Scholarly article on topic 'Risk Factors for Depression in Patients Undergoing Hematopoietic Cell Transplantation'

Risk Factors for Depression in Patients Undergoing Hematopoietic Cell Transplantation Academic research paper on "Clinical medicine"

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Abstract of research paper on Clinical medicine, author of scientific article — Samantha B. Artherholt, Fangxin Hong, Donna L. Berry, Jesse R. Fann

Abstract Despite the prevalence and known adverse impacts of depression after hematopoietic cell transplantation (HCT), little is known about the trajectory of depression occurring after HCT, or which pretransplantation risk factors might help predict new or worsening post-HCT depression. This secondary analysis evaluated the relationships between pre-HCT patient-reported outcomes and demographic characteristics and post-HCT depression. A total of 228 adult HCT patients were evaluated pre-HCT (T1) and again at 6 to 7 weeks post-HCT (T2), using touch-screen computers in the transplantation clinic during participation in a larger trial. Measures evaluated included the Symptom Distress Scale, the EORTC QLQ-C30 for quality of life, a single-item pain intensity question, and the Patient Health Questionnaire 9 for measurement of depression. At T1, rates of depression were quite low, with only 6% of participants reporting moderate or higher depression. At T2, however, the prevalence of moderate or higher depression was 31%. We observed a strong linear relationship in PHQ-9 scores between T1 and T2 (P < .0001). Depression score at T1 was a significant predictor of depression score at T2 (P = .03), as was poorer emotional function at T1 (P < .01). Our results indicate that post-HCT depression is common, even in patients with a low pre-HCT depression score. Frequent screening for symptoms of depression at critical time points, including 6 to 7 weeks post-HCT, are needed in this population, followed by referrals to supportive care as appropriate.

Academic research paper on topic "Risk Factors for Depression in Patients Undergoing Hematopoietic Cell Transplantation"

Biol Blood Marrow Transplant xxx (2014) 1—5

American Society for Blood and Marrow Transplantation

Risk Factors for Depression in Patients Undergoing Hematopoietic Cell Transplantation

Samantha B. Artherholt1,22, Fangxin Hong Donna L. Berry 5'6, Jesse R. Fann1,2,7,8,*

1 Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, Seattle, Washington

2 Seattle Cancer Care Alliance, Seattle, Washington

3 Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts

4 Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts

5 Department of Nursing and Patient Care Sevices, Dana-Farber Cancer Institute, Boston, Massachusetts

6 Department of Medicine, Harvard Medical School, Boston, Massachusetts

7 School of Public Health and Community Medicine, University of Washington, Seattle, Washington

8 Fred Hutchinson Cancer Research Center, Seattle, Washington

Article history:

Received 27 November 2013 Accepted 10 March 2014

Key Words:

Hematopoietic stem cell

transplantation

Depression

Hematopoietic cell

transplantation

Bone marrow transplantation

Quality of life

abstract

Despite the prevalence and known adverse impacts of depression after hematopoietic cell transplantation (HCT), little is known about the trajectory of depression occurring after HCT, or which pretransplantation risk factors might help predict new or worsening post-HCT depression. This secondary analysis evaluated the relationships between pre-HCT patient-reported outcomes and demographic characteristics and post-HCT depression. A total of 228 adult HCT patients were evaluated pre-HCT (T1) and again at 6 to 7 weeks post-HCT (T2), using touch-screen computers in the transplantation clinic during participation in a larger trial. Measures evaluated included the Symptom Distress Scale, the EORTC QLQ-C30 for quality of life, a single-item pain intensity question, and the Patient Health Questionnaire 9 for measurement of depression. At T1, rates of depression were quite low, with only 6% of participants reporting moderate or higher depression. At T2, however, the prevalence of moderate or higher depression was 31%. We observed a strong linear relationship in PHQ-9 scores between T1 and T2 (P < .0001). Depression score at T1 was a significant predictor of depression score at T2 (P = .03), as was poorer emotional function at T1 (P < .01). Our results indicate that post-HCT depression is common, even in patients with a low pre-HCT depression score. Frequent screening for symptoms of depression at critical time points, including 6 to 7 weeks post-HCT, are needed in this population, followed by referrals to supportive care as appropriate.

