Patient Personality and Illness Perceptions in Relation to Follow-Up Appointment Adherence in Neuro-Ophthalmology

Background: Improving patient attendance at medical follow-up visits may have a notable impact on disease and overall health outcomes. Understanding factors contributing to poor attendance is important for identifying at-risk patients and designing interventions to improve clinical outcomes. Our objective was to identify personality and illness perception factors associated with attendance at recommended follow-up visits in a neuro-ophthalmology practice. Methods: New or established patients (≥18 years) with scheduled neuro-ophthalmology (study) or glaucoma (comparison) appointments at a tertiary care academic medical center completed the Brief Illness Perception Questionnaire and Ten-Item Personality Inventory. Physician recommendations made during the visit were recorded (medications, referrals, follow-up, testing, and procedures). A chart review was performed 18 months after enrollment to assess attendance at follow-up appointment and adherence with other physician recommendations. Multiple variable logistic regression models studied associations between follow-up appointment attendance and demographic factors, appointment factors, and survey responses. Results: Among 152 respondents (97% response rate (152 of 157), aged 19-97 years, 58% female, 34% new, 80 neuro-ophthalmology, 72 glaucoma), neuro-ophthalmology subjects were younger, more likely to be White, non-Hispanic, female and new to the practice than subjects with glaucoma. They reported higher emotional impact, identity, and consequences related to their illness (P = 0.001-0.03). Neuro-ophthalmology physician recommendations included more referrals to other services (17.5% vs 1.4%, P = 0.001, chi-square) and more radiology studies (15% vs 0%, P = 0.001, chi-square), but fewer follow-up visits (75% vs 97%, P < 0.0005, chi-square). Among those with recommended follow-up visits, neuro-ophthalmology subjects had lower rates of on-time appointment attendance (55% vs 77%, P = 0.009, chi-square). In a multiple variable model, on-time follow-up attendance was associated with shorter recommended follow-up interval (≤90 days, P < 0.0005), established (vs new) patient status at enrollment visit (P = 0.04), and glaucoma (P = 0.08), but not subject demographics, illness perception, or personality factors. Conclusions: Patient demographics, illness perception, and personality traits were not associated with follow-up appointment attendance and therefore unlikely to be useful for identifying patients at risk of being lost to follow-up. New neuro-ophthalmology patients with a follow-up recommended ≥90 days in advance may benefit from targeted interventions to improve follow-up appointment adherence.

Original Contribution Section Editors: Clare Fraser, MD Susan Mollan, MD Patient Personality and Illness Perceptions in Relation to Follow-Up Appointment Adherence in NeuroOphthalmology Rem Aziz, BSc, Megha P. Bindiganavale, BSc, Robert T. Chang, MD, Heather E. Moss, MD, PhD Background: Improving patient attendance at medical follow-up visits may have a notable impact on disease and overall health outcomes. Understanding factors contributing to poor attendance is important for identifying at-risk patients and designing interventions to improve clinical outcomes. Our objective was to identify personality and illness perception factors associated with attendance at recommended follow-up visits in a neuro-ophthalmology practice. Methods: New or established patients ($18 years) with scheduled neuro-ophthalmology (study) or glaucoma (comparison) appointments at a tertiary care academic medical center completed the Brief Illness Perception Questionnaire and Ten-Item Personality Inventory. Physician recommendations made during the visit were recorded (medications, referrals, follow-up, testing, and procedures). A chart review was performed 18 months after enrollment to assess attendance at follow-up appointment and adherence with other physician recommendations. Multiple variable logistic regression models studied associations between follow-up appointment attendance and demographic factors, appointment factors, and survey responses. Results: Among 152 respondents (97% response rate (152 of 157), aged 19–97 years, 58% female, 34% new, 80 neuro-ophthalmology, 72 glaucoma), neuro-ophthalmology subjects were younger, more likely to be White, nonHispanic, female and new to the practice than subjects with glaucoma. They reported higher emotional impact, identity, and consequences related to their illness (P = 0.001–0.03). Neuro-ophthalmology physician recommendations included more referrals to other services (17.5% vs Faculty of Medicine, University of British Columbia (RZ), Vancouver, Canada; R. Aziz is Previously Department of Ophthalmology, Stanford University, Palo Alto, Ca; Department