Faculty Bibliography

Trace elements such as cadmium, arsenic, zinc or selenium increase or decrease risk of a wide range of human diseases. Their levels in toenails may provide a measure of mid-term intake of trace elements for studies in humans. However, in biologically and clinically aggressive diseases as pancreatic cancer, the progression of the disease could modify such concentrations and produce reverse causation bias. The aim was to analyze the influence of specific time intervals between several clinical events and the collection of toenails upon concentrations of trace elements in patients with pancreatic cancer. Subjects were 118 incident cases of pancreatic adenocarcinoma prospectively recruited in eastern Spain. Toenails were collected at cancer diagnosis, and soon thereafter interviews were conducted. Information on cancer signs and symptoms was obtained from medical records and patient interviews. Levels of 12 trace elements were determined in toenail samples by inductively coupled plasma mass spectrometry. General linear models adjusting for potential confounders were applied to analyze relations between log concentrations of trace elements and the time intervals, including the interval from first symptom of cancer to toenail collection (iST). Toenail concentrations of the 12 trace elements were weakly or not influenced by the progression of the disease or the diagnostic procedures. Concentrations of aluminum were slightly higher in subjects with a longer iST (age, sex and stage adjusted geometric means: 11.44 vs. 7.75 µg/g for iST > 120 days vs. ≤ 40 days). There was a weak inverse relation of iST with concentrations of zinc and selenium (maximum differences of about 20 and 0.08 µg/g, respectively). Conclusions: concentrations of the trace elements were weakly or not influenced by the development of the disease before toenail collection. Only concentrations of aluminum increased slightly with increasing iST, whereas levels of zinc and selenium decreased weakly. Even in an aggressive disease as pancreatic cancer, toenail concentrations of trace elements may provide a valid measure of mid-term intake of trace elements, unaffected by clinical events and disease progression.

CONTEXT/BACKGROUND:In a previous study we reported that anti-Müllerian hormone (AMH), a marker of ovarian reserve, is positively associated with breast cancer risk, consistent with other studies. OBJECTIVE:Assess whether risk factors for breast cancer are correlates of AMH concentration. DESIGN/METHODS:Cross-sectional. PARTICIPANTS/METHODS:3831 healthy premenopausal women (aged 21-57, 87% aged 35-49). SETTING/METHODS:Ten cohort studies, general population. RESULTS:Adjusting for age and cohort, we observed positive associations of AMH with age at menarche (p<0.0001) and parity (p=0.0008), and an inverse association with hysterectomy/partial oophorectomy (p=0.0008). Compared to women of normal weight (BMI 18.5-24.9 kg/m 2, AMH was lower (relative geometric mean difference 27%, p<0.0001) among women who were obese (BMI>30). Current oral contraceptive use and current/former smoking were associated with lower AMH concentration than never use (40% and 12% lower, respectively, p<0.0001). We observed higher AMH concentrations among women who had had a benign breast biopsy (15% higher, p=0.03), a surrogate for benign breast disease, an association that has not been reported. In analyses stratified by age (<40/≥40), associations of AMH with BMI and oral contraceptives were similar in younger and older women, while associations with the other factors (menarche, parity, hysterectomy/partial oophorectomy, smoking, and benign breast biopsy) were limited to women ≥40 (p-interaction<0.05). CONCLUSION/CONCLUSIONS:This is the largest study of AMH and breast cancer risk factors among women from the general population (not presenting with infertility), and suggests that most of the associations are limited to women over 40, who are approaching menopause and whose AMH concentration is declining.

Background Sacubitril/valsartan, a first-in-class angiotensin receptor neprilysin inhibitor, received US Food and Drug Administration approval in 2015 for heart failure with reduced ejection fraction (HFrEF). Our objective was to describe the sacubitril/valsartan initiation rate, associated characteristics, and 6-month follow-up dosing among veterans with HFrEF who are renin-angiotensin-aldosterone system inhibitor (RAASi) naïve. Methods and Results Retrospective cohort study of veterans with HFrEF who are RAASi naïve defined as left ventricular ejection fraction (LVEF) ≤40%; ≥1 in/outpatient heart failure visit, first RAASi (sacubitril/valsartan, angiotensin-converting enzyme inhibitor [ACEI]), or angiotensin-II receptor blocker [ARB]) fill from July 2015 to June 2019. Characteristics associated with sacubitril/valsartan initiation were identified using Poisson regression models. From July 2015 to June 2019, we identified 3458 sacubitril/valsartan and 29 367 ACEI or ARB initiators among veterans with HFrEF who are RAASi naïve. Sacubitril/valsartan initiation increased from 0% to 26.5%. Sacubitril/valsartan (versus ACEI or ARB) initiators were less likely to have histories of stroke, myocardial infarction, or hypertension and more likely to be older and have diabetes mellitus and lower LVEF. At 6-month follow-up, the prevalence of ≥50% target daily dose for sacubitril/valsartan, ACEI, and ARB initiators was 23.5%, 43.2%, and 47.1%, respectively. Conclusions Sacubitril/valsartan initiation for HFrEF in the Veterans Administration increased in the 4 years immediately following Food and Drug Administration approval. Sacubitril/valsartan (versus ACEI or ARB) initiators had fewer baseline cardiovascular comorbidities and the lowest proportion on ≥50% target daily dose at 6-month follow-up. Identifying the reasons for lower follow-up dosing of sacubitril/valsartan could support guideline recommendations and quality improvement strategies for patients with HFrEF.

