetheless, I believe there are valid clinical reasons why we should continue to prescribe FDA-approved medications for nonapproved indications. In my practice, I treat some conditions that are sufficiently uncommon or heterogeneous in expression that large-scale clinical trials are logistically hard to carry out or deemed financially unviable by the corporate sponsor, even though clinical experience has informed us of a reasonable likelihood of efficacy. Sometimes drugs have “failed” in clinical trials, but experience and post hoc subset analysis of data have indicated a likely positive response in certain patients.

Although a drug that has been FDA approved has passed significant safety testing, the patients exposed to the drug when it was evaluated for treating a certain disease may be strikingly different from patients who have a different disease—the age, sex, comorbidities, and coprescribed medications may all differ significantly in the population of patients with the “off-label” disorder. Hence, appropriate caution is warranted, and if relevant, this should be explained to patients before giving them the medication.

In this issue of the Journal, 2 papers address the use of medications in an “off-label” manner. Schneider and colleagues discuss several frequent clinical uses of tricyclic antidepressants for reasons other than depression, and Modesto-Lowe and colleagues review the more controversial use of gabapentin in patients with alcohol use disorder. The hoped-for benefits in both circumstances are symptomatic, and both benefits and side effects are dose-related in ways not necessarily coinciding with those in the FDA-labeled indications.

My experience in using tricyclics as adjunctive treatment for fibromyalgia is that patients are quite sensitive to some of the side effects of the drugs (eg, oral dryness and fatigue), even in low doses. Moreover, we should expect only modest benefits, which should be explicitly described to the patient: improved quality of sleep with resultant decreased fatigue (while we watch closely for worsened fatigue from too-high dosing) and a modest reduction in pain over time as part of a multimodality treatment plan. I often find that practitioners who are less familiar with the use of these medications in this setting tend to start at lowish (but higher than often tolerated) doses, have patients take the medication too close to bedtime (resulting in some morning hangover sensation), fail to discuss the timing and degree of expected pain relief, don’t titrate the dose over time, and are not aware of the different responses that patients may experience with different medications within the same class. As with all prescribed medications, the benefits and ill effects must be frequently assessed, and particularly with these medications, one must be willing to discontinue them if appropriate outcomes are not achieved.

“Off-label” should not imply off the table as a therapeutic option. But it is incumbent on us to devote sufficient time to explain to each patient the anticipated side effects and hoped-for benefits, particularly since in most cases, we and our patients cannot refer to the results of definitive phase 3 clinical trials or patient online information sites that are totally relevant, reliable, data supported, and FDA reviewed.

In no way do I minimize the value of the imprimatur of FDA approval stating a drug, after appropriate preclinical and clinical studies, is deemed safe and effective. Whatever the agency’s shortcomings, the story of thalidomide (a drug never approved by the FDA) gives credence to the value of having a robust approval process. Arguments will likely continue forever as to whether the agency errs on the side of being too permissive or too restrictive in its approval process.

Nonetheless, I believe there are valid clinical reasons why we should continue to prescribe FDA-approved medications for nonapproved indications. In my practice, I treat some conditions that are sufficiently uncommon or heterogeneous in expression that large-scale clinical trials are logistically hard to carry out or deemed financially unviable by the corporate sponsor, even though clinical experience has informed us of a reasonable likelihood of efficacy. Sometimes drugs have “failed” in clinical trials, but experience and post hoc subset analysis of data have indicated a likely positive response in certain patients.

Although a drug that has been FDA approved has passed significant safety testing, the patients exposed to the drug when it was evaluated for treating a certain disease may be strikingly different from patients who have a different disease—the age, sex, comorbidities, and coprescribed medications may all differ significantly in the population of patients with the “off-label” disorder. Hence, appropriate caution is warranted, and if relevant, this should be explained to patients before giving them the medication.

In this issue of the Journal, 2 papers address the use of medications in an “off-label” manner. Schneider and colleagues discuss several frequent clinical uses of tricyclic antidepressants for reasons other than depression, and Modesto-Lowe and colleagues review the more controversial use of gabapentin in patients with alcohol use disorder. The hoped-for benefits in both circumstances are symptomatic, and both benefits and side effects are dose-related in ways not necessarily coinciding with those in the FDA-labeled indications.

My experience in using tricyclics as adjunctive treatment for fibromyalgia is that patients are quite sensitive to some of the side effects of the drugs (eg, oral dryness and fatigue), even in low doses. Moreover, we should expect only modest benefits, which should be explicitly described to the patient: improved quality of sleep with resultant decreased fatigue (while we watch closely for worsened fatigue from too-high dosing) and a modest reduction in pain over time as part of a multimodality treatment plan. I often find that practitioners who are less familiar with the use of these medications in this setting tend to start at lowish (but higher than often tolerated) doses, have patients take the medication too close to bedtime (resulting in some morning hangover sensation), fail to discuss the timing and degree of expected pain relief, don’t titrate the dose over time, and are not aware of the different responses that patients may experience with different medications within the same class. As with all prescribed medications, the benefits and ill effects must be frequently assessed, and particularly with these medications, one must be willing to discontinue them if appropriate outcomes are not achieved.

“Off-label” should not imply off the table as a therapeutic option. But it is incumbent on us to devote sufficient time to explain to each patient the anticipated side effects and hoped-for benefits, particularly since in most cases, we and our patients cannot refer to the results of definitive phase 3 clinical trials or patient online information sites that are totally relevant, reliable, data supported, and FDA reviewed.

In no way do I minimize the value of the imprimatur of FDA approval stating a drug, after appropriate preclinical and clinical studies, is deemed safe and effective. Whatever the agency’s shortcomings, the story of thalidomide (a drug never approved by the FDA) gives credence to the value of having a robust approval process. Arguments will likely continue forever as to whether the agency errs on the side of being too permissive or too restrictive in its approval process.

Nonetheless, I believe there are valid clinical reasons why we should continue to prescribe FDA-approved medications for nonapproved indications. In my practice, I treat some conditions that are sufficiently uncommon or heterogeneous in expression that large-scale clinical trials are logistically hard to carry out or deemed financially unviable by the corporate sponsor, even though clinical experience has informed us of a reasonable likelihood of efficacy. Sometimes drugs have “failed” in clinical trials, but experience and post hoc subset analysis of data have indicated a likely positive response in certain patients.

Although a drug that has been FDA approved has passed significant safety testing, the patients exposed to the drug when it was evaluated for treating a certain disease may be strikingly different from patients who have a different disease—the age, sex, comorbidities, and coprescribed medications may all differ significantly in the population of patients with the “off-label” disorder. Hence, appropriate caution is warranted, and if relevant, this should be explained to patients before giving them the medication.

In this issue of the Journal, 2 papers address the use of medications in an “off-label” manner. Schneider and colleagues discuss several frequent clinical uses of tricyclic antidepressants for reasons other than depression, and Modesto-Lowe and colleagues review the more controversial use of gabapentin in patients with alcohol use disorder. The hoped-for benefits in both circumstances are symptomatic, and both benefits and side effects are dose-related in ways not necessarily coinciding with those in the FDA-labeled indications.

My experience in using tricyclics as adjunctive treatment for fibromyalgia is that patients are quite sensitive to some of the side effects of the drugs (eg, oral dryness and fatigue), even in low doses. Moreover, we should expect only modest benefits, which should be explicitly described to the patient: improved quality of sleep with resultant decreased fatigue (while we watch closely for worsened fatigue from too-high dosing) and a modest reduction in pain over time as part of a multimodality treatment plan. I often find that practitioners who are less familiar with the use of these medications in this setting tend to start at lowish (but higher than often tolerated) doses, have patients take the medication too close to bedtime (resulting in some morning hangover sensation), fail to discuss the timing and degree of expected pain relief, don’t titrate the dose over time, and are not aware of the different responses that patients may experience with different medications within the same class. As with all prescribed medications, the benefits and ill effects must be frequently assessed, and particularly with these medications, one must be willing to discontinue them if appropriate outcomes are not achieved.

“Off-label” should not imply off the table as a therapeutic option. But it is incumbent on us to devote sufficient time to explain to each patient the anticipated side effects and hoped-for benefits, particularly since in most cases, we and our patients cannot refer to the results of definitive phase 3 clinical trials or patient online information sites that are totally relevant, reliable, data supported, and FDA reviewed.

Is the relationship between A-fib and sleep apnea more than a coincidence stemming from the number of shared associated comorbidities? Significantly, the treatment of obstructive sleep apnea with continuous positive airway pressure (CPAP) has been shown to decrease the recurrence of A-fib after pharmacologic or electrical conversion and after interventional pulmonary vein interruption.¹ This suggests that at least in some cases, sleep apnea plays an active role in initiating and possibly also maintaining A-fib. The immediate culprit mediators that come to mind are hypoxia and hypercapnea; both are at least partially ameliorated by the successful use of CPAP, and both are reasonable physiologic candidates for induction of A-fib. Hypoxia is supported by clinical observation, and hypercapnea by experimental modeling.²

It is easy for clinicians to conceptualize the organ effects of hypoxia and hypercapnea. We are accustomed to seeing clinical ramifications of these in the emergency department and intensive care unit, particularly those affecting the brain and heart, organs critically dependent on transmembrane ion flow. We may recall from biochemistry classes the effects of hypoxia on intracellular metabolism and the implications on energy stores, mitochondrial function, and ion translocation. Recent work on the cellular effects of hypoxia, including research that resulted in a Nobel prize, has drawn major attention to patterned cellular responses to intermittent and persistent hypoxia. This includes recognition of epigenetic changes resulting in localized cardiac remodeling and fibrosis,³ factors that clearly affect the expression of arrhythmias, including A-fib.

But the interrelationship between A-fib and sleep apnea may be even more convoluted and intriguing. It now seems that most things cardiac are associated with inflammation in some guise, and the A-fib connection with sleep apnea may not be an exception. Almost 20 years ago, it was recognized that A-fib is associated with an elevation in circulating C-reactive protein (CRP),⁴ a biomarker of “inflammation,” although not necessarily an active participant. Recent reviews of this connection have been published,⁵ and successful anti-inflammatory approaches to preventing A-fib using colchicine have been described.⁶ So how does this tie in with sleep apnea?

A number of papers have now demonstrated that sleep apnea is also associated with an elevation in CRP,⁷ perhaps due to increases in tumor necrosis factor (TNF)-alpha in response to the intermittent hypoxia of sleep apnea. TNF can drive the inflammatory response through increased expression of genes regulated by nuclear factor kappa-B.⁸ While it certainly warrants consideration that the elevated biomarkers of inflammation in patients with sleep apnea actually reflect the presence of the frequent comorbidities, including visceral obesity, treating sleep apnea with CPAP (comparable to what I noted above in patients with A-fib) has been shown to reduce circulating CRP levels.⁹

As our understanding of the biologic underpinnings of A-fib and sleep apnea continue to grow, the practical clinical implications of the relationship between them, as described by Ayache et al, may achieve greater clarity. The two conditions commonly coexist, and treating the sleep apnea results in better rhythm-directed outcomes in the A-fib.

Stay tuned, there is certainly more to learn about this.

Is the relationship between A-fib and sleep apnea more than a coincidence stemming from the number of shared associated comorbidities? Significantly, the treatment of obstructive sleep apnea with continuous positive airway pressure (CPAP) has been shown to decrease the recurrence of A-fib after pharmacologic or electrical conversion and after interventional pulmonary vein interruption.¹ This suggests that at least in some cases, sleep apnea plays an active role in initiating and possibly also maintaining A-fib. The immediate culprit mediators that come to mind are hypoxia and hypercapnea; both are at least partially ameliorated by the successful use of CPAP, and both are reasonable physiologic candidates for induction of A-fib. Hypoxia is supported by clinical observation, and hypercapnea by experimental modeling.²

It is easy for clinicians to conceptualize the organ effects of hypoxia and hypercapnea. We are accustomed to seeing clinical ramifications of these in the emergency department and intensive care unit, particularly those affecting the brain and heart, organs critically dependent on transmembrane ion flow. We may recall from biochemistry classes the effects of hypoxia on intracellular metabolism and the implications on energy stores, mitochondrial function, and ion translocation. Recent work on the cellular effects of hypoxia, including research that resulted in a Nobel prize, has drawn major attention to patterned cellular responses to intermittent and persistent hypoxia. This includes recognition of epigenetic changes resulting in localized cardiac remodeling and fibrosis,³ factors that clearly affect the expression of arrhythmias, including A-fib.

