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Chronic Pain Without Clear Etiology in Low- and Middle-Income Countries: A Narrative Review

Jackson, Tracy MD*; Thomas, Sarah BS; Stabile, Victoria BA; Han, Xue MPH§; Shotwell, Matthew PhD; McQueen, K. A. Kelly MD, MPH

doi: 10.1213/ANE.0000000000001287
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Globally, 8 of the top 12 disabling conditions are related either to chronic pain or to the psychological conditions strongly associated with persistent pain. In this narrative review, we explore the demographic and psychosocial associations with chronic pain exclusively from low- and middle-income countries (LMICs) and compare them with current global data. One hundred nineteen publications in 28 LMICs were identified for review; associations with depression, anxiety, posttraumatic stress, insomnia, disability, gender, age, rural/urban location, education level, income, and additional sites of pain were analyzed for each type of chronic pain without clear etiology. Of the 119 publications reviewed, pain was described in association with disability in 50 publications, female gender in 40 publications, older age in 34 publications, depression in 36 publications, anxiety in 19 publications, and multiple somatic complaints in 13 publications. Women, elderly patients, and workers, especially in low-income and low-education subgroups, were more likely to have pain in multiple sites, mood disorders, and disabilities. In high-income countries, multisite pain without etiology, female gender, and association with mood disturbance and disability may be suggestive of a central sensitization syndrome (CSS). Because each type of prevalent chronic pain without known etiology reviewed had similar associations in LMICs, strategies for assessment and treatment of chronic pain worldwide should consider the possibility of prevalent CSS. Recognition is especially critical in resource-poor areas, because treatment of CSS is vastly different than localized chronic pain.

From the *Department of Anesthesiology and Pain Medicine, Vanderbilt Outpatient Pain Clinics, Vanderbilt University, Nashville, Tennessee; University of Tennessee Health Science Center, Memphis, Tennessee; Operation Smile International Headquarters, Virginia Beach, Virginia; §Vanderbilt University School of Medicine, Nashville, Tennessee; Department of Biostatistics, Vanderbilt University, Nashville, Tennessee; and Department of Anesthesiology, Vanderbilt Institute for Global Health, Vanderbilt University, Nashville, Tennessee.

Accepted for publication February 17, 2016.

Funding: None.

The authors declare no conflicts of interest.

Reprints will not be available from the authors.

Address correspondence to Tracy Jackson, MD, Vanderbilt University, 719 Thompson Ln., Suite 22200, Nashville, TN 37204. Address e-mail to tracy.jackson@vanderbilt.edu.

Pain is recognized as an important contributor to the global burden of disability. Although technically defined as an experience,1 pain is also a symptom, and in some cases, especially when persistent and without clear etiology, pain may be actually a pathologic entity of self-propagating central nervous system sensitization. Because these sensitized central neural pathways regulate pain, sleep, and mood, chronic pain in these cases can both predate and follow the development of depression, anxiety, and insomnia. The term used to describe this phenomenon is controversial and evolving along with knowledge about its physiologic underpinnings garnered from functional brain imaging and neurophysiologic research.2 “Central sensitization syndrome” (CSS) is the most general term and the one used here, although “centralized pain” also is used to describe an ongoing peripheral insult or inflammatory process resulting in sensitization of the central nervous system. Fibromyalgia, chronic widespread pain, and even so-called somatoform disorders are all diagnoses reflecting central nervous system sensitization causing diffuse chronic pain without clear etiology. Widespread hyperalgesia and allodynia often are found in these patients, but objective sensory testing is limited to research settings, and validated diagnostic values for CSS are elusive.3 The ideal tool for diagnosing CSS remains controversial, but in the case of fibromyalgia, for example, diagnosis is typically made with the use of questionnaires that consider multisite pain (with or without objective tender points on examination) and other disabling symptoms like fatigue.2 Regardless of how the diagnosis of CSS is made (or even what the phenomenon should be called), the key is to recognize CSS as a possibility in instances of chronic pain without known etiology, because the treatment is vastly different to that of localized, isolated pain with clear cause.