of Ophthalmology (MPB, RTC), Stanford University, Palo Alto, California; and Departments of Ophthalmology and Neurology and Neurological Sciences (HEM), Stanford University, Palo Alto, California. Supported by NIH P30 026877 and Research to Prevent Blindness unrestricted grant to the Stanford Department of Ophthalmology. The authors report no conflicts of interest. Address correspondence to Heather E. Moss, MD, PhD, Spencer Center for Vision Research at Stanford, 2370 Watson Court, Suite 200, MC 5353, Palo Alto, CA 94303; E-mail: [e-mail] 180 1.4%, P = 0.001, chi-square) and more radiology studies (15% vs 0%, P = 0.001, chi-square), but fewer follow-up visits (75% vs 97%, P , 0.0005, chi-square). Among those with recommended follow-up visits, neuroophthalmology subjects had lower rates of on-time appointment attendance (55% vs 77%, P = 0.009, chisquare). In a multiple variable model, on-time follow-up attendance was associated with shorter recommended follow-up interval (#90 days, P , 0.0005), established (vs new) patient status at enrollment visit (P = 0.04), and glaucoma (P = 0.08), but not subject demographics, illness perception, or personality factors. Conclusions: Patient demographics, illness perception, and personality traits were not associated with follow-up appointment attendance and therefore unlikely to be useful for identifying patients at risk of being lost to follow-up. New neuro-ophthalmology patients with a follow-up recommended $90 days in advance may benefit from targeted interventions to improve follow-up appointment adherence. Journal of Neuro-Ophthalmology 2022;42:180–186 doi: 10.1097/WNO.0000000000001533 © 2022 by North American Neuro-Ophthalmology Society A dherence to medical recommendations (medications, follow-up, and testing) is a cornerstone of successful management known to improve health outcomes and quality of life. However, the average rate of adherence to physician recommendations in developed countries hovers around 50% (1). Effective adherence strategies may have a greater impact on patient health than improvements in medical treatment (2). Developing effective intervention strategies necessitates an understanding of patient-centered factors that influence adherence. Previous literature has demonstrated that personality traits and patient beliefs are associated with glaucoma treatment adherence (3,4) and that those with greater concern for their glaucoma had increased acceptance of novel treatment methods (5). Outside of ophthalmology, studies of patients with chronic Aziz et al: J Neuro-Ophthalmol 2022; 42: 180-186 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution disease have shown that patient beliefs had more influence on medication adherence than clinical factors (6). The primary objective of this study was to identify factors associated with patient attendance at follow-up appointments in a neuro-ophthalmology clinic. Characterizing adherence with other physician recommendations (ancillary testing, medications, etc.) was a secondary objective. METHODS Study Design and Subject Recruitment This was a prospective study of adult patients with neuroophthalmology and glaucoma appointments at an academic tertiary center (Byers Eye Institute, Stanford University). Patients with glaucoma serve as a within-practice comparison as ophthalmic subspecialty patients with an important medical management component. Inclusion criteria were English-speaking adults ($18 years) with scheduled outpatient appointments at the neuro-ophthalmology or glaucoma clinics. Sampling was performed sequentially in the neuro-ophthalmology practice of 1 provider (H.E.M.). Convenience sampling was performed in the glaucoma practice of 1 provider (R.T.C.). Enrollment occurred over a 1-month period from May to June 2019. Study approval was granted from the Stanford University Research Compliance Office. Subjects provided informed consent before enrollment. Subjects were recruited during their clinic visit to complete a brief survey. Demographic information, appointment parameters, physician-recommended followup timing, and other recommendations made during the visit were recorded. Eighteen months after enrollment, medical records were reviewed to assess attendance at the recommended follow-up appointment and patient adherence to other recommendations. Each component is described below in detail. Survey Selection and Administration Two brief questionnaires were selected to capture illness perceptions and personality traits, which have previously been shown to relate to patient adherence (3,4,7,8). Brief surveys were favored because they offer practical multidimensional analysis of large constructs by eliminating item redundancy and reducing testing duration, survey fatigue, and participant frustration with repeat questions (9). Subjects completed the self-administered survey through web interface (Qualtrics) using