© 2014 American Society for Blood and Marrow Transplantation.

INTRODUCTION

Success rates for hematopoietic cell transplantation (HCT) have continued to improve as the procedure has been increasingly refined [1,2]. Despite this significant progress, HCT remains an extraordinarily stressful procedure physically, mentally, and emotionally [3,4]. One significant, and potentially limiting, symptom associated with HCT is depression. Depression is one of the most common psychiatric conditions occurring during and after cancer treatment. The estimated prevalence of depression across cancer patients ranges from 3% to >50%, depending on the timing and method used to measure the symptoms [5]. Studies have indicated that depression is prevalent in patients undergoing HCT, with an estimated one-quarter to one-third of HCT recipients experiencing depression during the first 100 days post-transplantation or during recovery from transplantation [3,6-9].

Depression has many potential negative psychosocial and physical consequences in HCT recipients. It can interfere

Financial disclosure: See Acknowledgments on page 4.

* Correspondence and reprint requests: Jesse R. Fann, MD, MPH, University of Washington, Box 356560, 1959 NE Pacific St, Seattle, WA 98195-6560.

E-mail address: fann@uw.edu (J.R. Fann).

significantly with quality of life; physical, social, and recreational activities; and overall health, and can be comorbid with other significant concerns, such as post-traumatic stress disorder and suicidal ideation in HCT survivors [3,10,11]. Depression also can interfere with cancer treatment adherence and is associated with negative health behaviors, such as tobacco and alcohol use [12,13]. Depression is well known to be associated with increased mortality in the general population [14-16], as well as in cancer patients [17]. Depression may be an independent risk factor for survival after HCT over and above its status as a potential indicator of poorer health status [7,18].

National accreditation bodies, including the National Comprehensive Cancer Network [19] and the Commission on Cancer [20], have mandated that distress screening be completed during treatment. For patients with clinical evidence of moderate or severe distress, the oncology team must "assess the psychological, behavioral, and social problems.that may interfere with their ability to participate fully in their health care and manage their illness and its consequences" [20]. Patients must then be referred for appropriate supportive care and creation of a follow-up plan. Thus, for HCT clinicians, early identification of depression is a critical element of comprehensive HCT care, along with appropriate referrals and interventions to address symptoms. Understanding the risk factors and clinical course of

1083-8791/$ — see front matter © 2014 American Society for Blood and Marrow Transplantation. http://dx.doi.org/10.1016/j.bbmt.2014.03.010

depressive symptoms after HCT will help inform with whom and at what time points screening should occur [11].

The time course of depressive symptoms may vary significantly among HCT recipients. In some, depression may occur before HCT and persist (or even worsen) throughout the course of treatment, whereas in others, depression may not appear until weeks or months after HCT, remaining a long-term concern for patients undergoing HCT. In one study of HCT survivors at 1 to 3 years post-transplantation, 15% reported moderate to severe depressive symptoms, with recipients of allogeneic HCT (versus recipients of autologous HCT) and those with poorer functional status reporting higher levels of depression [10]. Another long-term study of recovery post-HCT found that 19% of patients continued to experience depressive symptoms at 5 years post-HCT [6].

Despite the prevalence and known adverse impacts of depression after HCT, little is known about the trajectory of depression immediately after HCT, or which pretransplantation risk factors might help predict new or worsening depression post-HCT. We conducted the present analysis to evaluate the relationships between pre-HCT patient-reported outcomes and demographic characteristics and post-HCT depression. Variables of interest included symptom distress, quality of life, demographic data, and social roles (eg, vocational status, relationship status). The purpose of the analysis is to aid clinicians in identifying patients who might be at high risk for depression in the early post-HCT period, facilitating early detection and thus more effective intervention for those patients.

PATIENTS AND METHODS Sample

Research participants in the larger Electronic Self-Report Assessment-Cancer (ESRA-C) study [21], from which these data were collected, were recruited from the Seattle Cancer Care Alliance (SCCA), a consortium of the University of Washington Medical Center, Fred Hutchinson Cancer Research Center, and Seattle Children's Hospital. The SCCA cared for 3609 new patients in 2006, when these data were collected, the majority of whom (85%) were from Washington state. Eligibility criteria for the analytic sample included the following: new patients being evaluated for HCT, at least 18 years of age, able to communicate in English, and able to understand the study information and provide informed consent. Participants were included irrespective of the presence of diagnosis or treatment of psychiatric conditions, as long as they met the criteria for HCT. Between April 2005 and November 2006, a total of 228 eligible HCT patients were enrolled in the study.