But the interrelationship between A-fib and sleep apnea may be even more convoluted and intriguing. It now seems that most things cardiac are associated with inflammation in some guise, and the A-fib connection with sleep apnea may not be an exception. Almost 20 years ago, it was recognized that A-fib is associated with an elevation in circulating C-reactive protein (CRP),⁴ a biomarker of “inflammation,” although not necessarily an active participant. Recent reviews of this connection have been published,⁵ and successful anti-inflammatory approaches to preventing A-fib using colchicine have been described.⁶ So how does this tie in with sleep apnea?

A number of papers have now demonstrated that sleep apnea is also associated with an elevation in CRP,⁷ perhaps due to increases in tumor necrosis factor (TNF)-alpha in response to the intermittent hypoxia of sleep apnea. TNF can drive the inflammatory response through increased expression of genes regulated by nuclear factor kappa-B.⁸ While it certainly warrants consideration that the elevated biomarkers of inflammation in patients with sleep apnea actually reflect the presence of the frequent comorbidities, including visceral obesity, treating sleep apnea with CPAP (comparable to what I noted above in patients with A-fib) has been shown to reduce circulating CRP levels.⁹

As our understanding of the biologic underpinnings of A-fib and sleep apnea continue to grow, the practical clinical implications of the relationship between them, as described by Ayache et al, may achieve greater clarity. The two conditions commonly coexist, and treating the sleep apnea results in better rhythm-directed outcomes in the A-fib.

Stay tuned, there is certainly more to learn about this.

Is the relationship between A-fib and sleep apnea more than a coincidence stemming from the number of shared associated comorbidities? Significantly, the treatment of obstructive sleep apnea with continuous positive airway pressure (CPAP) has been shown to decrease the recurrence of A-fib after pharmacologic or electrical conversion and after interventional pulmonary vein interruption.¹ This suggests that at least in some cases, sleep apnea plays an active role in initiating and possibly also maintaining A-fib. The immediate culprit mediators that come to mind are hypoxia and hypercapnea; both are at least partially ameliorated by the successful use of CPAP, and both are reasonable physiologic candidates for induction of A-fib. Hypoxia is supported by clinical observation, and hypercapnea by experimental modeling.²

It is easy for clinicians to conceptualize the organ effects of hypoxia and hypercapnea. We are accustomed to seeing clinical ramifications of these in the emergency department and intensive care unit, particularly those affecting the brain and heart, organs critically dependent on transmembrane ion flow. We may recall from biochemistry classes the effects of hypoxia on intracellular metabolism and the implications on energy stores, mitochondrial function, and ion translocation. Recent work on the cellular effects of hypoxia, including research that resulted in a Nobel prize, has drawn major attention to patterned cellular responses to intermittent and persistent hypoxia. This includes recognition of epigenetic changes resulting in localized cardiac remodeling and fibrosis,³ factors that clearly affect the expression of arrhythmias, including A-fib.

But the interrelationship between A-fib and sleep apnea may be even more convoluted and intriguing. It now seems that most things cardiac are associated with inflammation in some guise, and the A-fib connection with sleep apnea may not be an exception. Almost 20 years ago, it was recognized that A-fib is associated with an elevation in circulating C-reactive protein (CRP),⁴ a biomarker of “inflammation,” although not necessarily an active participant. Recent reviews of this connection have been published,⁵ and successful anti-inflammatory approaches to preventing A-fib using colchicine have been described.⁶ So how does this tie in with sleep apnea?

A number of papers have now demonstrated that sleep apnea is also associated with an elevation in CRP,⁷ perhaps due to increases in tumor necrosis factor (TNF)-alpha in response to the intermittent hypoxia of sleep apnea. TNF can drive the inflammatory response through increased expression of genes regulated by nuclear factor kappa-B.⁸ While it certainly warrants consideration that the elevated biomarkers of inflammation in patients with sleep apnea actually reflect the presence of the frequent comorbidities, including visceral obesity, treating sleep apnea with CPAP (comparable to what I noted above in patients with A-fib) has been shown to reduce circulating CRP levels.⁹

As our understanding of the biologic underpinnings of A-fib and sleep apnea continue to grow, the practical clinical implications of the relationship between them, as described by Ayache et al, may achieve greater clarity. The two conditions commonly coexist, and treating the sleep apnea results in better rhythm-directed outcomes in the A-fib.

Stay tuned, there is certainly more to learn about this.

We need to recognize the diverse problems that patients with potential multisystem disease can develop, lobby when necessary for them to be seen promptly by the relevant specialists, and initiate appropriate diagnostic testing and management in less-urgent scenarios. Most of us need frequent refreshers on the clinical manifestations of these disorders so that we can recognize them when they appear unannounced in our exam rooms.

The caregiver with a prepared mind is more likely to experience the diagnostic epiphany, and then use point-of-care references to hone in on the details. With many patients and clinical conundrums, the basics matter.

Dr. Chester Oddis, in this issue of the Journal, reviews the basics of several primary muscle disorders. He discusses, in a case-based format extracted from his recent Medicine Grand Rounds presentation at Cleveland Clinic, nuances of specific diagnoses and the clinical progression of diseases that are critical to be aware of in order to recognize and manage them, and expeditiously refer the patient to our appropriate subspecialty colleagues.

Major challenges exist in recognizing the inflammatory myopathies and their mimics early in their course. These are serious but uncommon entities, and in part because patients and physicians often attribute their early symptoms to more-common causes, diagnosis can be elusive—until the possibility is considered. We hope that Dr. Oddis’s article will make it easier to rapidly recognize these muscle disorders.

Patients often struggle to explain their symptoms of early muscle dysfunction. Since patients often verbalize their fatigue as “feeling weak,” we often misconstrue complaints of true muscle weakness (like difficulty walking up steps) as being due to fatigue. Add in some anemia from chronic inflammation and some “liver test” abnormalities, and it is easy to see how the recognition of true muscle weakness can be delayed.

We can tease muscle weakness from fatigue or dyspnea by asking the patient to specifically and functionally describe their “weakness,” and then by asking pointed questions: “Do you have difficulty getting up from the toilet without using your arms? Do you have trouble brushing your hair or teeth?” Physical examination can clearly help here, but without routine examination of muscle strength in normal fragile elderly patients, the degree of muscle weakness can be difficult to assess. Likewise challenging is detecting the early onset of weakness by examination in a 280-lb power-lifter.

Obtaining an accurate functional and behavioral history is often critical to the early recognition of muscle disease. Muscle pain, as Dr. Oddis notes, is not a characteristic feature of many myopathies, whereas, paradoxically, the coexistence of new-onset symmetrical small-joint pain (especially with arthritis) along with muscle weakness can be a powerful clue to the diagnosis of an inflammatory myopathy.

An elevated creatine kinase (CK) level generally points directly to a muscle disease, although some neurologic disorders are associated with elevations in CK, and the entity of benign “hyperCKemia” must be recognized and not overmanaged. The latter becomes a problem when laboratory tests are allowed to drive the diagnostic evaluation in a vacuum of clinical details.

A more common scenario is the misinterpretation of common laboratory test abnormalities in the setting of a patient with “fatigue” or generalized weakness who has elevations in aspartate aminotransferase (AST) and alanine aminotransferase (ALT). Although AST and ALT are often called “liver function tests,” these enzymes are also abundant in skeletal muscle, and since they are included on routine biochemical panels, their elevation often leads to liver imaging and sometimes even biopsy before anyone recognizes muscle disease as the cause of the patient’s symptoms and laboratory test abnormalities. Hence, a muscle source (or hemolysis) should at least be considered when AST and ALT are elevated in the absence of elevated alkaline phosphatase or gamma-glutamyl transferase.

When evaluating innumerable clinical scenarios, experienced clinicians can most certainly generate similar principles of diagnostic reasoning, based on having a few fundamental facts at their fingertips. Increasing the chances of having a prepared mind when confronted with a patient with a less-than-straightforward set of symptoms is one of my major arguments in support of continuing to read and generate internal medicine teaching literature and to attend and participate in clinical teaching conferences such as Medicine Grand Rounds. It is also why we will continue to appreciate and publish presentations like this one in the Journal.

I don’t expect to retain all the details from these and similar papers, and I know we all carry virtually infinite databases in our pockets. But keeping a few clinical pearls outside of my specialty in my head comes in handy. Having a prepared mind makes it much easier to converse with patients, to promptly initiate appropriate testing, plans, and consultations, and to then decide what to search for on my smartphone between patients.

We need to recognize the diverse problems that patients with potential multisystem disease can develop, lobby when necessary for them to be seen promptly by the relevant specialists, and initiate appropriate diagnostic testing and management in less-urgent scenarios. Most of us need frequent refreshers on the clinical manifestations of these disorders so that we can recognize them when they appear unannounced in our exam rooms.

The caregiver with a prepared mind is more likely to experience the diagnostic epiphany, and then use point-of-care references to hone in on the details. With many patients and clinical conundrums, the basics matter.

Dr. Chester Oddis, in this issue of the Journal, reviews the basics of several primary muscle disorders. He discusses, in a case-based format extracted from his recent Medicine Grand Rounds presentation at Cleveland Clinic, nuances of specific diagnoses and the clinical progression of diseases that are critical to be aware of in order to recognize and manage them, and expeditiously refer the patient to our appropriate subspecialty colleagues.

Major challenges exist in recognizing the inflammatory myopathies and their mimics early in their course. These are serious but uncommon entities, and in part because patients and physicians often attribute their early symptoms to more-common causes, diagnosis can be elusive—until the possibility is considered. We hope that Dr. Oddis’s article will make it easier to rapidly recognize these muscle disorders.

Patients often struggle to explain their symptoms of early muscle dysfunction. Since patients often verbalize their fatigue as “feeling weak,” we often misconstrue complaints of true muscle weakness (like difficulty walking up steps) as being due to fatigue. Add in some anemia from chronic inflammation and some “liver test” abnormalities, and it is easy to see how the recognition of true muscle weakness can be delayed.

We can tease muscle weakness from fatigue or dyspnea by asking the patient to specifically and functionally describe their “weakness,” and then by asking pointed questions: “Do you have difficulty getting up from the toilet without using your arms? Do you have trouble brushing your hair or teeth?” Physical examination can clearly help here, but without routine examination of muscle strength in normal fragile elderly patients, the degree of muscle weakness can be difficult to assess. Likewise challenging is detecting the early onset of weakness by examination in a 280-lb power-lifter.

Obtaining an accurate functional and behavioral history is often critical to the early recognition of muscle disease. Muscle pain, as Dr. Oddis notes, is not a characteristic feature of many myopathies, whereas, paradoxically, the coexistence of new-onset symmetrical small-joint pain (especially with arthritis) along with muscle weakness can be a powerful clue to the diagnosis of an inflammatory myopathy.

An elevated creatine kinase (CK) level generally points directly to a muscle disease, although some neurologic disorders are associated with elevations in CK, and the entity of benign “hyperCKemia” must be recognized and not overmanaged. The latter becomes a problem when laboratory tests are allowed to drive the diagnostic evaluation in a vacuum of clinical details.

A more common scenario is the misinterpretation of common laboratory test abnormalities in the setting of a patient with “fatigue” or generalized weakness who has elevations in aspartate aminotransferase (AST) and alanine aminotransferase (ALT). Although AST and ALT are often called “liver function tests,” these enzymes are also abundant in skeletal muscle, and since they are included on routine biochemical panels, their elevation often leads to liver imaging and sometimes even biopsy before anyone recognizes muscle disease as the cause of the patient’s symptoms and laboratory test abnormalities. Hence, a muscle source (or hemolysis) should at least be considered when AST and ALT are elevated in the absence of elevated alkaline phosphatase or gamma-glutamyl transferase.

When evaluating innumerable clinical scenarios, experienced clinicians can most certainly generate similar principles of diagnostic reasoning, based on having a few fundamental facts at their fingertips. Increasing the chances of having a prepared mind when confronted with a patient with a less-than-straightforward set of symptoms is one of my major arguments in support of continuing to read and generate internal medicine teaching literature and to attend and participate in clinical teaching conferences such as Medicine Grand Rounds. It is also why we will continue to appreciate and publish presentations like this one in the Journal.

I don’t expect to retain all the details from these and similar papers, and I know we all carry virtually infinite databases in our pockets. But keeping a few clinical pearls outside of my specialty in my head comes in handy. Having a prepared mind makes it much easier to converse with patients, to promptly initiate appropriate testing, plans, and consultations, and to then decide what to search for on my smartphone between patients.

We need to recognize the diverse problems that patients with potential multisystem disease can develop, lobby when necessary for them to be seen promptly by the relevant specialists, and initiate appropriate diagnostic testing and management in less-urgent scenarios. Most of us need frequent refreshers on the clinical manifestations of these disorders so that we can recognize them when they appear unannounced in our exam rooms.