a tablet device. A survey administrator remained available to provide reading assistance to those with visual impairment. Illness Perception Dimensions The Brief Illness Perception Questionnaire (Brief IPQ) is a validated reliable tool designed to assess cognitive and emotional aspects of illness (10). It has been published in Aziz et al: J Neuro-Ophthalmol 2022; 42: 180-186 multiple languages with good psychometric properties and applied widely across various clinical applications and disease populations (11). Relevant to this study, it has been used in glaucoma to evaluate illness perceptions as they relate to intentional and unintentional adherence behavior, difference in medication compliance across different cultures, and acceptance of novel drug delivery methods (4,5,7). The Brief IPQ consists of 8 questions, each corresponding to an illness perception dimension: perceived illness outcomes (consequence), chronicity of condition (timeline), self-control (personal control), treatment efficacy (treatment control), severity of symptoms (identity), degree of illness concern (concern), understanding of the condition (coherence), and associated emotional burden (emotional impact). Questions are scored 0–10 (low to high). Personal control, treatment control, and coherence scores were reversed to reflect lack thereof such that a higher score corresponds to a more negative perception for all dimensions. Personality Domains The Ten-Item Personality Inventory (TIPI) is a validated adaptation of the Five-Factor Personality Model developed by Costa and McCrae to measure the “Big Five” personality domains (Extraversion, Agreeableness, Conscientiousness, Emotional Stability, and Openness to Experience) (9). Relevant to this study, it has been used to assess the relationship between personality traits and adherence behavior in glaucoma and to determine predominant personality types of at-risk individuals with visual disability in need of family-centered counseling and social support (3,8). Questions are rated on a 7-point Likert scale (1 = “disagree strongly” and 7 = “agree strongly”). The score for each personality domain is calculated as an average of the 2 questions corresponding to it. Enrollment Visit Data Age, sex, race, ethnicity, zip code, number of medications, health insurance, and appointment status (new/established) were extracted from the medical record. Distance traveled was calculated using Google Maps to measure shortest driving distance from the subject’s zip code to the clinic. Number of medications served as a proxy for health condition. Insurance was classified as Medicare, commercial, other government (Veterans Affairs or Medicaid), or none. Number of persons accompanying the subject at enrollment visit was noted as a proxy for available support. Physician recommendations made during the enrollment visit were recorded based on documentation in medical records. This included follow-up with enrollment visit provider (time frame noted in days), medications (new/ continuing prescription), diagnostic testing, procedures, and referral to different specialties. Diagnostic testing recommendations were subcategorized as eye testing (visual fields, ophthalmic imaging, and electrophysiology), radiology testing (computed tomography and magnetic resonance imaging), and laboratory testing (blood testing). 181 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution Assessment of Adherence to Physician Recommendations Adherence with physician recommendations was assessed 18 months after enrollment visit through thorough examination of the medical record. Adherence with follow-up appointments was assessed based on the availability of a clinic note within double the time frame of recommended follow-up indicating patient attendance. In cases where a range was recommended, the midpoint was used as the reference time. Follow-up beyond this time was considered delayed. Medication adherence was assessed based on documentation at subsequent visits with the same provider. Adherence to procedures, referrals, radiology, and laboratory testing were assessed based on the availability of a report or result dated after the enrollment visit or documentation of completion in the provider’s note. Data Analysis Distribution of baseline data (demographics, appointment data, recommendations, illness perception, and personality traits) was compared between neuro-ophthalmology subjects and subjects with glaucoma, using the t test for normally distributed continuous data, Mann–Whitney for nonnormally distributed continuous data, and chi-square for categorical data. Adherence to physician recommendations was compared between subject groups using a similar strategy. Attendance at follow-up appointment was further analyzed using multiple variable analysis to assess associations between factors and attendance. For the purposes of inclusion in