Procedures

The methods and procedures of the ESRA-C study have been described in detail elsewhere [21]. In brief, baseline assessments (T1) were administered via touch-screen computer at a clinic visit before the start of HCT conditioning. At the first ambulatory visit post-HCT (at 6 to 7 weeks), patients were surveyed a second time (T2) using the same methodology. The technical aspects and navigability of the ESRA-C program have been described previously [22-24]. The ESRA-C has been well received by patients [21,25]. During the T1 session, patients were presented with an introductory screen, followed by demographic questions. They were then presented with 4 validated questionnaires during both the T1 and T2 survey sessions:

• Symptom Distress Scale (SDS) [26]. The 13-item SDS assesses the level of symptom distress for 11 symptoms, including nausea, appetite, insomnia, pain, fatigue, concentration, and others. Each item is scored on a scale of 1 to 5 with descriptive options. The SDS score is the sum of all item scores.

• The European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-C30, version 3 [27]. The EORTC QLQ-C30 is a questionnaire developed to assess the quality of life of cancer patients, including those undergoing HCT [28]. The QLQ-C30 incorporates 9 multi-item scales, including 5 functional scales (physical, role, cognitive, emotional and social), 3 symptom scales (fatigue, pain, nausea and vomiting), and a global health and

quality of life scale. Each subscale is a multi-item index that yields a score of 0 to 100, with higher scores indicating better function for the functional scales (eg, emotional function) and more symptoms for the symptom scales (eg, fatigue). Emotional function questions cover such symptoms as irritability, worry, tension, and depression.

• A single-item numerical pain intensity scale of 0 to 10, with 0 indicating no pain and 10 indicating the worst pain imaginable.

• The 9-item Patient Health Questionnaire (PHQ-9) depression scale [29]. The PHQ-9 has been validated for in-person self-report or interviewer administration, as well as for administration over the telephone [30-33]. Standard PHQ-9 depression scores were categorized as follows: none (<4), mild (5 to 9), moderate (10 to 14), moderately severe (15 to 19), and severe (>20). A score of 10 has been identified as the optimal cutoff for identifying probable major depressive disorder (sensitivity, 0.88; specificity, 0.88) in primary care patients [29]. For analysis, we classified patients into 2 groups, "no/mild" depression (PHQ-9 total score <10) and "moderate or higher" depression (PHQ-9 total score >10). To minimize patient burden, we used the presence of at least 1 cardinal symptom of depression on at least half of the days in the previous 2 weeks, either anhedonia or depressed mood, as a trigger for completing the remaining 7 items of the PHQ-9. Initial screening in this manner, known as the PHQ-2, has been validated in medical populations [34-36]. Participants who did not trigger the full PHQ-9 were classified as having "no/mild" depression. To provide additional data for distressed subjects, the full PHQ-9 was also triggered in the case of specific responses on the QLQ-C30 (score of <50 on a possible 100 for the Emotional Function or Cognitive Function subscale) or SDS (score of>3 on the response range of1 to 5 for the fear/worry, concentration, or sleep disturbance items).

Analysis

Baseline patient socioeconomic factors and quality of life measures were compared between dropouts and those completing the study using the t-test for continuous variables (age) or the Fisher exact/chi-square test for categorical variables. A generalized McNemar test was used to check for potential pattern changes in depression between T1 and T2. Logistic regression was used to predict moderate or higher depression at T2, with a list of preselected baseline variables, including minority (or not), income, education, working status, computer use, partnered (or not), transplant type, and baseline measures on the QLQ-C30, SDS, pain intensity scale, and the PHQ-9. The factors were first checked individually, adjusting for T1 depression status, and then factors with a P value <.20 were included in the multivariable model. Backward model selection was used for variable selection, and all variables with a P value <.10 were retained in the final model. Odds ratios and 2-sided P values were calculated. Analyses were performed with SAS version 9.2 (SAS Institute, Cary, NC) and R version 2.15.0 (R Institute for Statistical Computing, Vienna, Austria).