The caregiver with a prepared mind is more likely to experience the diagnostic epiphany, and then use point-of-care references to hone in on the details. With many patients and clinical conundrums, the basics matter.

Dr. Chester Oddis, in this issue of the Journal, reviews the basics of several primary muscle disorders. He discusses, in a case-based format extracted from his recent Medicine Grand Rounds presentation at Cleveland Clinic, nuances of specific diagnoses and the clinical progression of diseases that are critical to be aware of in order to recognize and manage them, and expeditiously refer the patient to our appropriate subspecialty colleagues.

Major challenges exist in recognizing the inflammatory myopathies and their mimics early in their course. These are serious but uncommon entities, and in part because patients and physicians often attribute their early symptoms to more-common causes, diagnosis can be elusive—until the possibility is considered. We hope that Dr. Oddis’s article will make it easier to rapidly recognize these muscle disorders.

Patients often struggle to explain their symptoms of early muscle dysfunction. Since patients often verbalize their fatigue as “feeling weak,” we often misconstrue complaints of true muscle weakness (like difficulty walking up steps) as being due to fatigue. Add in some anemia from chronic inflammation and some “liver test” abnormalities, and it is easy to see how the recognition of true muscle weakness can be delayed.

We can tease muscle weakness from fatigue or dyspnea by asking the patient to specifically and functionally describe their “weakness,” and then by asking pointed questions: “Do you have difficulty getting up from the toilet without using your arms? Do you have trouble brushing your hair or teeth?” Physical examination can clearly help here, but without routine examination of muscle strength in normal fragile elderly patients, the degree of muscle weakness can be difficult to assess. Likewise challenging is detecting the early onset of weakness by examination in a 280-lb power-lifter.

Obtaining an accurate functional and behavioral history is often critical to the early recognition of muscle disease. Muscle pain, as Dr. Oddis notes, is not a characteristic feature of many myopathies, whereas, paradoxically, the coexistence of new-onset symmetrical small-joint pain (especially with arthritis) along with muscle weakness can be a powerful clue to the diagnosis of an inflammatory myopathy.

An elevated creatine kinase (CK) level generally points directly to a muscle disease, although some neurologic disorders are associated with elevations in CK, and the entity of benign “hyperCKemia” must be recognized and not overmanaged. The latter becomes a problem when laboratory tests are allowed to drive the diagnostic evaluation in a vacuum of clinical details.

A more common scenario is the misinterpretation of common laboratory test abnormalities in the setting of a patient with “fatigue” or generalized weakness who has elevations in aspartate aminotransferase (AST) and alanine aminotransferase (ALT). Although AST and ALT are often called “liver function tests,” these enzymes are also abundant in skeletal muscle, and since they are included on routine biochemical panels, their elevation often leads to liver imaging and sometimes even biopsy before anyone recognizes muscle disease as the cause of the patient’s symptoms and laboratory test abnormalities. Hence, a muscle source (or hemolysis) should at least be considered when AST and ALT are elevated in the absence of elevated alkaline phosphatase or gamma-glutamyl transferase.

When evaluating innumerable clinical scenarios, experienced clinicians can most certainly generate similar principles of diagnostic reasoning, based on having a few fundamental facts at their fingertips. Increasing the chances of having a prepared mind when confronted with a patient with a less-than-straightforward set of symptoms is one of my major arguments in support of continuing to read and generate internal medicine teaching literature and to attend and participate in clinical teaching conferences such as Medicine Grand Rounds. It is also why we will continue to appreciate and publish presentations like this one in the Journal.

I don’t expect to retain all the details from these and similar papers, and I know we all carry virtually infinite databases in our pockets. But keeping a few clinical pearls outside of my specialty in my head comes in handy. Having a prepared mind makes it much easier to converse with patients, to promptly initiate appropriate testing, plans, and consultations, and to then decide what to search for on my smartphone between patients.

There has been increasing emphasis from drug regulatory agencies on collecting robust data on multiple outcomes from clinical trials in addition to the efficacy outcomes and usual safety data. For about a decade, the US Food and Drug Administration has required the collection of cardiovascular outcome data during the testing of new antidiabetic therapies. There are several potential consequences of this mandate, in addition to our now having a better understanding of cardiovascular risk. Studies are likely to be larger, longer, and more expensive. Patient cohorts are selected with this in mind, meaning that studies may be harder to compare, and labeled indications may be more specific. And we now have several drugs carrying a specific indication to reduce cardiovascular death in patients with diabetes!

But as we dig deeper into the reduction in cardiovascular deaths seen in clinical trials with some of the sodium-glucose cotransporter 2 (SGLT2) inhibitors, several questions arise. Why is their effect on mortality and cardiovascular events (and preservation of renal function) not a consistent drug class effect? All of these inhibitors decrease glucose reabsorption and thus cause glucosuria, resulting in lower blood glucose levels with modest caloric wasting and weight loss, as well as natriuresis with mild volume depletion. But the individual drugs behaved slightly differently in clinical trials. Perhaps this was due to slightly different trial populations, or chance (despite large trial numbers), or maybe molecular differences in the drugs despite their shared effect on glucosuria, resulting in distinct “off-target” effects. Perhaps the drugs differentially affect other transporters, on cells other than renal tubular cells, altering their function. An additional known effect of the drug class is uricosuria and mild relative hypouricemia. The differential effects of these drugs on urate transport into and out of different cells that may influence components of the metabolic syndrome and cardiovascular and renal outcomes has yet to be fully explored.

But one thing that seems to be true is that the effect of empagliflozin and canagliflozin on cardiac mortality is not due to simply lowering the blood glucose. Trials like the UK Prospective Diabetes Study¹ demonstrated that better glucose control reduced microvascular complications, but they did not initially show a reduction in myocardial infarction. It took long-term follow-up studies to indicate that more intensive initial glucose control could reduce cardiovascular events. But a beneficial effect of empagliflozin (compared with placebo) on cardiovascular mortality (but interestingly not on stroke or nonfatal myocardial infarction) was seen within 3 months.² This observation suggests unique properties of this drug and some others in the class, in addition to their glucose-lowering effect. Puzzling to me, looking at several of the SGLT2 inhibitor drug studies, is why they seemed to behave differently in terms of different cardiovascular outcomes (eg, heart failure, stroke, nonfatal myocardial infarction, need for limb amputation). While some of these seemingly paradoxical outcomes have also been seen in studies of other drugs, these differences are hard for me to understand on a biological basis: they do not seem consistent with simply differential drug effects on either acute thrombosis or chronic hypoperfusion. We have much more to learn.

For the moment, I suppose we should let our practice be guided by the results of specific clinical trials, hoping that at some point head-to-head comparator drug trials will be undertaken to provide us with even better guidance in drug selection.

We can also hope that our patients with diabetes will somehow be able to afford our increasingly complex and evidence-supported pharmacotherapy, as now not only can we lower the levels of blood glucose and biomarkers of comorbidity, we can also reduce adverse cardiovascular outcomes.

There has been increasing emphasis from drug regulatory agencies on collecting robust data on multiple outcomes from clinical trials in addition to the efficacy outcomes and usual safety data. For about a decade, the US Food and Drug Administration has required the collection of cardiovascular outcome data during the testing of new antidiabetic therapies. There are several potential consequences of this mandate, in addition to our now having a better understanding of cardiovascular risk. Studies are likely to be larger, longer, and more expensive. Patient cohorts are selected with this in mind, meaning that studies may be harder to compare, and labeled indications may be more specific. And we now have several drugs carrying a specific indication to reduce cardiovascular death in patients with diabetes!

But as we dig deeper into the reduction in cardiovascular deaths seen in clinical trials with some of the sodium-glucose cotransporter 2 (SGLT2) inhibitors, several questions arise. Why is their effect on mortality and cardiovascular events (and preservation of renal function) not a consistent drug class effect? All of these inhibitors decrease glucose reabsorption and thus cause glucosuria, resulting in lower blood glucose levels with modest caloric wasting and weight loss, as well as natriuresis with mild volume depletion. But the individual drugs behaved slightly differently in clinical trials. Perhaps this was due to slightly different trial populations, or chance (despite large trial numbers), or maybe molecular differences in the drugs despite their shared effect on glucosuria, resulting in distinct “off-target” effects. Perhaps the drugs differentially affect other transporters, on cells other than renal tubular cells, altering their function. An additional known effect of the drug class is uricosuria and mild relative hypouricemia. The differential effects of these drugs on urate transport into and out of different cells that may influence components of the metabolic syndrome and cardiovascular and renal outcomes has yet to be fully explored.

But one thing that seems to be true is that the effect of empagliflozin and canagliflozin on cardiac mortality is not due to simply lowering the blood glucose. Trials like the UK Prospective Diabetes Study¹ demonstrated that better glucose control reduced microvascular complications, but they did not initially show a reduction in myocardial infarction. It took long-term follow-up studies to indicate that more intensive initial glucose control could reduce cardiovascular events. But a beneficial effect of empagliflozin (compared with placebo) on cardiovascular mortality (but interestingly not on stroke or nonfatal myocardial infarction) was seen within 3 months.² This observation suggests unique properties of this drug and some others in the class, in addition to their glucose-lowering effect. Puzzling to me, looking at several of the SGLT2 inhibitor drug studies, is why they seemed to behave differently in terms of different cardiovascular outcomes (eg, heart failure, stroke, nonfatal myocardial infarction, need for limb amputation). While some of these seemingly paradoxical outcomes have also been seen in studies of other drugs, these differences are hard for me to understand on a biological basis: they do not seem consistent with simply differential drug effects on either acute thrombosis or chronic hypoperfusion. We have much more to learn.

For the moment, I suppose we should let our practice be guided by the results of specific clinical trials, hoping that at some point head-to-head comparator drug trials will be undertaken to provide us with even better guidance in drug selection.

We can also hope that our patients with diabetes will somehow be able to afford our increasingly complex and evidence-supported pharmacotherapy, as now not only can we lower the levels of blood glucose and biomarkers of comorbidity, we can also reduce adverse cardiovascular outcomes.

There has been increasing emphasis from drug regulatory agencies on collecting robust data on multiple outcomes from clinical trials in addition to the efficacy outcomes and usual safety data. For about a decade, the US Food and Drug Administration has required the collection of cardiovascular outcome data during the testing of new antidiabetic therapies. There are several potential consequences of this mandate, in addition to our now having a better understanding of cardiovascular risk. Studies are likely to be larger, longer, and more expensive. Patient cohorts are selected with this in mind, meaning that studies may be harder to compare, and labeled indications may be more specific. And we now have several drugs carrying a specific indication to reduce cardiovascular death in patients with diabetes!

But as we dig deeper into the reduction in cardiovascular deaths seen in clinical trials with some of the sodium-glucose cotransporter 2 (SGLT2) inhibitors, several questions arise. Why is their effect on mortality and cardiovascular events (and preservation of renal function) not a consistent drug class effect? All of these inhibitors decrease glucose reabsorption and thus cause glucosuria, resulting in lower blood glucose levels with modest caloric wasting and weight loss, as well as natriuresis with mild volume depletion. But the individual drugs behaved slightly differently in clinical trials. Perhaps this was due to slightly different trial populations, or chance (despite large trial numbers), or maybe molecular differences in the drugs despite their shared effect on glucosuria, resulting in distinct “off-target” effects. Perhaps the drugs differentially affect other transporters, on cells other than renal tubular cells, altering their function. An additional known effect of the drug class is uricosuria and mild relative hypouricemia. The differential effects of these drugs on urate transport into and out of different cells that may influence components of the metabolic syndrome and cardiovascular and renal outcomes has yet to be fully explored.

But one thing that seems to be true is that the effect of empagliflozin and canagliflozin on cardiac mortality is not due to simply lowering the blood glucose. Trials like the UK Prospective Diabetes Study¹ demonstrated that better glucose control reduced microvascular complications, but they did not initially show a reduction in myocardial infarction. It took long-term follow-up studies to indicate that more intensive initial glucose control could reduce cardiovascular events. But a beneficial effect of empagliflozin (compared with placebo) on cardiovascular mortality (but interestingly not on stroke or nonfatal myocardial infarction) was seen within 3 months.² This observation suggests unique properties of this drug and some others in the class, in addition to their glucose-lowering effect. Puzzling to me, looking at several of the SGLT2 inhibitor drug studies, is why they seemed to behave differently in terms of different cardiovascular outcomes (eg, heart failure, stroke, nonfatal myocardial infarction, need for limb amputation). While some of these seemingly paradoxical outcomes have also been seen in studies of other drugs, these differences are hard for me to understand on a biological basis: they do not seem consistent with simply differential drug effects on either acute thrombosis or chronic hypoperfusion. We have much more to learn.