BACKGROUND:Almost half of Veterans with localized prostate cancer receive inappropriate, wasteful staging imaging. Our team has explored the barriers and facilitators of guideline-concordant prostate cancer imaging and found that (1) patients with newly diagnosed prostate cancer have little concern for radiographic staging but rather focus on treatment and (2) physicians trust imaging guidelines but are apt to follow their own intuition, fear medico-legal consequences, and succumb to influence from imaging-avid colleagues. We used a theory-based approach to design a multi-level intervention strategy to promote guideline-concordant imaging to stage incident prostate cancer. METHODS:We designed the Prostate Cancer Imaging Stewardship (PCIS) intervention: a multi-site, stepped wedge, cluster-randomized trial to determine the effect of a physician-focused behavioral intervention on Veterans Health Administration (VHA) prostate cancer imaging use. The multi-level intervention, developed according to the Theoretical Domains Framework (TDF) and Behavior Change Wheel, combines traditional physician behavior change methods with novel methods of communication and data collection. The intervention consists of three components: (1) a system of audit and feedback to clinicians informing individual clinicians and their sites about how their behavior compares to their peers' and to published guidelines, (2) a program of academic detailing with the goal to educate providers about prostate cancer imaging, and (3) a CPRS Clinical Order Check for potentially guideline-discordant imaging orders. The intervention will be introduced to 10 participating geographically distributed study sites. DISCUSSION/CONCLUSIONS:This study is a significant contribution to implementation science, providing VHA an opportunity to ensure delivery of high-quality care at the lowest cost using a theory-based approach. The study is ongoing. Preliminary data collection and recruitment have started; analysis has yet to be performed. TRIAL REGISTRATION/BACKGROUND:CliniclTrials.gov NCT03445559. Prospectively registered on February 26, 2018.

OBJECTIVE:Approximately half of male childhood cancer survivors experience impaired fertility, yet fertility preservation (FP) remains underutilized. Although parent recommendation influences adolescents' decision-making, parents may be uncertain and/or underrate their sons' parenthood goals. This study assessed parent-adolescent and family-level concordance regarding adolescent fertility perspectives (i.e., values, goals) and associations with FP attempts. METHODS:A prospective pilot study examined the impact of a family-centered values clarification tool (FAST) on banking attempts among adolescent males newly diagnosed with cancer at risk for infertility. The FAST assessed adolescent and parent perceptions of adolescents' fertility values and goals (i.e., perceived threat of infertility, perceived benefits/barriers to banking). Parent-adolescent concordance and family-level concordance on fertility perspectives were examined, along with associations with banking attempts and salient demographic factors. RESULTS:Ninety-eight participants (32 adolescents aged 12-20, 37 mothers, 29 fathers) from 32 families completed the FAST before treatment initiation. Parent-adolescent dyads were concordant on approximately one-half of responses. Banking attempts were associated with higher family-level concordance regarding perceived benefits, r(32) = .40, p = .02. Older adolescent age was associated with higher family-level concordance regarding perceived threat, r(31) = .37, p = .04, and benefits, r(32) = .40, p = .03. Fathers' education was associated with higher family-level concordance regarding barriers, r(21) = .53, p = .01. CONCLUSIONS:When parents were concordant with their son's fertility values and goals, particularly perceived benefits, adolescents were more likely to attempt FP. Clinicians should facilitate sharing of fertility perspectives within families before cancer treatment, especially with younger adolescents. Psychosocial support for families facing FP decisions is recommended at diagnosis and across the care continuum.

In Sub-Saharan Africa, communicable and other tropical infectious diseases remain major challenges apart from the continuing HIV/AIDS epidemic. Recognition and prevalence of non-communicable diseases have risen throughout Africa, and the reimagining of healthcare delivery is needed to support communities coping with not only with HIV, tuberculosis, and COVID-19, but also cancer, cardiovascular disease, diabetes, and depression. Many non-communicable diseases can be prevented or treated with low-cost interventions, yet implementation of such care has been limited in the region. In this Perspective piece, we argue that deployment of an integrated service delivery model is an urgent next step, propose a South African model for integration, and conclude with recommendations for next steps in research and implementation. An approach that is inspired by South African experience would build on existing HIV-focused infrastructure that has been developed by Ministries of Health with strong support from the U.S. President's Emergency Response for AIDS Relief (PEPFAR) and the Global Fund to Fight AIDS, Tuberculosis and Malaria. An integrated chronic healthcare model holds promise to sustainably deliver infectious disease and non-communicable disease care. Integrated care will be especially critical as health systems seek to cope with the unprecedented challenges associated with COVID-19 and future pandemic threats.