multiple variable analysis, categorical variables with small cell sizes were collapsed. Skewed variables were recoded as categorical. Those variables with P , 0.1 in unadjusted analysis were included in a multiple variable logistic regression model of compliance. The final model was chosen using a backward selection technique with a threshold of P , 0.1 for inclusion in the final model. Statistical significance was set at P , 0.05. Statistical analysis was performed using SPSS 26 (IBM Inc). RESULTS Demographic Data One hundred fifty-seven subjects were approached, of whom 152 (97%) agreed to participate in the study. Subjects were divided according to subspecialty clinic in which they had their enrollment visit: neuro-ophthalmology (n = 80) and glaucoma (n = 72) (Table 1). Survey Results On the Brief IPQ, neuro-ophthalmology subjects scored higher in perceived illness outcomes (consequence) (P = 182 0.03), severity of symptoms (identity) (P = 0.001), and degree of emotional burden (emotional impact) (P = 0.013) while subjects with glaucoma scored higher in perceived chronicity (timeline) (P = 0.04), lack of treatment efficacy (lack of treatment control) (P = 0.001), and lack of understanding (lack of coherence) (P , 0.0005). Subject groups did not differ in perceived lack of personal control or degree of illness concern. On the TIPI questionnaire, neuro-ophthalmology subjects tended to score lower in the emotional stability domain (4.71 vs 5.16, P = 0.03, t test), however, had a similar rating to glaucoma for all other TIPI traits (Fig. 1). Adherence to Physician Recommendations Eighteen months after their enrollment visit, neuroophthalmology subjects were less likely to have attended follow-up appointments than glaucoma (55.0% vs 76.8%, P = 0.009) (Table 2). Of those with a recommended followup visit (n = 130), 86 completed follow-up on time, 16 were delayed more than twice the recommended follow-up interval, 27 did not complete follow-up within 18 months, and 1 moved. Recommended follow-up intervals ranged from 7 to 365 days (median 90 days). Across both specialties, subjects who followed up on time were of similar age (P = 0.88, t test) and sex (P = 0.32, chi-square) to those who did not. Subjects of Asian race were more likely to follow up on time (83.7% vs 50.9% White non-Hispanic, vs 71.4% Other, P = 0.002, chi-square). Rates of follow-up were similar across insurance categories (P = 0.62, chi-square) and did not differ according to residential distance from clinic (P = 0.17, Mann–Whitney) or number of medications at enrollment visit (P = 0.38, Mann–Whitney). Subjects who were established patients at enrollment were more likely to follow up on time (71.4% vs 55.3%, P = 0.08, chi-square), regardless of whether they were accompanied (P = 0.31, chi-square). Shorter follow-up intervals were associated with on-time follow-up (median 90 days vs 120 days, P , 0.0005, Mann–Whitney). None of the personality domains were associated with on-time follow-up. Of the studied illness perception dimensions, on-time follow-up was associated with lower treatment control scores, corresponding to a lower confidence in treatment (P = 0.06, t test), and lower coherence scores, corresponding to a worse understanding of disease (P = 0.06, t test). In a multiple variable logistic model considering variables associated with on-time follow-up in unadjusted analysis and using backward selection retaining variables with P , 0.1, the final model contained a recommended follow-up of #90 days (P , 0.0005), established status at enrollment visit (P = 0.04), and glaucoma appointment (P = 0.08) as factors associated with on-time follow-up. With regards to other physician recommendations, neuro-ophthalmology patients were less likely to have completed recommended ophthalmic testing (63.9% vs Aziz et al: J Neuro-Ophthalmol 2022; 42: 180-186 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution TABLE 1. Baseline comparison of neuro-ophthalmology subjects and subjects with glaucoma Subject Demographics Age in yrs (range) Mean (SD) Sex: female Race/ethnicity White non-Hispanic White Hispanic Asian Black Other Missing Distance traveled, median (range) No. of medications, median (range) Insurance Medicare Private Other (VA, Medicaid) None Appointment type: new Accompanied by $1 companion Recommendation Follow-up visit Medication Referral Laboratory tests Ophthalmic tests Radiology studies Procedures Neuro-Ophthalmology (n = 80) Glaucoma (n = 72) 19–91 52.0 (19.4) 52 (65.0%) 25–97 62.5 (13.5) 36 (50.0%) 53 (66.3%) 9 (11.3%) 11 (13.8%) 1 (1.3%) 4 (5.0%) 2 (2.5%) 21.8 (1–743 min) 7 (0–27) 16 (22.2%) 6 (8.3%) 36 (50.0%) 0 (0.0%) 12 (16.7%) 2 (2.8%) 16.4 (3–122 min) 7 (0–23) P ,0.0005* 0.06† ,0.0005† 0.02‡ 0.78‡ 0.017† 21 45 13 1 42 40 (26.3%) (56.3%) (17.5%) (1.3%) (52.5%) (50.0%) 36 30 6 0 10 21 (50.0%) (41.7%) (8.3%) (0.0%) (13.9%) (29.2%) ,0.0005† 0.009† 60 19 14 3 36 12 0 (75.0%) (23.8%) (17.5%) (3.8%) (45.0%) (15.0%) (0.0%) 70 58 1 0 24 0 11 (97.2%) (80.6%) (1.4%) (0.0%) (33.3%) (0.0%) (15.3%) ,0.0005† ,0.0005† 0.001† 0.097† 0.245† 0.001† ,0.0005† Neuro-ophthalmology subjects tended to be younger, female, and of White non-Hispanic origin compared with subjects with glaucoma. They traveled longer distances to attend appointments and were more likely to be new to clinic. They tended to have less follow-up appointment recommendations, prescribed medications, and procedures performed, but more referrals and radiology studies recommended. *t test. † Chi-square. ‡ Mann–Whitney. 