For the moment, I suppose we should let our practice be guided by the results of specific clinical trials, hoping that at some point head-to-head comparator drug trials will be undertaken to provide us with even better guidance in drug selection.

We can also hope that our patients with diabetes will somehow be able to afford our increasingly complex and evidence-supported pharmacotherapy, as now not only can we lower the levels of blood glucose and biomarkers of comorbidity, we can also reduce adverse cardiovascular outcomes.

In a study from the University of Pennsylvania,² Sedrak et al surveyed residents about their lab test ordering practices. Almost all responders recognized that they ordered “unnecessary tests.” The authors of the paper probed to understand why, and strikingly, the more common responses were the same that my resident peers and I would have given 4 decades ago: the culture of the system (“We don’t want to miss anything or be asked on rounds for data that hadn’t been checked”), the lack of transparency of cost of the tests, and the lack of role-modeling by teaching staff. There has been hope that the last of these would be resolved by increased visibility of subspecialists in hospital medicine, well-versed in the nuances of system-based practice. And the Society of Hospital Medicine, along with the American College of Physicians and others, has pushed hard to promote choosing wisely when ordering diagnostic studies. But we have a way to go.

Lab tests represent a small fraction of healthcare costs. Imaging tests, especially advanced and complex imaging studies, comprise a far greater fraction of healthcare costs. And here is the challenge: developers of new imaging modalities are now able to design and refine specific tests that are good enough to become the gold standard for diagnosis and staging of specific diseases—great for clinical care, bad for cost savings. One need only review a few new guidelines or clinical research protocols to appreciate the successful integration of these tests into clinical practice. Some tests are supplanting the need for aggressive biopsies, angiography, or a series of alternative imaging tests. This is potentially good for patients, but many of these tests are strikingly expensive and are being adopted for use prior to full vetting of their utility and limitations in large clinical studies; the cost of the tests can be an impediment to conducting a series of clinical studies that include appropriate patient subsets. The increasingly proposed use of positron emission tomography in patients with suspected malignancy, inflammation, or infection is a great example of a useful test that we are still learning how best to interpret in several conditions.

In this issue of the Journal, two testing scenarios are discussed. Lacy et al address the question of when patients with pyelonephritis should receive imaging studies. There are data to guide this decision process, but as noted in the study by Sedrak et al,² there are forces at work that challenge the clinician to bypass the rational guidelines—not the least of which are the desire for efficiency (don’t take the chance that the test may be required later and delay discharge from the hospital or observation area) and greater surety in the clinical diagnosis. Although fear of litigation was not high on Sedrak’s list of reasons for ordering more “unnecessary” tests, I posit that a decrease in the confidence placed on clinical diagnosis drives a significant amount of imaging, in conjunction with the desire for shorter hospital stays.

The second paper, by Mgbojikwe et al, relates to the issue of which advanced technology should be ordered, and when. They review the limitations of traditional (echocardiographic) diagnosis and staging of infective endocarditis, and discuss the strengths and limitations of several advanced imaging tools in the setting of suspected or known infectious endocarditis. I suspect that in most medical centers the decisions to utilize these tests will rest with the infectious disease, cardiology, and cardiothoracic surgery consultants. But it is worth being aware of how the diagnostic and staging strategies are evolving, and of the limitations to these studies.

We have come a long way from diagnosing bacterial endocarditis with a valve abscess on the basis of finding changing murmurs, a Roth spot, a palpable spleen tip, new conduction abnormalities on the ECG, and documented daily afternoon fevers. Performing that physical examination is cheap but not highly reproducible. The new testing algorithms are not cheap but, hopefully, will offer superior sensitivity and specificity. Used correctly—and we likely have a way to go to learn what that means—these pictures may well be worth the cost.

Although someone still has to suspect the diagnosis of endocarditis.

In a study from the University of Pennsylvania,² Sedrak et al surveyed residents about their lab test ordering practices. Almost all responders recognized that they ordered “unnecessary tests.” The authors of the paper probed to understand why, and strikingly, the more common responses were the same that my resident peers and I would have given 4 decades ago: the culture of the system (“We don’t want to miss anything or be asked on rounds for data that hadn’t been checked”), the lack of transparency of cost of the tests, and the lack of role-modeling by teaching staff. There has been hope that the last of these would be resolved by increased visibility of subspecialists in hospital medicine, well-versed in the nuances of system-based practice. And the Society of Hospital Medicine, along with the American College of Physicians and others, has pushed hard to promote choosing wisely when ordering diagnostic studies. But we have a way to go.

Lab tests represent a small fraction of healthcare costs. Imaging tests, especially advanced and complex imaging studies, comprise a far greater fraction of healthcare costs. And here is the challenge: developers of new imaging modalities are now able to design and refine specific tests that are good enough to become the gold standard for diagnosis and staging of specific diseases—great for clinical care, bad for cost savings. One need only review a few new guidelines or clinical research protocols to appreciate the successful integration of these tests into clinical practice. Some tests are supplanting the need for aggressive biopsies, angiography, or a series of alternative imaging tests. This is potentially good for patients, but many of these tests are strikingly expensive and are being adopted for use prior to full vetting of their utility and limitations in large clinical studies; the cost of the tests can be an impediment to conducting a series of clinical studies that include appropriate patient subsets. The increasingly proposed use of positron emission tomography in patients with suspected malignancy, inflammation, or infection is a great example of a useful test that we are still learning how best to interpret in several conditions.

In this issue of the Journal, two testing scenarios are discussed. Lacy et al address the question of when patients with pyelonephritis should receive imaging studies. There are data to guide this decision process, but as noted in the study by Sedrak et al,² there are forces at work that challenge the clinician to bypass the rational guidelines—not the least of which are the desire for efficiency (don’t take the chance that the test may be required later and delay discharge from the hospital or observation area) and greater surety in the clinical diagnosis. Although fear of litigation was not high on Sedrak’s list of reasons for ordering more “unnecessary” tests, I posit that a decrease in the confidence placed on clinical diagnosis drives a significant amount of imaging, in conjunction with the desire for shorter hospital stays.

The second paper, by Mgbojikwe et al, relates to the issue of which advanced technology should be ordered, and when. They review the limitations of traditional (echocardiographic) diagnosis and staging of infective endocarditis, and discuss the strengths and limitations of several advanced imaging tools in the setting of suspected or known infectious endocarditis. I suspect that in most medical centers the decisions to utilize these tests will rest with the infectious disease, cardiology, and cardiothoracic surgery consultants. But it is worth being aware of how the diagnostic and staging strategies are evolving, and of the limitations to these studies.

We have come a long way from diagnosing bacterial endocarditis with a valve abscess on the basis of finding changing murmurs, a Roth spot, a palpable spleen tip, new conduction abnormalities on the ECG, and documented daily afternoon fevers. Performing that physical examination is cheap but not highly reproducible. The new testing algorithms are not cheap but, hopefully, will offer superior sensitivity and specificity. Used correctly—and we likely have a way to go to learn what that means—these pictures may well be worth the cost.

Although someone still has to suspect the diagnosis of endocarditis.

In a study from the University of Pennsylvania,² Sedrak et al surveyed residents about their lab test ordering practices. Almost all responders recognized that they ordered “unnecessary tests.” The authors of the paper probed to understand why, and strikingly, the more common responses were the same that my resident peers and I would have given 4 decades ago: the culture of the system (“We don’t want to miss anything or be asked on rounds for data that hadn’t been checked”), the lack of transparency of cost of the tests, and the lack of role-modeling by teaching staff. There has been hope that the last of these would be resolved by increased visibility of subspecialists in hospital medicine, well-versed in the nuances of system-based practice. And the Society of Hospital Medicine, along with the American College of Physicians and others, has pushed hard to promote choosing wisely when ordering diagnostic studies. But we have a way to go.

Lab tests represent a small fraction of healthcare costs. Imaging tests, especially advanced and complex imaging studies, comprise a far greater fraction of healthcare costs. And here is the challenge: developers of new imaging modalities are now able to design and refine specific tests that are good enough to become the gold standard for diagnosis and staging of specific diseases—great for clinical care, bad for cost savings. One need only review a few new guidelines or clinical research protocols to appreciate the successful integration of these tests into clinical practice. Some tests are supplanting the need for aggressive biopsies, angiography, or a series of alternative imaging tests. This is potentially good for patients, but many of these tests are strikingly expensive and are being adopted for use prior to full vetting of their utility and limitations in large clinical studies; the cost of the tests can be an impediment to conducting a series of clinical studies that include appropriate patient subsets. The increasingly proposed use of positron emission tomography in patients with suspected malignancy, inflammation, or infection is a great example of a useful test that we are still learning how best to interpret in several conditions.

In this issue of the Journal, two testing scenarios are discussed. Lacy et al address the question of when patients with pyelonephritis should receive imaging studies. There are data to guide this decision process, but as noted in the study by Sedrak et al,² there are forces at work that challenge the clinician to bypass the rational guidelines—not the least of which are the desire for efficiency (don’t take the chance that the test may be required later and delay discharge from the hospital or observation area) and greater surety in the clinical diagnosis. Although fear of litigation was not high on Sedrak’s list of reasons for ordering more “unnecessary” tests, I posit that a decrease in the confidence placed on clinical diagnosis drives a significant amount of imaging, in conjunction with the desire for shorter hospital stays.

The second paper, by Mgbojikwe et al, relates to the issue of which advanced technology should be ordered, and when. They review the limitations of traditional (echocardiographic) diagnosis and staging of infective endocarditis, and discuss the strengths and limitations of several advanced imaging tools in the setting of suspected or known infectious endocarditis. I suspect that in most medical centers the decisions to utilize these tests will rest with the infectious disease, cardiology, and cardiothoracic surgery consultants. But it is worth being aware of how the diagnostic and staging strategies are evolving, and of the limitations to these studies.

We have come a long way from diagnosing bacterial endocarditis with a valve abscess on the basis of finding changing murmurs, a Roth spot, a palpable spleen tip, new conduction abnormalities on the ECG, and documented daily afternoon fevers. Performing that physical examination is cheap but not highly reproducible. The new testing algorithms are not cheap but, hopefully, will offer superior sensitivity and specificity. Used correctly—and we likely have a way to go to learn what that means—these pictures may well be worth the cost.

Although someone still has to suspect the diagnosis of endocarditis.

The clinical update of giant cell arteritis (GCA) by Rinden et al in this issue of the Journal reminded me of just how much of our management of this disease has, for decades, been based on retrospective studies (we owe a lot to clinicians from the Mayo Clinic for their compiled observations) tempered by our own recalled experiences, which we may at times twist a bit to fit prevailing paradigms. Several prospective interventional studies, perhaps most importantly the Giant-Cell Arteritis Actemra (GIACTA) trial,¹ evaluated the ability of the interleukin 6 (IL-6) antagonist tocilizumab to supplant the protracted use of glucocorticoids in the treatment of GCA. But I learned much more from this trial, in the form of collected clinical tidbits, than just the bottom-line abstract conclusion that IL-6 antagonism is at least a promising approach in many patients with GCA.

As teachers, we tell students to read the entire published clinical trial report, not just the abstract and conclusions. Over the years, I have been impatient with those who violated this dictum, but I now often find myself among the ranks of those who would have been targets of my disapproval. Usually, the articles that I merely skim lie outside my subsubspecialty areas of interest, as time constraints make this abridged reading a necessity for survival, but that excuse does not diminish the self-recognition of my often less-than-complete understanding of the clinical condition being reported. Delving into the nuances of GIACTA truly emphasized that point.

The external validity of any trial rests on understanding the trial’s methods. In the case of GIACTA, there was much more to be learned and affirmed from the trial¹ than that 1 year of tocilizumab treatment met the primary end point of increasing the percent of patients achieving sustained remission at week 52 after a rapid 26-week tapering off of prednisone compared with placebo.

One treatment group in the GIACTA trial underwent an aggressive 6-month tapering of prednisone, while another underwent a more protracted tapering over 12 months (more in line with common practice). Patients tapered over 6 months also received either the IL-6 antagonist or placebo for the full year. The concept was that if IL-6 blockade is a correct approach, then it will maintain remission in more patients, and significantly reduce the total amount of steroid needed to control the disease, despite rapid, aggressive steroid tapering. This turned out to be correct, although more than 20% of the drug-treated patients still experienced a flare of GCA (vs 68% of the placebo-treated group).