RESULTS

A total of 228 HCT recipients were enrolled in the study. Thirty-six of the participants did not complete the assessment at both time points, with attrition due mainly to death or illness; thus, the final analytic sample comprised 192 participants. There were no significant differences in demographic characteristics between study completers and noncompleters, although there were trends toward older age (P = .06) and lower likelihood of working at T1 (P = .07) in noncompleters compared with completers. However, non-completers did have significantly lower global quality of life scores (subscale of the QLQ-C30) at T1 compared with completers (P = .04).

Demographic and clinical characteristics of the 192 study participants are shown in Table 1. The sample was 59% male, and the majority were married, had 2 or more years of college education, and used computers at home and/or work. Participants were predominately Caucasian and non-Hispanic/Latino (91%). The majority of participants (59%) were working, on medical leave, or in school.

Changes in PHQ-9 depression categories from T1 to T2 are presented in Table 2. At T1, rates of depression were low, with only 11 participants (6%) reporting moderate or higher

Table 1

Baseline Demographic Data and Clinical Characteristics (n = 192)

Variable Value

Age, yr, median (range) 51(19-75)

Male sex, n (%) 114(59)

Minority race/ethnicity, n (%)* 17(9)

Married or partnered, n (%) 139(72)

College education or more, n (%) 147 (77)

Annual income >$55,000, n (%) 103(54)

Working at T1, n (%)y 114(59)

Computer user, n (%)* 177 (92)

Cancer diagnosis, n (%)

Leukemias 92 (48)

Lymphomas 59 (31)

Myelomas 38 (20)

Other 3 (2)

Transplant type, n (%)

Autologous 76 (40)

Allogeneic 116(60)

* Defined as non-Caucasian race and/or Hispanic/Latino ethnicity, by self-report.

y Defined as working full-time, part-time, on full or partial medical leave, or student. "Not working" is defined as being unemployed or fully retired.

* Uses a computer sometimes or often at home or work.

depression. This number increased to 60 (31%) at T2, however. This difference in the percentage of participants experiencing moderate or higher depression between T2 and T1 was significant (P < .001, generalized McNemar test).

We found a strong linear relationship in PHQ-9 category scores between T1 and T2 (P < .0001). Results of univariate analyses are shown in Table 3. Adjusting for T1 depression status, depression at T2 was associated with poorer emotional function (P < .01) and greater symptom distress (P = .02) at T1. Transplant type (autologous versus alloge-neic) was not a significant predictor of elevated depression at T2. The prevalence of moderate or higher depression was 7% (8 of 116) at T1 and 34% (40 of 116) at T2 in the allo-geneic HCT recipients, and 4% (3 of 76) at T1 and 26% (20 of 76) at T2 in the autologous HCT recipients. These differences were not statistically significant (P = .53 at T1, P = .27 at T2).

The results of multivariate analyses are shown in Table 4. In multivariate analysis, T1 depression score remained a significant predictor of depression scores at T2 (P = .03), as did poorer emotional function at T1 (P < .01); however, elevated symptom distress was no longer significant (P =.18) in predicting elevated depression at T2. T1 working status trended toward significance (P = .07), such that those who were working at T1 (even if on medical leave during their treatment) had higher rates of depression at T2. All possible 2-way interactions in the multivariate model were tested, and none were found to be significant.

Table 2

Change in PHQ-9 Depression Scores from T1 to T2

T2 Total

No/mild Moderate or higher

T1 No/mild Moderate or higher Total 131 (68.2%) 1 (0.5%) 132 (68.7%) 50 (26.1%) 10 (5.2%) 60 (31.3%) 181 (94.3%) 11 (5.7%) 192 (100%)

PHQ-9 indicates 9-item Patient Health Questionnaire; T1, pre-HCT. The number of participants (with percentage of total number) meeting criteria for no/mild and moderate or higher depression categories, based on PHQ-9 scores, is listed at each time point. Categories: no/mild depression, PHQ-9 score <10; moderate or higher depression, PHQ-9 score >10.