The major barrier to evaluation and treatment of CSS is that health care providers (even in high-income countries [HICs]) often do not consider that the presence of chronic pain may be indicative of CSS, instead focusing on separate assessment and treatment strategies for each individual pain location. Furthermore, patients with pain in multiple sites may only seek care for 1 “chief” complaint and may not be asked or offer information about other pain sites or associated mood or sleep disorders. Yet, low back pain, neck pain, temporomandibular disorders, migraine and tension-type headache, chronic prostatitis/pelvic pain, chronic abdominal pain, and irritable bowel syndrome often coexist in a patient with CSS. Eight of the top 12 disabling conditions globally are as follows: low back and neck pain, migraine, arthritis, other musculoskeletal conditions, depression, anxiety, and drug use disorder are all either pain conditions or psychological conditions strongly associated with chronic pain syndromes and, therefore, may be indicative of unrecognized but prevalent underlying CSSs.4 The focus of this narrative review is to explore the demographic and psychosocial associations with chronic pain, specifically CSS, in low- and middle-income countries (LMICs) so that future assessment and resource allocation for chronic pain treatment can proceed with more accurate information for appropriate interventions to reduce the global disability burden.

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METHODS

A search of the available literature published until January 2014 was performed. Low- and middle-income classification was confirmed by cross-referencing with the World Bank List of Countries by income level. Low-income economies are defined as those with a gross national income per capita, calculated using the World Bank Atlas method, of $1045 or less in 2013; middle-income economies are those with a gross national income per capita of >$1045 but <$12,746. Search terms included “pain and (chronic or persistent) and (low-income countries or middle-income countries or LMIC or Africa or Asia or Central America or Latin America or South America) and (incidence or prevalence).”

To prevent inadvertent exclusion of any LMIC, the query was repeated 145 more times for each of the individual LMICs listed in the World Bank database with use of the string “pain and (chronic or persistent) and (incidence or prevalence) and (name of LMIC).” All languages were included. Populations younger than 18 years and those with acute pain or pain known to be related to surgery, trauma, infection, or underlying disease were excluded. Databases searched included PubMed, Medline, Embase, Scopus, PsychINFO, and the Cochrane Database of Systematic Reviews. Copies of unpublished or unavailable studies were sought out by direct author communication, resulting in 2 additional articles. Studies not in English were translated via Google Translate.

One thousand, two hundred fifty articles were identified from this initial search. After abstract review by 2 independent reviewers, 311 were deemed potentially relevant. Two hundred thirteen of these were excluded: 17 had no full text available; 11 were review articles; and 186 were related to acute pain, chronic pain treatment, validation of pain tools, or described pain related to surgery, concurrent trauma, infection, or other medical conditions unrelated to the 8 pain-related noncommunicable diseases identified as contributing to global pain burden.

Table 1.

Table 1.

Figure 1.

Figure 1.

After reference review of the remaining 97 relevant full texts, 58 additional articles were identified and reviewed; 20 of these were only available as abstracts and 16 were review articles. With the 22 additional relevant texts from references, 119 full-text articles were identified (Fig. 1). The prevalence of associations that may be indicative of CSS was extracted systematically from 119 articles (Appendix 1) describing 441,516 people in 28 LMICs, per protocol described in Table 1. Given the significant heterogeneity of metrics and statistical analysis used in the 119 articles detailing multiple types of pain without clear etiology, it was impossible to accurately represent these results graphically nor subject them to a systematic review or meta-analysis per the Preferred Reporting Items for Systematic Review and Meta-Analysis guidelines. For this reason, a narrative review of the results, compared with published reviews and analyses of the global burden of chronic pain and disability (in HIC and combined LMIC/HIC populations), follows.

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RESULTS

Figure 2.

Figure 2.

Figure 3.

Figure 3.

Figure 4.

Figure 4.

The countries represented in the review are listed in Figure 2; 1 limitation is that there is a preponderance of data from Brazil, a middle-income country representing 33% of the publications found (N = 39). The most common types of metrics used to define chronic pain and its associations are listed in Figure 3; significant heterogeneity was the rule, with 51 different types of metrics reported. The number of publications that reported each relevant association is depicted in Figure 4.