Somewhat surprising was that almost 20% of the entered patients did not achieve an initial remission despite receiving high-dose prednisone. The traditional teaching is that if a patient diagnosed with GCA does not respond to high-dose steroids, the diagnosis should be questioned.

Another interesting facet of the study relates to the diagnosis. We are becoming more aware of the different GCA phenotypes, which include prominent polymyalgia rheumatica or constitutional features, “classic” GCA with cranial symptoms, and dominant large-vessel vasculitis (aortitis and major aortic branch disease). In GIACTA, even though imaging was not mandated, 37% of participants were enrolled based in part on imaging results (CT, MRI, angiography, or PET-CT), not on the results of temporal artery biopsy. This forces us to think more broadly about diagnosing and staging GCA, and to wonder if we should even modify our approach to other clinical challenges, including unexplained fever and wasting in older patients.

Another tidbit that came out of the study relates to the relationship between the acute-phase response and clinical flares. We already knew that a rise in the erythrocyte sedimentation rate is a nonspecific sign and does not equate with a flare. In this trial one-third of patients in the placebo group who had a flare had a normal sedimentation rate or C-reactive protein during the flare, and about one-third of patients in the placebo group were receiving more than 10 mg of prednisone. In preliminary reports of follow-up after  52 weeks of treatment,² patients who had achieved complete remission with the IL-6 antagonist and were off of prednisone were still not out of the woods; when the drug was discontinued, many flares continued to occur over the 2-year study extension. We have more to learn about what triggers and drives flares in this disease.

Thus, in addition to informing us of a successful “steroid-sparing” and rescue drug option for our patients with GCA, the details of this well-conducted trial both challenge and reaffirm some of our clinical impressions. Clearly, GCA must be defined for many patients as a very chronic disease, perhaps with occult vascular reservoirs, the biologic basis of which remains to be defined.

The clinical update of giant cell arteritis (GCA) by Rinden et al in this issue of the Journal reminded me of just how much of our management of this disease has, for decades, been based on retrospective studies (we owe a lot to clinicians from the Mayo Clinic for their compiled observations) tempered by our own recalled experiences, which we may at times twist a bit to fit prevailing paradigms. Several prospective interventional studies, perhaps most importantly the Giant-Cell Arteritis Actemra (GIACTA) trial,¹ evaluated the ability of the interleukin 6 (IL-6) antagonist tocilizumab to supplant the protracted use of glucocorticoids in the treatment of GCA. But I learned much more from this trial, in the form of collected clinical tidbits, than just the bottom-line abstract conclusion that IL-6 antagonism is at least a promising approach in many patients with GCA.

As teachers, we tell students to read the entire published clinical trial report, not just the abstract and conclusions. Over the years, I have been impatient with those who violated this dictum, but I now often find myself among the ranks of those who would have been targets of my disapproval. Usually, the articles that I merely skim lie outside my subsubspecialty areas of interest, as time constraints make this abridged reading a necessity for survival, but that excuse does not diminish the self-recognition of my often less-than-complete understanding of the clinical condition being reported. Delving into the nuances of GIACTA truly emphasized that point.

The external validity of any trial rests on understanding the trial’s methods. In the case of GIACTA, there was much more to be learned and affirmed from the trial¹ than that 1 year of tocilizumab treatment met the primary end point of increasing the percent of patients achieving sustained remission at week 52 after a rapid 26-week tapering off of prednisone compared with placebo.

One treatment group in the GIACTA trial underwent an aggressive 6-month tapering of prednisone, while another underwent a more protracted tapering over 12 months (more in line with common practice). Patients tapered over 6 months also received either the IL-6 antagonist or placebo for the full year. The concept was that if IL-6 blockade is a correct approach, then it will maintain remission in more patients, and significantly reduce the total amount of steroid needed to control the disease, despite rapid, aggressive steroid tapering. This turned out to be correct, although more than 20% of the drug-treated patients still experienced a flare of GCA (vs 68% of the placebo-treated group).

Somewhat surprising was that almost 20% of the entered patients did not achieve an initial remission despite receiving high-dose prednisone. The traditional teaching is that if a patient diagnosed with GCA does not respond to high-dose steroids, the diagnosis should be questioned.

Another interesting facet of the study relates to the diagnosis. We are becoming more aware of the different GCA phenotypes, which include prominent polymyalgia rheumatica or constitutional features, “classic” GCA with cranial symptoms, and dominant large-vessel vasculitis (aortitis and major aortic branch disease). In GIACTA, even though imaging was not mandated, 37% of participants were enrolled based in part on imaging results (CT, MRI, angiography, or PET-CT), not on the results of temporal artery biopsy. This forces us to think more broadly about diagnosing and staging GCA, and to wonder if we should even modify our approach to other clinical challenges, including unexplained fever and wasting in older patients.

Another tidbit that came out of the study relates to the relationship between the acute-phase response and clinical flares. We already knew that a rise in the erythrocyte sedimentation rate is a nonspecific sign and does not equate with a flare. In this trial one-third of patients in the placebo group who had a flare had a normal sedimentation rate or C-reactive protein during the flare, and about one-third of patients in the placebo group were receiving more than 10 mg of prednisone. In preliminary reports of follow-up after  52 weeks of treatment,² patients who had achieved complete remission with the IL-6 antagonist and were off of prednisone were still not out of the woods; when the drug was discontinued, many flares continued to occur over the 2-year study extension. We have more to learn about what triggers and drives flares in this disease.

Thus, in addition to informing us of a successful “steroid-sparing” and rescue drug option for our patients with GCA, the details of this well-conducted trial both challenge and reaffirm some of our clinical impressions. Clearly, GCA must be defined for many patients as a very chronic disease, perhaps with occult vascular reservoirs, the biologic basis of which remains to be defined.

The clinical update of giant cell arteritis (GCA) by Rinden et al in this issue of the Journal reminded me of just how much of our management of this disease has, for decades, been based on retrospective studies (we owe a lot to clinicians from the Mayo Clinic for their compiled observations) tempered by our own recalled experiences, which we may at times twist a bit to fit prevailing paradigms. Several prospective interventional studies, perhaps most importantly the Giant-Cell Arteritis Actemra (GIACTA) trial,¹ evaluated the ability of the interleukin 6 (IL-6) antagonist tocilizumab to supplant the protracted use of glucocorticoids in the treatment of GCA. But I learned much more from this trial, in the form of collected clinical tidbits, than just the bottom-line abstract conclusion that IL-6 antagonism is at least a promising approach in many patients with GCA.

As teachers, we tell students to read the entire published clinical trial report, not just the abstract and conclusions. Over the years, I have been impatient with those who violated this dictum, but I now often find myself among the ranks of those who would have been targets of my disapproval. Usually, the articles that I merely skim lie outside my subsubspecialty areas of interest, as time constraints make this abridged reading a necessity for survival, but that excuse does not diminish the self-recognition of my often less-than-complete understanding of the clinical condition being reported. Delving into the nuances of GIACTA truly emphasized that point.

The external validity of any trial rests on understanding the trial’s methods. In the case of GIACTA, there was much more to be learned and affirmed from the trial¹ than that 1 year of tocilizumab treatment met the primary end point of increasing the percent of patients achieving sustained remission at week 52 after a rapid 26-week tapering off of prednisone compared with placebo.

One treatment group in the GIACTA trial underwent an aggressive 6-month tapering of prednisone, while another underwent a more protracted tapering over 12 months (more in line with common practice). Patients tapered over 6 months also received either the IL-6 antagonist or placebo for the full year. The concept was that if IL-6 blockade is a correct approach, then it will maintain remission in more patients, and significantly reduce the total amount of steroid needed to control the disease, despite rapid, aggressive steroid tapering. This turned out to be correct, although more than 20% of the drug-treated patients still experienced a flare of GCA (vs 68% of the placebo-treated group).

Somewhat surprising was that almost 20% of the entered patients did not achieve an initial remission despite receiving high-dose prednisone. The traditional teaching is that if a patient diagnosed with GCA does not respond to high-dose steroids, the diagnosis should be questioned.

Another interesting facet of the study relates to the diagnosis. We are becoming more aware of the different GCA phenotypes, which include prominent polymyalgia rheumatica or constitutional features, “classic” GCA with cranial symptoms, and dominant large-vessel vasculitis (aortitis and major aortic branch disease). In GIACTA, even though imaging was not mandated, 37% of participants were enrolled based in part on imaging results (CT, MRI, angiography, or PET-CT), not on the results of temporal artery biopsy. This forces us to think more broadly about diagnosing and staging GCA, and to wonder if we should even modify our approach to other clinical challenges, including unexplained fever and wasting in older patients.

Another tidbit that came out of the study relates to the relationship between the acute-phase response and clinical flares. We already knew that a rise in the erythrocyte sedimentation rate is a nonspecific sign and does not equate with a flare. In this trial one-third of patients in the placebo group who had a flare had a normal sedimentation rate or C-reactive protein during the flare, and about one-third of patients in the placebo group were receiving more than 10 mg of prednisone. In preliminary reports of follow-up after  52 weeks of treatment,² patients who had achieved complete remission with the IL-6 antagonist and were off of prednisone were still not out of the woods; when the drug was discontinued, many flares continued to occur over the 2-year study extension. We have more to learn about what triggers and drives flares in this disease.

Thus, in addition to informing us of a successful “steroid-sparing” and rescue drug option for our patients with GCA, the details of this well-conducted trial both challenge and reaffirm some of our clinical impressions. Clearly, GCA must be defined for many patients as a very chronic disease, perhaps with occult vascular reservoirs, the biologic basis of which remains to be defined.

So why are we, the trustworthy, having such a tough time convincing people to get routine vaccines for themselves and for their kids? In a sea of truthopenia, we need to do more.

Not everyone refuses vaccines. It is the rare patient in my examination room who, after a discussion, still steadfastly refuses to get a flu shot or pneumonia vaccine. But our dialogue has changed somewhat. Patients still tell me that they or someone they know got the flu from the flu shot or got sick from the pneumonia vaccine (explainable by discussing the immune system’s systemic anamnestic response to a vaccine in the setting of partial immunity—“It’s a good thing”). But more often, I’m hearing detailed stories from the Internet or social media. We heard a less-than-endorsing reflection on the value of vaccines from 2 potential presidential candidates, 1 being a physician, during a televised presidential primary debate. Then there are the tabloid stories, and, of course, there are the celebrity authors and TV talk show doctors touting the unsubstantiated or incompletely substantiated virtues of “anti-inflammatory” and “immune-boosting” diets and supplements as obvious and total truth, while I’m  recommending vaccinations and traditional drug therapies. Who can the patient believe? In our limited office-visit time, we must somehow put this external noise into perspective and individualize our suggestions for the patient in front of us.

Certainly the major news media research teams and the on-screen physician consultants to the major news networks have offered up evidence-based discussions on vaccination, the impact of preventable infections on the unvaccinated, and the limitations and reasonable potential benefits of specific dietary interventions and supplements. Unfortunately, their message is being contaminated by the untrusting aura that surrounds mainstream written and TV media.

Despite physicians’ continued high professional rating in the 2018 Gallup poll, some patients, families, and communities are swayed by arguments offered outside of our offices. And when it comes to our summarizing large studies published in major medical journals, the rolling echo of possible fake news and alternative facts comes to the fore. Can they really trust the establishment? There remains doubt in some patients’ minds.

The problem with measles, as Porter and Goldfarb discuss in this issue of the Journal, is that it is extremely contagious. For “herd immunity” to provide protection and prevent outbreaks, nearly everyone must be vaccinated or have natural immunity from childhood infection. Those who are at special risk from infection include the very young, who have an underdeveloped immune system, and adults who were not appropriately vaccinated (eg, those who may only have gotten a single measles vaccination as a child or whose immune system is weakened by disease or immunosuppressive drugs).

What can we do? We need, as a united front, to know the evidence that supports the relative value of vaccination of our child and adult patients and pass it on. We need to confront, accept, and explain to patients that all vaccines are not 100% successful (measles seems to be pretty close, based on the near-eradication of the disease in vaccinated communities up until now), but that even partial immunity is probably beneficial with all vaccines. We need to have a united front when discussing the bulk of evidence that debunks the vaccination-autism connection. We need to support federal and state funding so that all children can get their routine medical exams and vaccinations. We need to support sufficient financial protection for those companies who in good faith continue to develop and test new and improved vaccines for use in this country and around the world; infections can be introduced by travelers who have passed through areas endemic for infections rarely seen in the United States and who may not be aware of their own infection.