91.7%, P = 0.015) compared with subjects with glaucoma, although they had better medication adherence. There was no significant difference between groups regarding referral completion (Table 2). Sample sizes and distributions precluded study of association with demographic, personality, and illness perception factors. CONCLUSIONS Poor follow-up has been identified as major concern in chronic eye conditions, leading to vision loss (12). Understanding of psychosocial factors associated with attendance at neuro-ophthalmology physician–recommended followup is important for identifying patients at risk of poor adherence and designing interventions to improve outcomes. Toward this end, our study compared patients in neuro-ophthalmology and glaucoma clinics at a tertiary care academic medical center in the United States to understand differences in these patient populations, characterize adherence with physician-recommended follow-up, and identify Aziz et al: J Neuro-Ophthalmol 2022; 42: 180-186 features that may predict those at risk of nonadherence as a basis for targeted intervention. Neuro-ophthalmology subjects had both fewer follow-up appointment recommendations and lower attendance rates than subjects with glaucoma. This may reflect the tendency of neuro-ophthalmology to be a consultative practice with a wide catchment area, necessitating lengthy travel for many patients. By contrast, longitudinal progression of glaucoma drives the need for regular follow-up for chronic disease management. Although illness perception factors (lack of treatment control and coherence) were associated with follow-up completion in unadjusted analysis, these did not reach statistical significance in the multiple variable model. Factors associated with poor attendance at follow-up visit in multiple variable models were neuro-ophthalmology appointment, longer duration of follow-up interval, and being new to clinic at enrollment visit. Neuroophthalmology appointment may point to inherent differences in practice which are discussed in more detail below. Longer follow-up intervals may indicate challenges with 183 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution FIG. 1. Illness perception and personality traits in neuroophthalmology subjects and subjects with glaucoma. Scores for the Brief Illness Perception Questionnaire (Brief IPQ) domains (top). Scores for the Ten-Item Personality Inventory (TIPI) personality traits (bottom). Hashed marker is average for subjects with glaucoma. Solid marker is average for neuro-ophthalmology subjects. P-values are compared for neuro-ophthalmology subjects and subjects with glaucoma in each domain (t test). scheduling, remembering, and possibly less severe disease. New patient status points to lack of established relationship with clinic and not having previously demonstrated followup compliance. Repercussions of appointment nonattendance extend beyond disease outcomes—they strain patient–provider relationships, reduce access to care for others, and contribute to the rising costs of health care (13,14)—making it therefore imperative to establish reliable measures to identify those at risk of loss to follow-up. Our results suggest prioritization of ongoing care with shorter follow-up intervals, perhaps using telehealth methods to check in, as opposed to dispersed intermittent visits as a way to improve longitudinal care. They also support the development of 184 interventions targeting new patients to improve follow-up attendance. Further research is required to identify factors accounting for the difference in attendance observed in neuroophthalmology patients. This may include extrinsic appointment factors not evaluated in this study, such as disease type, referral process, and community resources, and other patient factors including education, socioeconomic status, and patient–physician communication, which have been shown to affect adherence in other chronic disease conditions (15). At baseline, neuro-ophthalmology subjects differed from those in glaucoma in demographics, illness perception, and personality traits. Reasons for such differences may be inferred from intricacies of the cognitively driven resourceintensive and time-intensive subspecialty that often deals with patients with complex