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Female Gender

Figure 5.

Figure 5.

Fifty percent, or 60 total studies, commented on associations with chronic pain or psychological distress and female gender (Fig. 5). Forty studies specifically associated female gender with chronic pain in LMICs, consistent across all pain types. Women with pain also had a greater prevalence of “psychological disorder” and “psychosomatic disorders,” reported more unmet needs, and had a more negative self-rated health. Females had more fibromyalgia, widespread pain, and medically unexplained symptoms in every type of LMIC population including general populations, elderly, and workers (odds ratio [OR] 4–15) and were 2 to 3 times more likely to have pain at every location. Female patients had a greater prevalence of migraine and tension-type headache overall, although headache was the only surveyed pain location where male patients were reported to have equal or greater prevalence of nonmigraine headache than female patients in some high-education populations in Brazil.

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Age

Thirty-seven percent of reviewed articles (N = 44) report association of chronic pain or its associations with age; 34 studies specifically link increasing pain with age. In general, pain at any site appears to increase with age, with OR ranging from 1.54 to 16.7, increasing with each decade over age 50 years, and associated with lower health quality. Fibromyalgia is more prevalent in middle-aged populations, whereas widespread pain is reported to increase every decade over the age of 50 years. The association of headache and pelvic pain with age is less consistent.

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Mood

Forty-one percent of all literature reviewed (N = 49) mentioned associations of pain with mood. Some surveys used internationally standardized metrics to classify depression, anxiety, and posttraumatic stress disorder (PTSD); however, several others used terms such as “disturbed psychological profile,” “living under stress,” “psychosomatic problems,” and “psychological issues” to describe mood abnormalities. This highlights the difficulty in discussing, categorizing, or translating psychological illness across cultures. Still, both prevalence of pain and greater pain intensity were statistically associated with depression in 30% of reviewed literature in multiple LMICs (OR, 1.77–9.7). Every type of pain surveyed had an association with depression, with 20% to 36% of subjects with any pain reporting depressed mood. Likewise, in those with any pain, 14.1% to 17% reported anxiety; headache was the pain type most strongly associated with an anxious phenotype, with OR ranging from 2.3 to 7.02 in the 14% of articles commenting specifically on anxiety. The association of low back pain with all types of mood derangement was robust across surveyed LMIC populations. Fibromyalgia and widespread pain also were reported in association with depression, anxiety, and PTSD in multiple populations, and negative self-rated health was 3 times as likely to be associated with psychological stress and widespread musculoskeletal complaints. Similarly, those with widespread pain were significantly more likely to have a greater prevalence of mental illness.

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Disability

Forty-two percent of reviewed literature (N = 50) described associations of chronic pain with disability. Chronic pain in LMICs is predictably associated with poor self-rated health, increased dependence, unmet needs, and a ubiquitous reduction in general and occupational functionality, although the methods and instruments for reporting vary widely. Reduction in quality of life was widespread and statistically significant for every pain type throughout surveyed countries, and disability was generally described along a spectrum, reported as a percentage of subjects with “severe” disability, reported by 20.6% to 36% of respondents with various types of pain. Disruption in work often was described in terms of hours or days lost per variable units of time, with the inability to work or perform activities of daily living secondary to pain ranging from 3% of those with headache in Brazil to 78% of those with fibromyalgia in Indonesia.

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Other Associations

Insomnia was reported in association with pain in 17 studies, with rates ranging from 13.7% to 77% and ORs of 1.5 to 4.3. In the 7 articles that considered rural/urban status, significantly more pain was noted in rural populations, although medically unexplained symptoms in South Korea and pelvic pain in Malaysia were reported more commonly in urban dwellers. The association of low education with any type of chronic pain was consistent throughout 21 surveys, with the exception of tension headache, which was associated with greater levels of education in Brazil. Data about headache and income are conflicting, with 1 Brazilian study reporting high income as a risk factor for chronic daily headache, and another reporting low income as a risk factor for migraine. In general, however, low socioeconomic status was mentioned in 10 publications as a significant risk factor for chronic pain in LMICs.