We need to live up to our Gallup poll ranking as highly trusted professionals. And we need to partner with our even more highly trusted nursing colleagues to take every opportunity to inform our patients and fight the spread of disinformation.

The morbilliform rash attributed to measles—and not to a sulfa allergy—should have been a phenomenon of the past. We didn’t need to see it again.

So why are we, the trustworthy, having such a tough time convincing people to get routine vaccines for themselves and for their kids? In a sea of truthopenia, we need to do more.

Not everyone refuses vaccines. It is the rare patient in my examination room who, after a discussion, still steadfastly refuses to get a flu shot or pneumonia vaccine. But our dialogue has changed somewhat. Patients still tell me that they or someone they know got the flu from the flu shot or got sick from the pneumonia vaccine (explainable by discussing the immune system’s systemic anamnestic response to a vaccine in the setting of partial immunity—“It’s a good thing”). But more often, I’m hearing detailed stories from the Internet or social media. We heard a less-than-endorsing reflection on the value of vaccines from 2 potential presidential candidates, 1 being a physician, during a televised presidential primary debate. Then there are the tabloid stories, and, of course, there are the celebrity authors and TV talk show doctors touting the unsubstantiated or incompletely substantiated virtues of “anti-inflammatory” and “immune-boosting” diets and supplements as obvious and total truth, while I’m  recommending vaccinations and traditional drug therapies. Who can the patient believe? In our limited office-visit time, we must somehow put this external noise into perspective and individualize our suggestions for the patient in front of us.

Certainly the major news media research teams and the on-screen physician consultants to the major news networks have offered up evidence-based discussions on vaccination, the impact of preventable infections on the unvaccinated, and the limitations and reasonable potential benefits of specific dietary interventions and supplements. Unfortunately, their message is being contaminated by the untrusting aura that surrounds mainstream written and TV media.

Despite physicians’ continued high professional rating in the 2018 Gallup poll, some patients, families, and communities are swayed by arguments offered outside of our offices. And when it comes to our summarizing large studies published in major medical journals, the rolling echo of possible fake news and alternative facts comes to the fore. Can they really trust the establishment? There remains doubt in some patients’ minds.

The problem with measles, as Porter and Goldfarb discuss in this issue of the Journal, is that it is extremely contagious. For “herd immunity” to provide protection and prevent outbreaks, nearly everyone must be vaccinated or have natural immunity from childhood infection. Those who are at special risk from infection include the very young, who have an underdeveloped immune system, and adults who were not appropriately vaccinated (eg, those who may only have gotten a single measles vaccination as a child or whose immune system is weakened by disease or immunosuppressive drugs).

What can we do? We need, as a united front, to know the evidence that supports the relative value of vaccination of our child and adult patients and pass it on. We need to confront, accept, and explain to patients that all vaccines are not 100% successful (measles seems to be pretty close, based on the near-eradication of the disease in vaccinated communities up until now), but that even partial immunity is probably beneficial with all vaccines. We need to have a united front when discussing the bulk of evidence that debunks the vaccination-autism connection. We need to support federal and state funding so that all children can get their routine medical exams and vaccinations. We need to support sufficient financial protection for those companies who in good faith continue to develop and test new and improved vaccines for use in this country and around the world; infections can be introduced by travelers who have passed through areas endemic for infections rarely seen in the United States and who may not be aware of their own infection.

We need to live up to our Gallup poll ranking as highly trusted professionals. And we need to partner with our even more highly trusted nursing colleagues to take every opportunity to inform our patients and fight the spread of disinformation.

The morbilliform rash attributed to measles—and not to a sulfa allergy—should have been a phenomenon of the past. We didn’t need to see it again.

Concerns over fake news and alternative facts have permeated the fabric of our daily life. Trust in entrenched establishments seems to be at an all-time low. I grew up in the 1960s; I grew up with “don’t trust the man.” I grew up with the Vietnam War, Watergate, and the military-industrial complex, and I have read and heard enough since then to know that a good amount of our distrust was well founded. More recently, there has been increased public scrutiny of the “pharmaceutical-medical complex,” with concerns being raised in the media and by legislators regarding drug pricing, seemingly inappropriate physician prescribing of medications encouraged by drug manufacturers, and the overall costs of medical care. And yes, there is the finger-pointing related to the opioid epidemic. Yet despite these concerns directed at the medical community, as recently as December 2018, a Gallup poll (N = 1,025 US adults) found that physicians were the second most trusted professionals in the United States. (Nurses were number 1!)

So why are we, the trustworthy, having such a tough time convincing people to get routine vaccines for themselves and for their kids? In a sea of truthopenia, we need to do more.

Not everyone refuses vaccines. It is the rare patient in my examination room who, after a discussion, still steadfastly refuses to get a flu shot or pneumonia vaccine. But our dialogue has changed somewhat. Patients still tell me that they or someone they know got the flu from the flu shot or got sick from the pneumonia vaccine (explainable by discussing the immune system’s systemic anamnestic response to a vaccine in the setting of partial immunity—“It’s a good thing”). But more often, I’m hearing detailed stories from the Internet or social media. We heard a less-than-endorsing reflection on the value of vaccines from 2 potential presidential candidates, 1 being a physician, during a televised presidential primary debate. Then there are the tabloid stories, and, of course, there are the celebrity authors and TV talk show doctors touting the unsubstantiated or incompletely substantiated virtues of “anti-inflammatory” and “immune-boosting” diets and supplements as obvious and total truth, while I’m  recommending vaccinations and traditional drug therapies. Who can the patient believe? In our limited office-visit time, we must somehow put this external noise into perspective and individualize our suggestions for the patient in front of us.

Certainly the major news media research teams and the on-screen physician consultants to the major news networks have offered up evidence-based discussions on vaccination, the impact of preventable infections on the unvaccinated, and the limitations and reasonable potential benefits of specific dietary interventions and supplements. Unfortunately, their message is being contaminated by the untrusting aura that surrounds mainstream written and TV media.

Despite physicians’ continued high professional rating in the 2018 Gallup poll, some patients, families, and communities are swayed by arguments offered outside of our offices. And when it comes to our summarizing large studies published in major medical journals, the rolling echo of possible fake news and alternative facts comes to the fore. Can they really trust the establishment? There remains doubt in some patients’ minds.

The problem with measles, as Porter and Goldfarb discuss in this issue of the Journal, is that it is extremely contagious. For “herd immunity” to provide protection and prevent outbreaks, nearly everyone must be vaccinated or have natural immunity from childhood infection. Those who are at special risk from infection include the very young, who have an underdeveloped immune system, and adults who were not appropriately vaccinated (eg, those who may only have gotten a single measles vaccination as a child or whose immune system is weakened by disease or immunosuppressive drugs).

What can we do? We need, as a united front, to know the evidence that supports the relative value of vaccination of our child and adult patients and pass it on. We need to confront, accept, and explain to patients that all vaccines are not 100% successful (measles seems to be pretty close, based on the near-eradication of the disease in vaccinated communities up until now), but that even partial immunity is probably beneficial with all vaccines. We need to have a united front when discussing the bulk of evidence that debunks the vaccination-autism connection. We need to support federal and state funding so that all children can get their routine medical exams and vaccinations. We need to support sufficient financial protection for those companies who in good faith continue to develop and test new and improved vaccines for use in this country and around the world; infections can be introduced by travelers who have passed through areas endemic for infections rarely seen in the United States and who may not be aware of their own infection.

We need to live up to our Gallup poll ranking as highly trusted professionals. And we need to partner with our even more highly trusted nursing colleagues to take every opportunity to inform our patients and fight the spread of disinformation.

The morbilliform rash attributed to measles—and not to a sulfa allergy—should have been a phenomenon of the past. We didn’t need to see it again.

Two ongoing challenges in managing patients with a potential or real infection are how to distinguish early on between bacterial infection and sterile inflammation or sepsis syndrome and how to determine the optimal duration of antibiotic therapy. Both have implications for the patient—ie, starting appropriate antibiotic or alternative therapy early and avoiding adverse effects of unnecessarily prolonged antibiotic use—but also for society, particularly by limiting unnecessary antibiotic use, which contributes to the worldwide problem of antibiotic resistance.

Diagnostic algorithms have been proposed to help recognize infection in chronic obstructive pulmonary disease, rhinosinusitis syndrome, acute arthritis, pharyngitis, and possible sepsis. The algorithms have included laboratory tests and potential biomarkers, but all are imperfect despite achieving various degrees of acceptance in practice.

In this issue of the Journal, Dr. Fakheri updates us on using the data on serum procalcitonin levels to guide starting and stopping antibiotics in different clinical scenarios. As I read the paper, I wondered what was different about procalcitonin that might allow it to succeed where seemingly similar biomarkers like C-reactive protein (CRP) and the erythrocyte sedimentation rate (ESR) have failed.

Procalcitonin is the approximately 15,000-kD product of the CALC1 gene and the precursor of calcitonin. Not surprisingly, then, it is increased in patients with thyroid medullary carcinoma, and it is also often elevated in nonthyroid neuroendocrine malignancies. Proteolytic cleavage of procalcitonin to active calcitonin takes place mainly or only in the thyroid, and under normal homeostatic conditions, procalcitonin is almost unmeasurable in the circulation. However, under major stress such as systemic inflammation, sepsis, or burns, the CALC1 gene is activated in parenchymal cells in many organs, and procalcitonin is synthesized and released. Notably, under these conditions, the procalcitonin does not seem to be of thyroid origin; hence, calcitonin levels do not rise markedly. The physiologic role of nonthyroidal procalcitonin is unknown.

Procalcitonin synthesis and secretion is turned on in nonthyroid tissue by multiple cytokines; the cytokines most likely relevant to its association with inflammation and infections are interleukin (IL) 1 beta, tumor necrosis factor (TNF) alpha, and IL-6. Since these same mediators drive the acute-phase response and elicit the increase in circulating CRP and fibrinogen (the major contributor to the ESR), the obvious question is why procalcitonin might be a more reliable biomarker to distinguish bacterial infection from inflammation or a viral infection than the CRP level or ESR. And although it does indeed seem to do so in several conditions, as Dr. Fakheri discusses, the explanation is not obvious. But it is intriguing to hypothesize.

Induction of procalcitonin by endotoxin-stimulated cytokines is rapid and seems to be slightly faster than that of CRP, although there may be issues of assay sensitivity. The half-life of procalcitonin is similar to that of CRP (about 24 hours). Its degradation does not seem to be altered in renal insufficiency, and its synthesis seems to rapidly shut off as the cytokine level drops. But interestingly, and perhaps relevant to its possible unique biomarker behavior, its synthesis seems to depend on factors other than the increase in inflammatory cytokines such as IL-6. Under certain circumstances, in the same patient, there is a discrepancy between the levels of procalcitonin and CRP.

In a small study of patients with pulmonary embolism and fever, IL-6 levels increased in many with an expected accompanying increase in CRP and ESR, but procalcitonin did not markedly rise,¹ although all 3 markers rose as expected in patients with bacterial pneumonia.

Even more provocative is another study in 69 patients with systemic lupus erythematosus and bacterial infection (43 patients had sepsis, 11 of whom died). The CRP level rose dramatically in the infected patients, but procalcitonin did not.²

The intriguing aspect of this, assuming it holds true in other studies, is that interferon activity is high in lupus and many viral infections, and if interferon can suppress CALC1 gene activation³ but leave CRP activation unaffected, this may provide a clue as to why CRP but not procalcitonin is elevated in serious viral infections, thus allowing procalcitonin to more effectively distinguish bacterial from viral and other nonbacterial inflammatory responses.

The two studies I mention are small, some conflicting results have been published, and the results cannot yet be generalized. Plus, it has long been recognized there is sometimes discordance in a given patient between the elevation in ESR and CRP, not readily explained by the presence of a paraprotein, rheologic factors, or the different time course of decay in the ESR and CRP response. Whatever the explanation, procalcitonin’s biology is interesting, and clinical study results show promise. While tracking procalcitonin levels is not uniformly useful (eg, there is no convincing value in using procalcitonin in the diagnosis of prosthetic joint infections), there is accumulating evidence that it can guide us to using shorter but still effective courses of antibiotics in several clinical scenarios. Hopefully, more frequent use of the test will make a dent in our apparent excess use of antibiotics in patients with nonbacterial upper-respiratory infections.

Two ongoing challenges in managing patients with a potential or real infection are how to distinguish early on between bacterial infection and sterile inflammation or sepsis syndrome and how to determine the optimal duration of antibiotic therapy. Both have implications for the patient—ie, starting appropriate antibiotic or alternative therapy early and avoiding adverse effects of unnecessarily prolonged antibiotic use—but also for society, particularly by limiting unnecessary antibiotic use, which contributes to the worldwide problem of antibiotic resistance.