Table 3

Univariate Logistic Regression Predicting Moderate or Higher Depression (PHQ-9 Score >10) at T2, Adjusting for Depression Status at Baseline

T1 Predictor ß Odds Ratio P Value

Male sex -0.12 0.89 .73

Minority race/ethnicity* -0.97 0.38 .18

Working at T1y 0.54 1.72 .12

College education or more 0.58 1.78 .18

Married or partnered 0.53 1.69 .19

Annual income >$55,000 0.17 1.18 .63

Computer user* 0.01 1.01 .98

Global quality of life, EORTC QLQ-C30 -0.01 0.99 .15

Physical function, EORTC QLQ-C30 -0.01 0.99 .43

Role function, EORTC QLQ-C30) 0 1 .56

Emotional function, EORTC QLQ-C30 -0.04 0.96 <.01

Cognitive function, EORTC QLQ-C30 0 1 .66

Social function, EORTC QLQ-C30 0 1 .45

Fatigue, SDS 0.01 1.01 .15

Nausea/vomiting, SDS 0 1 .96

Pain, SDS 0 1 .94

Total symptom distress, SDS 0.08 1.08 .02

Allogenieic transplant 0.33 1.39 .33

Impact on sexual activities and interest 0.11 1.12 .32

Fever/chills -0.06 0.94 .89

PHQ-9 indicates 9-item Patient Health Questionnaire; T1, pre-HCT; EORTC European Organization for Research and Treatment of Cancer; SDS, Symp-ton Distress Scale.

Depression status at T1 is significantly associated with that at T2 (P < .0001). Significant predictors are in bold type.

* Defined as non-Caucasian race and/or Hispanic/Latino ethnicity, by self-report.

y Defined as working full-time, part-time, on full or partial medical leave, or student. "Not working" is defined as being unemployed or retired at T1.

* Uses a computer at least sometimes at home or work.

DISCUSSION

This exploratory investigation adds to the growing body of literature indicating that depression is common after HCT, and provides information to help identify patients at risk for post-HCT depression. Although few patients (6%) met the criteria for moderate or higher depression before HCT, nearly one-third (31%) met the criteria for moderate or higher depression when assessed at 6 to 7 weeks post-HCT. Many participants who had elevated depression scores at T2 were not depressed at T1, indicating that even if a patient seems to be doing well emotionally before HCT, he or she may be at significant risk for post-HCT depression.

At our center, as at many others, all HCT recipients receive a comprehensive social work evaluation before undergoing transplantation. Several factors put patients at elevated risk for post-HCT depression, and these factors should help clinicians identify patients who merit closer monitoring as they proceed through the transplantation process. Not surprisingly, depression scores at T1 were strongly associated with

Table 4

Multivariate Logistic Regression Predicting Moderate or Higher Depression (PHQ-9 Score >10) at T2, Adjusting for Depression Status at Baseline

T1 Predictor ß Odds Ratio P Value

Moderate or higher depression 2.44 11.49 .03

(PHQ-9 score >10)

Working at Tl* 0.65 1.92 .07

Emotional function, EORTC QLQ-C30 -0.034 0.96 <.01

PHQ-9 indicates 9-item Patient Health Questionnaire; T1, pre-HCT; EORTC, European Organization for Research and Treatment of Cancer. Bold text indicates significant predictors; predictors trending toward significance are in italics.

* Defined as working full-time, working part-time, on full or partial medical leave, or student. "Not working" is defined as being unemployed or fully retired at T1.

those at T2. Thus, patients who enter the HCT process with symptoms of depression should be monitored closely for worsening symptoms post-HCT. Another risk factor for elevated depression at T2 was lower self-reported emotional function, a subscale of the EORTC QLQ-C30, at T1. This effect was significant even after controlling for depression scores at T1, indicating the need for clinicians to attend not only to symptoms of depression per se, but also to other broad indicators of emotional distress before HCT, such as anxiety, tension, and irritability. Others also have identified pre-transplantation distress (usually defined as anxiety or depression) as the strongest predictor of post-HCT anxiety or depression [6,37].

The overall pretransplantation symptom burden was another predictor of post-transplantation difficulties with depression. Elevated SDS scores were predictive of high depression post-HCT in our univariate analysis (controlling for baseline depression), underscoring the importance of helping patients cope with their myriad symptoms before undergoing HCT and of rescreening patients with high baseline symptom burden for depression at 1 to 2 months post-HCT. The impact of symptom distress at T1 was not significant when analyzed in a multivariate model, however, possibly indicating that emotional distress (which may result in part from symptom burden) is a stronger factor predicting future depression.