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DISCUSSION

Definitive, statistically sound conclusions cannot be made about chronic pain without clear etiology and its associations in LMICs from this data extraction or narrative review, given the breadth and heterogeneity of the reviewed data; yet trends do emerge in LMICs that can be compared with existing literature from HICs and large surveys of global populations from all income levels.

Most importantly, because our data are limited to chronic pain conditions and associations in LMICs that do not have a clear reported etiology, the focus shifts for the first time to consideration of some chronic pain as its own disabling entity. In some cases, this may be a manifestation of an underlying CSS composed of chronic pain of unclear cause in multiple somatic sites and associated with female gender, mood disruption, and disability. Recognition of this possibility could result in an enhanced potential for accurate assessment and treatment opportunities in specific populations.

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Female Gender and Age

According to the most recent World Mental Health Surveys (WMHS), in 22 surveyed countries (12 of these being LMICs representing 51.7% of the evaluated worldwide population), 42.4% of LMIC populations have chronic pain. Greater chronic pain prevalence consistently occurs among female and older persons, but age-standardized prevalence rates of chronic pain conditions are reported to be even greater in LMICs.5 We confirm the common association of female gender and age with any type of pain in our review of LMICs.

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Mood

The WMHS also report anxiety and depression to be clearly associated with persistent pain globally (OR, 4.14). Our review of mood and pain associations supports this in LMICs. In fact, in surveyed subjects with depression, there was a statistically significant association with greater pain intensity and greater prevalence of chronic pain at any surveyed anatomic location in LMICs. Still, depression, and anxiety disorders generally are reported to be less prevalent in LMICs and may be underestimated secondary to known methodologic, societal, and semantic factors that limit accurate assessment in different cultures.5

It is important to note the reverse association is also true: The WMHS also report 12.1% to 14.8% of those with chronic pain have a “mental condition.” We found that, in those with chronic pain as the primary surveyed symptom, rates of depression ranged from 21.4% to 36.1% in LMICs, with 14% to 17% reporting associated anxiety. This is slightly greater than the WMHS and US data (where 18% of those with chronic pain report depression),6 perhaps reflecting a change in survey techniques or cultural awareness in LMICs in the intervening years.

Globally, chronic pain and disrupted mood frequently coexist: Published data on prevalent pain in the context of the global burden of disability analyses reveals that the presence of any condition, physical or mental, raised the likelihood of more: Respondents who reported 1 disorder had an average of 2.1 disorders, and 51% of those with >1 condition had >2 conditions.7 This is supported by a large study of urban primary care patients in 14 countries (6 LMICs). Of the 22% with persistent pain, 68% reported it in at least 2 sites, and 17.5% of the patients reporting persistent pain had pain in >4 anatomic sites.8 The probability of nonrecovery from pain was 49% at 12 months and was significantly associated with presence of 2 or more pain sites at baseline. Data from the United States report that the less defined the location of the pain disorder, the greater the rate of depression.6 Likewise, in our review, multiple surveys showed those with pain in multiple somatic sites also had a greater prevalence of depression, with the greatest rate of depression (41.6%) noted in fibromyalgia patients. This finding could suggest central sensitization of the common pain/mood pathways.

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Disability

Disability from any cause is costly in LMICs where functional workers are needed for economic viability. Globally, 37% of low back pain has been attributed to occupation, but many of the ergonomic/physical associations (heavy lifting/repetitive labor) are less predictive of pain in HICs after researchers controlled for pain at multiple sites, occupational stress, job dissatisfaction, litigation, perceived injustice, and other well-established predictive psychosocial determinants of poor occupational health.9,10 It is relevant to note that the multiple somatic sites, stress, low socioeconomic status, and low levels of social support well associated with disabling low back pain in HICs11 were associated with low back pain, as well as multiple other types of chronic pain, in our review of workers in LMICs as well. This highlights the need to consider this context when designing systems for evaluation and treatment of disabling chronic pain related to occupation at any somatic site.