multisystem disease who have been seen by multiple other specialists by the time of their referral (16). Neuro-ophthalmology subjects reported higher identity and consequence scores as well as lower emotional stability, indicating a more severe perception of symptoms, impact on quality of life, and emotional burden associated with their illness. High rates of misdiagnosis experienced by neuro-ophthalmology patients in addition to numerous unnecessary and potentially harmful tests and treatments (17) may underlie some of the differences in illness perception and recommendations we observed. These findings are deserving of future study because higher consequence, identity, and emotional representation have been associated with poorer psychosocial and physical functioning as well as worse overall illness outcomes (11). Furthermore, illness perception is known to influence physical health, mental health, and functional status; contribute to adherence and health-seeking behaviors; and serve as a predictor for quality of life, disability, and treatment outcomes (4,6,18–21). In addition, access to neuro-ophthalmologic care is currently limited by the shortage of specialists in the field, leading to significant wait times, further delay in diagnosis, and the need for patients to travel long distances to access care (16,22). Such conditions reinforce the need for improving access to neuro-ophthalmology care to minimize obstacles faced by patients and resultant physical, financial, and psychological burden. As expected, physician recommendation profiles differed between neuro-ophthalmology and glaucoma, with more referrals to other services and radiology studies in neuroophthalmology compared with more medical and surgical therapy in glaucoma. Differences in recommendations may be explained by the diagnostically complex nature of neuroophthalmic conditions, often involving systems beyond the eye and a higher proportion of new patients. It is also possible that personality and illness perception differences noted in neuro-ophthalmology subjects may prompt requests for additional testing and subspecialty referrals Aziz et al: J Neuro-Ophthalmol 2022; 42: 180-186 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution TABLE 2. Adherence to physician recommendations for follow-up, medications, referrals, and testing by neuroophthalmology subjects and subjects with glaucoma Adherence Follow-up on time Medication Referral Laboratory tests Ophthalmic tests Radiology studies Procedures Neuro-Ophthalmology Glaucoma P 33/60 (55.0%) 18/18 (100.0%) 6/14 (42.9%) 2/3 (66.7%) 23/36 (63.9%) 11/12 (91.7%) N/A 53/69 (76.8%) 53/57 (93.0%) 1/1 (100.0%) N/A 22/24 (91.7%) N/A 10/11 (90.9%) 0.009* 0.57† 0.467† — 0.015* — — Subjects who moved were excluded from the assessment of follow-up adherence. *Chi-square. † Fisher exact test. because patients seek better characterization and understanding of their illness. Our findings are not without limitations. Our sample sizes and distributions were insufficient to allow for analysis of adherence to other recommendations besides follow-up visits. Future studies might specifically investigate medication compliance and other physician recommendations through larger multicenter studies over a longer duration. Furthermore, generalizability of our study is limited by its single-center nature, thereby excluding geographic variability and relevant care obtained from outside providers. Glaucoma was chosen as a comparison group considering its medical therapeutic component in patients seen within the same clinical practice center. Comparing other ophthalmic subspecialty groups would be an area of interest for future study. Finally, single-provider–associated differences between ophthalmology subspecialties may have been a confounding factor (e.g., sex, ethnicity, and years of practice). In conclusion, we prospectively surveyed neuroophthalmology patients and patients with glaucoma to identify personality and illness perception factors associated with attendance at physician-recommended follow-up appointments, with the ultimate goal of developing targeted interventions to improve attendance. Neuro-ophthalmology patients differed from patients with glaucoma at baseline in intrinsic factors, appointment factors, and physician recommendations and were less likely to complete follow-up visits on time. Shorter follow-up duration and established patient status were associated with higher adherence to follow-up among all subjects. Further work is needed to identify modifiable risk factors associated with adherence to physician recommendations in neuro-ophthalmology to improve patient care and optimize health outcomes. STATEMENT OF AUTHORSHIP Category 1: a. Conception and design: R. Aziz and H. E. Moss; b. Acquisition of data: R. Aziz, R. T. Chang, and M. P. Bindiganavale; c. 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