Diagnostic algorithms have been proposed to help recognize infection in chronic obstructive pulmonary disease, rhinosinusitis syndrome, acute arthritis, pharyngitis, and possible sepsis. The algorithms have included laboratory tests and potential biomarkers, but all are imperfect despite achieving various degrees of acceptance in practice.

In this issue of the Journal, Dr. Fakheri updates us on using the data on serum procalcitonin levels to guide starting and stopping antibiotics in different clinical scenarios. As I read the paper, I wondered what was different about procalcitonin that might allow it to succeed where seemingly similar biomarkers like C-reactive protein (CRP) and the erythrocyte sedimentation rate (ESR) have failed.

Procalcitonin is the approximately 15,000-kD product of the CALC1 gene and the precursor of calcitonin. Not surprisingly, then, it is increased in patients with thyroid medullary carcinoma, and it is also often elevated in nonthyroid neuroendocrine malignancies. Proteolytic cleavage of procalcitonin to active calcitonin takes place mainly or only in the thyroid, and under normal homeostatic conditions, procalcitonin is almost unmeasurable in the circulation. However, under major stress such as systemic inflammation, sepsis, or burns, the CALC1 gene is activated in parenchymal cells in many organs, and procalcitonin is synthesized and released. Notably, under these conditions, the procalcitonin does not seem to be of thyroid origin; hence, calcitonin levels do not rise markedly. The physiologic role of nonthyroidal procalcitonin is unknown.

Procalcitonin synthesis and secretion is turned on in nonthyroid tissue by multiple cytokines; the cytokines most likely relevant to its association with inflammation and infections are interleukin (IL) 1 beta, tumor necrosis factor (TNF) alpha, and IL-6. Since these same mediators drive the acute-phase response and elicit the increase in circulating CRP and fibrinogen (the major contributor to the ESR), the obvious question is why procalcitonin might be a more reliable biomarker to distinguish bacterial infection from inflammation or a viral infection than the CRP level or ESR. And although it does indeed seem to do so in several conditions, as Dr. Fakheri discusses, the explanation is not obvious. But it is intriguing to hypothesize.

Induction of procalcitonin by endotoxin-stimulated cytokines is rapid and seems to be slightly faster than that of CRP, although there may be issues of assay sensitivity. The half-life of procalcitonin is similar to that of CRP (about 24 hours). Its degradation does not seem to be altered in renal insufficiency, and its synthesis seems to rapidly shut off as the cytokine level drops. But interestingly, and perhaps relevant to its possible unique biomarker behavior, its synthesis seems to depend on factors other than the increase in inflammatory cytokines such as IL-6. Under certain circumstances, in the same patient, there is a discrepancy between the levels of procalcitonin and CRP.

In a small study of patients with pulmonary embolism and fever, IL-6 levels increased in many with an expected accompanying increase in CRP and ESR, but procalcitonin did not markedly rise,¹ although all 3 markers rose as expected in patients with bacterial pneumonia.

Even more provocative is another study in 69 patients with systemic lupus erythematosus and bacterial infection (43 patients had sepsis, 11 of whom died). The CRP level rose dramatically in the infected patients, but procalcitonin did not.²

The intriguing aspect of this, assuming it holds true in other studies, is that interferon activity is high in lupus and many viral infections, and if interferon can suppress CALC1 gene activation³ but leave CRP activation unaffected, this may provide a clue as to why CRP but not procalcitonin is elevated in serious viral infections, thus allowing procalcitonin to more effectively distinguish bacterial from viral and other nonbacterial inflammatory responses.

The two studies I mention are small, some conflicting results have been published, and the results cannot yet be generalized. Plus, it has long been recognized there is sometimes discordance in a given patient between the elevation in ESR and CRP, not readily explained by the presence of a paraprotein, rheologic factors, or the different time course of decay in the ESR and CRP response. Whatever the explanation, procalcitonin’s biology is interesting, and clinical study results show promise. While tracking procalcitonin levels is not uniformly useful (eg, there is no convincing value in using procalcitonin in the diagnosis of prosthetic joint infections), there is accumulating evidence that it can guide us to using shorter but still effective courses of antibiotics in several clinical scenarios. Hopefully, more frequent use of the test will make a dent in our apparent excess use of antibiotics in patients with nonbacterial upper-respiratory infections.

Two ongoing challenges in managing patients with a potential or real infection are how to distinguish early on between bacterial infection and sterile inflammation or sepsis syndrome and how to determine the optimal duration of antibiotic therapy. Both have implications for the patient—ie, starting appropriate antibiotic or alternative therapy early and avoiding adverse effects of unnecessarily prolonged antibiotic use—but also for society, particularly by limiting unnecessary antibiotic use, which contributes to the worldwide problem of antibiotic resistance.

Diagnostic algorithms have been proposed to help recognize infection in chronic obstructive pulmonary disease, rhinosinusitis syndrome, acute arthritis, pharyngitis, and possible sepsis. The algorithms have included laboratory tests and potential biomarkers, but all are imperfect despite achieving various degrees of acceptance in practice.

In this issue of the Journal, Dr. Fakheri updates us on using the data on serum procalcitonin levels to guide starting and stopping antibiotics in different clinical scenarios. As I read the paper, I wondered what was different about procalcitonin that might allow it to succeed where seemingly similar biomarkers like C-reactive protein (CRP) and the erythrocyte sedimentation rate (ESR) have failed.

Procalcitonin is the approximately 15,000-kD product of the CALC1 gene and the precursor of calcitonin. Not surprisingly, then, it is increased in patients with thyroid medullary carcinoma, and it is also often elevated in nonthyroid neuroendocrine malignancies. Proteolytic cleavage of procalcitonin to active calcitonin takes place mainly or only in the thyroid, and under normal homeostatic conditions, procalcitonin is almost unmeasurable in the circulation. However, under major stress such as systemic inflammation, sepsis, or burns, the CALC1 gene is activated in parenchymal cells in many organs, and procalcitonin is synthesized and released. Notably, under these conditions, the procalcitonin does not seem to be of thyroid origin; hence, calcitonin levels do not rise markedly. The physiologic role of nonthyroidal procalcitonin is unknown.

Procalcitonin synthesis and secretion is turned on in nonthyroid tissue by multiple cytokines; the cytokines most likely relevant to its association with inflammation and infections are interleukin (IL) 1 beta, tumor necrosis factor (TNF) alpha, and IL-6. Since these same mediators drive the acute-phase response and elicit the increase in circulating CRP and fibrinogen (the major contributor to the ESR), the obvious question is why procalcitonin might be a more reliable biomarker to distinguish bacterial infection from inflammation or a viral infection than the CRP level or ESR. And although it does indeed seem to do so in several conditions, as Dr. Fakheri discusses, the explanation is not obvious. But it is intriguing to hypothesize.

Induction of procalcitonin by endotoxin-stimulated cytokines is rapid and seems to be slightly faster than that of CRP, although there may be issues of assay sensitivity. The half-life of procalcitonin is similar to that of CRP (about 24 hours). Its degradation does not seem to be altered in renal insufficiency, and its synthesis seems to rapidly shut off as the cytokine level drops. But interestingly, and perhaps relevant to its possible unique biomarker behavior, its synthesis seems to depend on factors other than the increase in inflammatory cytokines such as IL-6. Under certain circumstances, in the same patient, there is a discrepancy between the levels of procalcitonin and CRP.

In a small study of patients with pulmonary embolism and fever, IL-6 levels increased in many with an expected accompanying increase in CRP and ESR, but procalcitonin did not markedly rise,¹ although all 3 markers rose as expected in patients with bacterial pneumonia.

Even more provocative is another study in 69 patients with systemic lupus erythematosus and bacterial infection (43 patients had sepsis, 11 of whom died). The CRP level rose dramatically in the infected patients, but procalcitonin did not.²

The intriguing aspect of this, assuming it holds true in other studies, is that interferon activity is high in lupus and many viral infections, and if interferon can suppress CALC1 gene activation³ but leave CRP activation unaffected, this may provide a clue as to why CRP but not procalcitonin is elevated in serious viral infections, thus allowing procalcitonin to more effectively distinguish bacterial from viral and other nonbacterial inflammatory responses.

The two studies I mention are small, some conflicting results have been published, and the results cannot yet be generalized. Plus, it has long been recognized there is sometimes discordance in a given patient between the elevation in ESR and CRP, not readily explained by the presence of a paraprotein, rheologic factors, or the different time course of decay in the ESR and CRP response. Whatever the explanation, procalcitonin’s biology is interesting, and clinical study results show promise. While tracking procalcitonin levels is not uniformly useful (eg, there is no convincing value in using procalcitonin in the diagnosis of prosthetic joint infections), there is accumulating evidence that it can guide us to using shorter but still effective courses of antibiotics in several clinical scenarios. Hopefully, more frequent use of the test will make a dent in our apparent excess use of antibiotics in patients with nonbacterial upper-respiratory infections.

These days, it seems impossible to talk with physicians without hearing about some aspect of discontent with the practice of medicine. There is even a “Physician Misery Index” (www.geneia.com), and the name says it all. These conversations cover a gamut of concerns including reimbursement, reduced time spent with patients, increased regulatory oversight, the need for preapproval for testing and prescriptions, maintenance of certification, and of course for those of us who have been doing this for a while, there are the challenges of the electronic medical record (EMR). In the old days, we used to bore our nonmedical friends and family with energetic, jargonized discussions of diagnostic and therapeutic enigmas. Now, we numb them with our complaints about what we increasingly view as a job.

At the extreme, this discontent sears our professional being and results in early retirement, change of profession, and, for many, searching for ways to limit clinical practice time—while often saying how much they wish they could “just practice medicine.” Such are some of the manifestations of burnout.

Studies indicate that contributors to burnout are many. And as in all observational studies, the establishment of cause, effect, and degree of codependency is difficult if not impossible to ascertain. Many major changes have temporally coincided with the rise in physician dissatisfaction. One is the increasing corporatization of medicine. In 2016, in some parts of the country, over 40% of physicians were employed by hospitals.¹ Surveys indicate that these employed physicians have a modestly higher degree of dissatisfaction than those in “independent” practices, often citing loss of control of their practice style and increased regulatory demands as contributors to their misery—which is ironic, since the reason many physicians join large hospital-employed groups is to minimize external financial and regulatory pressures.

Astute corporate medical leaders have recognized the burnout issue and are struggling to diminish its negative impact on the healthcare system, patient care, and individual physicians. But many initial approaches have been aimed at soothing the already singed. Health days, yoga sessions, mindfulness classes, and various ways to soften the impact of the EMR on our lives have all been offered up along with other creative and well-intentioned balms. It is not clear to me that any of these address the primary issues contributing to the growing challenge of professional and personal discontent. Some of these approaches may take root and improve a few physicians’ ability to cope. But will that be sufficient to save a generation of skilled and experienced but increasingly disconnected physicians and clinical faculty?

On this landscape, Mangione and Kahn in this issue of the Journal argue for the humanities as part of the solution for what ails us. They cite Sir William Osler, the titan of internal medicine, who a century ago urged physicians to cultivate a strong background in the humanities as a counterweight to the objective science that he also so strongly endorsed and inculcated into the culture at Johns Hopkins. Mangione and Kahn present nascent data suggesting that students who choose to have extra interactions with the arts and humanities exhibit greater resilience, tolerance of ambiguity, and more of the empathetic traits that we desire in physicians, and they posit that these traits will decrease the sense of professional burnout.

We don’t know whether it is the impact of extra exposure to the humanities or the personality of those students who choose to partake of these programs that is the major contributor to the behavioral outcomes, though I suspect it is both. The real question is this: even if we can enhance through greater exposure to the humanities the desired attitudes in our medical students, residents, and young physicians, can we slow the rate of professional dissatisfaction and burnout in them?

To answer this, we need a deeper understanding of the burnout process and whether it will affect younger physicians and physicians currently in training the same way it has affected an older generation of physicians, many of whom have had to face the challenges of coping with the new digital world that our younger colleagues have grown up with. Many of us also have needed to change our practice patterns and expectations. Our younger colleagues may not be faced with the same contextual dissonance that we have had to adjust to in reconciling our (idealistic) image of clinical practice with the pragmatic business of medicine. Their expectations for both are, and will likely remain, quite different.