Still, the prevalence of disability is reported to be twice as high in HICs compared with LMICs, but there are clearly cultural aspects to disability that may differ from HICs to LMICs. The role of cultural factors on rates of disability was assessed in a small cohort of clinic patients with low back pain in 4 French-speaking countries (3 of which were LMICs). As opposed to Gureje et al.,12 who found pain prevalence similar, but disability rates different, in primary care populations worldwide, Genêt et al.13 found that levels of disability related to activities of daily living were similar, but there were wide variations in reports of pain prevalence and the methods of coping. This is clearly an area that will require cultural-specific investigation when considering systems to address disability in low-resource areas.

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SUMMARY

“Proving” the existence of prevalent CSS is currently impossible to do with existing data in LMICs, but it is considerably confounded by the same semantics that also plague its recognition in HICs. For example, the Cultural and Psychosocial Influences on Disability study assayed workers in 11 LMICs and 7 HICs and found an overall prevalence of widespread pain (solely by querying anatomic site) of 29.5% in female and 27.9% in male patients. Extensive pain (>6 anatomical sites) was strongly associated with female gender, older age, somatization, and occupational distress. These associations held even when subjects did not meet the diagnostic criteria for fibromyalgia (19% of the sample), suggesting that widespread pain may be even more prevalent than previously thought and that the number of painful sites may be more representative of risk than their anatomic distribution.14

Furthermore, diagnostic differences may be because of differences in symptom recognition among patients and physicians in the same culture. For example, one study found that <15% of physicians (including specialists) in either Latin America or Europe considered headache, joint pain, heightened pain sensitivity, or difficulty concentrating as part of fibromyalgia, even though >50% of fibromyalgia patients experienced these symptoms.15 This also implies that patients seeking care for headache, joint pain, or depression may not be questioned with regard to other somatic sites or mood symptoms that might be present and indicative of CSS, and health care providers will fail to change the treatment approach from one of localized pain to one of generalized pain. This is critical to consider when designing chronic pain assessment strategies for risk stratification and rational chronic pain treatment strategies in LMICs in the future.

Further queries about chronic pain by health care providers must also consider differences in culture and semantics in reporting. One systematic review in 8 LMICs of women with somatoform disorders revealed the prevalence of somatoform disorders and depression/anxiety was highly variable among countries, but a strong association between somatoform disorders and depression/anxiety was consistent (OR, 2.5–3.5). Interestingly, the included narrative reviews and qualitative studies demonstrated that women in these LMICs attributed their somatic symptoms to social and economic problems while denying depression and anxiety as a cause.16 Similarly, a WMHS in war-torn Iraq postulates underreporting of psychiatric diagnoses such as PTSD and substance use disorders, given the stigma of mental illness, harsh punishment, and religious implications for forbidden substance use. However, chronic headache, insomnia, chronic pain, and arthritis all significantly associated with psychological trauma and dysfunction globally, were the 4 most commonly reported physical disorders in Iraq.17 This example highlights the need to interpret somatic conditions contextually before considering resources for further research and intervention.

There also are indications that the lack of clear categorization of CSS as its own entity may be confounding the accurate global burden of disability calculations, especially with regard to pain and mood. Globally, low back pain and headache are the most prevalent conditions in LMICs, but “neurologic disorders not otherwise defined,” bipolar disorder, and PTSD have the most disabling individual effects.18 Those with CSS very often have a history of psychological trauma, which is rarely queried but strongly affects the prevalence of subsequent pain and mood disorders.19,20 Migraine, for instance, has been strongly associated worldwide with both childhood abuse and intimate partner violence in adulthood.21 Because the World Health Organization reports 35.6% of women have been the victim of physical or sexual violence worldwide, including up to 45.6% of African women, these associations cannot be discounted20; this is especially true because women who have experienced gender-based violence have greater rates and severity of mental disorders, greater mental health–related dysfunction, greater general disability, impaired quality of life, and increased rates of somatoform disorders.19,22 The prevalence of these “somatoform disorders” in HICs has been reported to be as high as 21.5%, about half of the reported prevalence of all chronic pain in LMICs.23 Because rates of poverty, trauma, disaster, and violence associated with chronic pain may be greater in LMIC populations,24 future pain assessment must query these associations.