An interesting, albeit nonsignificant, trend noted was that participants with a vocational status that implied continuing responsibility for this role (including those who were working full time or part time, on full- or part-time leave, or in school) at T1 had higher depression at T2. One potential explanation for this trend is that being employed or in school carries with it a set of expectations and stress that continues into HCT, even if the patient is on leave. It is possible that the added stress of these vocational demands contributes to depression after HCT. Indeed, a recent study of a non-HCT cancer sample found that work-related stress is common during cancer treatment, even in patients on medical leave [38]. Patients who are working or in school in some capacity during the HCT process may require additional support and strategies for managing vocational demands and stress in the context of diminished medical and psychosocial reserves. This issue merits exploration in future studies.

Strengths of this study include the use of reliable and validated self-reporting instruments at 2 time points in a well-established HCT program. Thus, we were able to identify several pretransplantation predictors associated with depression at T2. Nonetheless, the relative weakness of the associations that we found suggests that other predisposing and precipitating factors may contribute to depression post-HCT. The time course of depression symptoms from T1 to T2 likely reflects the uniqueness of HCT compared with other cancer treatments. Given the eligibility criteria for transplantation, it is possible that HCT recipients report that they are more optimistic and hopeful at baseline (ie, before transplantation) than other patients starting cancer treatment, who are often extremely distressed after receiving their diagnosis and before starting their initial treatments [8]. In addition, our T2 assessment was done at 6 to 7 weeks post-HCT, the time when most patients are discharged from the hospital and have had several weeks to recover from deconditioning and other lingering acute symptoms, thereby minimizing the direct effects of acute hospitalization on depressive symptoms. In many cases, however, adverse

physical symptoms are still present at 6 to 7 weeks post-HCT, and these symptoms might have affected self-reports of mood. Future studies should examine the course and longitudinal predictors of depression at additional post-HCT time points. In our analysis, transplant type (allogeneic versus autologous) was not predictive of post-HCT depression, but this variable warrants more thorough evaluation in future studies, given that these 2 groups of HCT recipients can have significantly different post-transplantation medical courses.

An additional strength of this study is the electronic collection of data via touch-screen computers. The majority of our participants were familiar with computers. Previous studies have shown that measurement of depression and symptom distress with touch screen computers is feasible and reliable [8]. Moreover, computer-administered symptom screens are clinically useful, readily providing real-time scores and symptom information to clinicians, who can then discuss it with patients in a timely manner [21]. Our data were collected only via computer, however, and our findings should be replicated in populations less well-acquainted with this modality.

The participants in this study were relatively well-educated and affluent, and predominantly Caucasian and non-Hispanic/Latino. It is possible that samples of more diverse groups might have differing rates of, and risk factors for, post-HCT depression. Future studies should address these concerns. Finally, there are broad knowledge gaps in terms of the effectiveness of brief interventions to address depression and enhance coping that can be implemented in the HCT setting.

Organizations such as the American College of Surgeons Commission on Cancer [20] mandate screening for distress (including depression, anxiety, and other psychosocial difficulties) at least once for all patients treated at participating cancer centers. However, our findings suggest that screening for distress just once pretransplantation may be insufficient, and that 6 to 7 weeks post-HCT may be an important assessment point. This study and others have demonstrated that depression screening is feasible and accepted by both patients and medical providers in a busy HCT clinic setting [8,11]. Our findings underscore the importance of assessing emotional distress in HCT clinics at multiple time points during the course of treatment. Periodic depression screening at pivotal points along the trajectory of treatment and recovery provides opportunities for earlier referral and intervention for those patients who are either already experiencing depressive symptoms or at risk for developing depression. Proactive efforts to manage depression in HCT recipients may improve their overall recovery and posttransplantation quality of life.

ACKNOWLEDGMENTS

The authors thank Barbara Halpenny, project director, and Rosemary Ford, transplant clinic nurse manager, for their assistance with this project.

Financial disclosure: This work was funded by the National Institute of Nursing Research (Grant R01 NR008726).

Conflict of interest statement: There are no conflicts of interest to report.

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