The next generation of physicians will undoubtedly have their own challenges. They are well familiarized with the digital and virtual world and will likely accept avatar medicine to a far greater degree than we have. But I think the study of the humanities will be of great value to them as well, not necessarily to imbue them with a greater sense of resilience in coping with the digital and science aspects of medicine, but to provide reminders of what Bruce Springsteen has called the “human touch.” Studying the humanities may provide the conceptual reminder of the value of humanness—as we physicians evolve into the world of providing an increasing amount of care via advanced-care providers, shortened real visits, and telemedicine and other virtual consultative visits.

Hopefully, we can indeed find a way to nurture within us Osler’s conceptual tree of medicine that harbors on the same stem the “twin berries” of “the Humanities and Science.”

These days, it seems impossible to talk with physicians without hearing about some aspect of discontent with the practice of medicine. There is even a “Physician Misery Index” (www.geneia.com), and the name says it all. These conversations cover a gamut of concerns including reimbursement, reduced time spent with patients, increased regulatory oversight, the need for preapproval for testing and prescriptions, maintenance of certification, and of course for those of us who have been doing this for a while, there are the challenges of the electronic medical record (EMR). In the old days, we used to bore our nonmedical friends and family with energetic, jargonized discussions of diagnostic and therapeutic enigmas. Now, we numb them with our complaints about what we increasingly view as a job.

At the extreme, this discontent sears our professional being and results in early retirement, change of profession, and, for many, searching for ways to limit clinical practice time—while often saying how much they wish they could “just practice medicine.” Such are some of the manifestations of burnout.

Studies indicate that contributors to burnout are many. And as in all observational studies, the establishment of cause, effect, and degree of codependency is difficult if not impossible to ascertain. Many major changes have temporally coincided with the rise in physician dissatisfaction. One is the increasing corporatization of medicine. In 2016, in some parts of the country, over 40% of physicians were employed by hospitals.¹ Surveys indicate that these employed physicians have a modestly higher degree of dissatisfaction than those in “independent” practices, often citing loss of control of their practice style and increased regulatory demands as contributors to their misery—which is ironic, since the reason many physicians join large hospital-employed groups is to minimize external financial and regulatory pressures.

Astute corporate medical leaders have recognized the burnout issue and are struggling to diminish its negative impact on the healthcare system, patient care, and individual physicians. But many initial approaches have been aimed at soothing the already singed. Health days, yoga sessions, mindfulness classes, and various ways to soften the impact of the EMR on our lives have all been offered up along with other creative and well-intentioned balms. It is not clear to me that any of these address the primary issues contributing to the growing challenge of professional and personal discontent. Some of these approaches may take root and improve a few physicians’ ability to cope. But will that be sufficient to save a generation of skilled and experienced but increasingly disconnected physicians and clinical faculty?

On this landscape, Mangione and Kahn in this issue of the Journal argue for the humanities as part of the solution for what ails us. They cite Sir William Osler, the titan of internal medicine, who a century ago urged physicians to cultivate a strong background in the humanities as a counterweight to the objective science that he also so strongly endorsed and inculcated into the culture at Johns Hopkins. Mangione and Kahn present nascent data suggesting that students who choose to have extra interactions with the arts and humanities exhibit greater resilience, tolerance of ambiguity, and more of the empathetic traits that we desire in physicians, and they posit that these traits will decrease the sense of professional burnout.

We don’t know whether it is the impact of extra exposure to the humanities or the personality of those students who choose to partake of these programs that is the major contributor to the behavioral outcomes, though I suspect it is both. The real question is this: even if we can enhance through greater exposure to the humanities the desired attitudes in our medical students, residents, and young physicians, can we slow the rate of professional dissatisfaction and burnout in them?

To answer this, we need a deeper understanding of the burnout process and whether it will affect younger physicians and physicians currently in training the same way it has affected an older generation of physicians, many of whom have had to face the challenges of coping with the new digital world that our younger colleagues have grown up with. Many of us also have needed to change our practice patterns and expectations. Our younger colleagues may not be faced with the same contextual dissonance that we have had to adjust to in reconciling our (idealistic) image of clinical practice with the pragmatic business of medicine. Their expectations for both are, and will likely remain, quite different.

The next generation of physicians will undoubtedly have their own challenges. They are well familiarized with the digital and virtual world and will likely accept avatar medicine to a far greater degree than we have. But I think the study of the humanities will be of great value to them as well, not necessarily to imbue them with a greater sense of resilience in coping with the digital and science aspects of medicine, but to provide reminders of what Bruce Springsteen has called the “human touch.” Studying the humanities may provide the conceptual reminder of the value of humanness—as we physicians evolve into the world of providing an increasing amount of care via advanced-care providers, shortened real visits, and telemedicine and other virtual consultative visits.

Hopefully, we can indeed find a way to nurture within us Osler’s conceptual tree of medicine that harbors on the same stem the “twin berries” of “the Humanities and Science.”

These days, it seems impossible to talk with physicians without hearing about some aspect of discontent with the practice of medicine. There is even a “Physician Misery Index” (www.geneia.com), and the name says it all. These conversations cover a gamut of concerns including reimbursement, reduced time spent with patients, increased regulatory oversight, the need for preapproval for testing and prescriptions, maintenance of certification, and of course for those of us who have been doing this for a while, there are the challenges of the electronic medical record (EMR). In the old days, we used to bore our nonmedical friends and family with energetic, jargonized discussions of diagnostic and therapeutic enigmas. Now, we numb them with our complaints about what we increasingly view as a job.

At the extreme, this discontent sears our professional being and results in early retirement, change of profession, and, for many, searching for ways to limit clinical practice time—while often saying how much they wish they could “just practice medicine.” Such are some of the manifestations of burnout.

Studies indicate that contributors to burnout are many. And as in all observational studies, the establishment of cause, effect, and degree of codependency is difficult if not impossible to ascertain. Many major changes have temporally coincided with the rise in physician dissatisfaction. One is the increasing corporatization of medicine. In 2016, in some parts of the country, over 40% of physicians were employed by hospitals.¹ Surveys indicate that these employed physicians have a modestly higher degree of dissatisfaction than those in “independent” practices, often citing loss of control of their practice style and increased regulatory demands as contributors to their misery—which is ironic, since the reason many physicians join large hospital-employed groups is to minimize external financial and regulatory pressures.

Astute corporate medical leaders have recognized the burnout issue and are struggling to diminish its negative impact on the healthcare system, patient care, and individual physicians. But many initial approaches have been aimed at soothing the already singed. Health days, yoga sessions, mindfulness classes, and various ways to soften the impact of the EMR on our lives have all been offered up along with other creative and well-intentioned balms. It is not clear to me that any of these address the primary issues contributing to the growing challenge of professional and personal discontent. Some of these approaches may take root and improve a few physicians’ ability to cope. But will that be sufficient to save a generation of skilled and experienced but increasingly disconnected physicians and clinical faculty?

On this landscape, Mangione and Kahn in this issue of the Journal argue for the humanities as part of the solution for what ails us. They cite Sir William Osler, the titan of internal medicine, who a century ago urged physicians to cultivate a strong background in the humanities as a counterweight to the objective science that he also so strongly endorsed and inculcated into the culture at Johns Hopkins. Mangione and Kahn present nascent data suggesting that students who choose to have extra interactions with the arts and humanities exhibit greater resilience, tolerance of ambiguity, and more of the empathetic traits that we desire in physicians, and they posit that these traits will decrease the sense of professional burnout.

We don’t know whether it is the impact of extra exposure to the humanities or the personality of those students who choose to partake of these programs that is the major contributor to the behavioral outcomes, though I suspect it is both. The real question is this: even if we can enhance through greater exposure to the humanities the desired attitudes in our medical students, residents, and young physicians, can we slow the rate of professional dissatisfaction and burnout in them?

To answer this, we need a deeper understanding of the burnout process and whether it will affect younger physicians and physicians currently in training the same way it has affected an older generation of physicians, many of whom have had to face the challenges of coping with the new digital world that our younger colleagues have grown up with. Many of us also have needed to change our practice patterns and expectations. Our younger colleagues may not be faced with the same contextual dissonance that we have had to adjust to in reconciling our (idealistic) image of clinical practice with the pragmatic business of medicine. Their expectations for both are, and will likely remain, quite different.

The next generation of physicians will undoubtedly have their own challenges. They are well familiarized with the digital and virtual world and will likely accept avatar medicine to a far greater degree than we have. But I think the study of the humanities will be of great value to them as well, not necessarily to imbue them with a greater sense of resilience in coping with the digital and science aspects of medicine, but to provide reminders of what Bruce Springsteen has called the “human touch.” Studying the humanities may provide the conceptual reminder of the value of humanness—as we physicians evolve into the world of providing an increasing amount of care via advanced-care providers, shortened real visits, and telemedicine and other virtual consultative visits.

Hopefully, we can indeed find a way to nurture within us Osler’s conceptual tree of medicine that harbors on the same stem the “twin berries” of “the Humanities and Science.”

May et al discuss one of the most common laboratory tests we order, the complete blood cell count, and how to interpret and unlock additional information that we often overlook.

Singh et al explain the utility and limitations of assessing hepatic fibrosis in patients with known liver disease using specialized and increasingly available imaging techniques in patients with common diseases that may progress to liver failure.

Using several clinical scenarios, Suresh explores the limitations of serologic testing in patients with a potential “autoimmune” or systemic inflammatory syndrome (which, based on new consultations I see in my rheumatology clinic, seems to be virtually everyone who has experienced pain or fatigue).

The Journal also continues our ongoing series on Smart Testing that has focused on tests and testing strategies that have a strong evidence basis to support or discourage their utilization in specific settings. But in most real-life clinical scenarios, relatively little directly applicable evidence can be brought to bear on our decision process with a specific patient. Hence the ongoing need for each of us to refine our clinical reasoning skills, and to recognize the continuing challenges facing the incorporation of artificial intelligence and algorithmic practice into the management of the individual patient sitting or lying in front of us.

The challenge is to balance input from Watson, “Dr. Google,” our accumulated anecdotal and group experience, and specific data from the patient’s physical examination and provided history. All these sources are valuable, and I believe that how we thoughtfully and purposefully weigh and incorporate this information into practice defines us as the clinicians we are.

May et al discuss one of the most common laboratory tests we order, the complete blood cell count, and how to interpret and unlock additional information that we often overlook.

Singh et al explain the utility and limitations of assessing hepatic fibrosis in patients with known liver disease using specialized and increasingly available imaging techniques in patients with common diseases that may progress to liver failure.

Using several clinical scenarios, Suresh explores the limitations of serologic testing in patients with a potential “autoimmune” or systemic inflammatory syndrome (which, based on new consultations I see in my rheumatology clinic, seems to be virtually everyone who has experienced pain or fatigue).

The Journal also continues our ongoing series on Smart Testing that has focused on tests and testing strategies that have a strong evidence basis to support or discourage their utilization in specific settings. But in most real-life clinical scenarios, relatively little directly applicable evidence can be brought to bear on our decision process with a specific patient. Hence the ongoing need for each of us to refine our clinical reasoning skills, and to recognize the continuing challenges facing the incorporation of artificial intelligence and algorithmic practice into the management of the individual patient sitting or lying in front of us.

The challenge is to balance input from Watson, “Dr. Google,” our accumulated anecdotal and group experience, and specific data from the patient’s physical examination and provided history. All these sources are valuable, and I believe that how we thoughtfully and purposefully weigh and incorporate this information into practice defines us as the clinicians we are.

May et al discuss one of the most common laboratory tests we order, the complete blood cell count, and how to interpret and unlock additional information that we often overlook.

Singh et al explain the utility and limitations of assessing hepatic fibrosis in patients with known liver disease using specialized and increasingly available imaging techniques in patients with common diseases that may progress to liver failure.

Using several clinical scenarios, Suresh explores the limitations of serologic testing in patients with a potential “autoimmune” or systemic inflammatory syndrome (which, based on new consultations I see in my rheumatology clinic, seems to be virtually everyone who has experienced pain or fatigue).

The Journal also continues our ongoing series on Smart Testing that has focused on tests and testing strategies that have a strong evidence basis to support or discourage their utilization in specific settings. But in most real-life clinical scenarios, relatively little directly applicable evidence can be brought to bear on our decision process with a specific patient. Hence the ongoing need for each of us to refine our clinical reasoning skills, and to recognize the continuing challenges facing the incorporation of artificial intelligence and algorithmic practice into the management of the individual patient sitting or lying in front of us.

The challenge is to balance input from Watson, “Dr. Google,” our accumulated anecdotal and group experience, and specific data from the patient’s physical examination and provided history. All these sources are valuable, and I believe that how we thoughtfully and purposefully weigh and incorporate this information into practice defines us as the clinicians we are.