Perhaps the following is the most important reason to identify and further investigate CSS and its associations when considering the global burden of pain and disability: if it is unrecognized or treated like chronic single-site pain with known etiology, costs soar and health-related quality outcomes suffer. A cross-sectional analysis of 28,000 patients in 9 populations (1 LMIC) demonstrated that high total somatic symptom score (as occurs in CSS) predicts poor health status and greater health care cost.25 In HIC surgical settings, those who develop costly and disabling persistent postoperative pain had greater preoperative pain scores, multiple painful areas preoperatively, anxiety, greater fibromyalgia survey scores, and sensory testing showing widespread baseline hyperalgesia26,27; as surgical access grows in LMIC, it is critical to assess and treat both acute and chronic pain contextually to facilitate rational resource allocation.28 Both clinically and financially, it is vitally important to suspect CSS in every health care setting. It will most often manifest as pain without clear etiology in multiple sites associated with mood disorders and disability (especially in women, elderly, and workers); appropriate assessment is critical for prevention and mitigation of global disease and disability in any fiscally responsible health care system.

Countries struggling to ensure other basic human rights often do not allocate resources to address basic health care adequately, much less provide for acute or chronic pain management. Yet, it is important to note that access to pain management has long been considered a fundamental human right,29,30 solidified by the Declaration of Montreal, last updated in September 2015.31 For that right to become reality, the possibility of CSS and its clinical, demographic, and social associations must be appreciated as countries of any income begin to address the global burden of prevalent chronic pain.

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Recommendations/Editorial Notes

  1. More information is needed from LMICs in Central America, Africa, and Eastern Europe.
  2. Health care providers and policy makers in LMICs should ask about pain at every pain site when evaluating any pain site. Pain-assessment tools should be standardized and consistently applied for meaningful comparison.
  3. Globally, standardized nomenclature for discussing and evaluating chronic pain and CSS is needed. The key elements conferring global risk of morbidity related to chronic pain are presence of pain in multiple somatic sites and presence of psychologic trauma and mood disruption. All pain assessment tools used in LMICs in the future should specifically query these factors. Cultural differences may mandate variability in the assessment tools used for psychological variables.
  4. The evaluation of disabled people in LMIC, especially workers, should consider the presence of CSS, including evaluation and treatment underlying psychosocial variables, to ensure meaningful functional recovery.
  5. Resource allocation for nonpharmacologic treatment and/or social reform strategies for the underlying and related social, economic, and psychological stress contributing to CSS must be considered when developing chronic pain management strategies in LMICs.
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APPENDIX 1

Manuscripts Included in Narrative Review

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DISCLOSURES

Name: Tracy Jackson, MD.

Contribution: This author was involved with the concept, protocol design, search, data extraction, manuscript preparation, and editing of the manuscript.

Attestation: Tracy Jackson approved the final version of the manuscript.

Name: Sarah Thomas, BS.

Contribution: This author was involved with the search, data extraction, and table and figure creation of the manuscript.

Attestation: Sarah Thomas approved the final version of the manuscript.

Name: Victoria Stabile, BA.

Contribution: This author was involved with the background research and reference assimilation of the manuscript.

Attestation: Victoria Stabile approved the final version of the manuscript.

Name: Xue Han, MPH.

Contribution: This author was involved with the statistical protocols, analysis, and preparation of statistical sections of manuscript.

Attestation: Xue Han approved the final version of the manuscript.

Name: Matthew Shotwell, PhD.

Contribution: This author was involved with the statistical protocols, analysis, and preparation of statistical sections of manuscript.

Attestation: Matthew Shotwell approved the final version of the manuscript.

Name: K. A. Kelly McQueen, MD, MPH.

Contribution: This author was involved with the concept, mentoring, and editing of the manuscript.

Attestation: K. A. Kelly McQueen approved the final version of the manuscript.

This manuscript was handled by: Steven L. Shafer, MD.

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