BACKGROUND:Disease surveillance of diabetes among youth has relied mainly upon manual chart review. However, increasingly available structured electronic health record (EHR) data have been shown to yield accurate determinations of diabetes status and type. Validated algorithms to determine date of diabetes diagnosis are lacking. The objective of this work is to validate two EHR-based algorithms to determine date of diagnosis of diabetes. METHODS:A rule-based ICD-10 algorithm identified youth with diabetes from structured EHR data over the period of 2009 through 2017 within three children's hospitals that participate in the SEARCH for Diabetes in Youth Study: Cincinnati Children's Hospital, Cincinnati, OH, Seattle Children's Hospital, Seattle, WA, and Children's Hospital Colorado, Denver, CO. Previous research and a multidisciplinary team informed the creation of two algorithms based upon structured EHR data to determine date of diagnosis among diabetes cases. An ICD-code algorithm was defined by the year of occurrence of a second ICD-9 or ICD-10 diabetes code. A multiple-criteria algorithm consisted of the year of first occurrence of any of the following: diabetes-related ICD code, elevated glucose, elevated HbA1c, or diabetes medication. We assessed algorithm performance by percent agreement with a gold standard date of diagnosis determined by chart review. RESULTS:Among 3777 cases, both algorithms demonstrated high agreement with true diagnosis year and differed in classification (p = 0.006): 86.5% agreement for the ICD code algorithm and 85.9% agreement for the multiple-criteria algorithm. Agreement was high for both type 1 and type 2 cases for the ICD code algorithm. Performance improved over time. CONCLUSIONS:Year of occurrence of the second ICD diabetes-related code in the EHR yields an accurate diagnosis date within these pediatric hospital systems. This may lead to increased efficiency and sustainability of surveillance methods for incidence of diabetes among youth.

BACKGROUND:Text message (ie, short message service, SMS) smoking cessation interventions have demonstrated efficacy in high-income countries but are less well studied in low- and middle-income countries, including Vietnam. OBJECTIVE:The goal of the research is to assess the feasibility, acceptability, and preliminary efficacy of a fully automated bidirectional SMS cessation intervention adapted for Vietnamese smokers. METHODS:The study was conducted in 3 phases. In phase 1, we adapted the SMS library from US-based SMS cessation programs (ie, SmokefreeTXT and Text2Quit). The adaptation process consisted of 7 focus groups with 58 smokers to provide data on culturally relevant patterns of tobacco use and assess message preferences. In phase 2, we conducted a single-arm pilot test of the SMS intervention with 40 smokers followed by in-depth interviews with 10 participants to inform additional changes to the SMS library. In phase 3, we conducted a 2-arm pilot randomized controlled trial (RCT) with 100 smokers. Participants received either the SMS program (intervention; n=50) or weekly text assessment on smoking status (control; n=50). The 6-week SMS program consisted of a 2-week prequit period and a 4-week postquit period. Participants received 2 to 4 automated messages per day. The main outcomes were engagement and acceptability which were assessed at 6 weeks (end of intervention). We assessed biochemically confirmed smoking abstinence at 6 weeks and 12 weeks. Postintervention in-depth interviews explored user experiences among a random sample of 16 participants in the intervention arm. RESULTS:Participants in both arms reported high levels of engagement and acceptability. Participants reported using the program for an average of 36.4 (SD 3.4) days for the intervention arm and 36.0 (SD 3.9) days for the control arm. Four of the 50 participants in the intervention arm (8%) reset the quit date and 19 (38%) texted the keyword TIPS. The majority of participants in both arms reported that they always or usually read the text messages. Compared to the control arm, a higher proportion of participants in the intervention arm reported being satisfied with the program (98% [49/50] vs 82% [41/50]). Biochemically verified abstinence was higher in the intervention arm at 6 weeks (20% [10/50] vs 2% [1/50]; P=.01), but the effect was not significant at 12 weeks (12% [6/50] vs 6% [3/50]; P=.49). In-depth interviews conducted after the RCT suggested additional modifications to enhance the program including tailoring the timing of messages, adding more opportunities to interact with the program, and placing a greater emphasis on messages that described the harms of smoking. CONCLUSIONS:The study supported the feasibility and acceptability of an SMS program adapted for Vietnamese smokers. Future studies need to assess whether, with additional modifications, the program is associated with prolonged abstinence. TRIAL REGISTRATION/BACKGROUND:ClinicalTrials.gov NCT03219541; https://clinicaltrials.gov/ct2/show/NCT03219541.

BACKGROUND:Neuroscience education therapy (NET) has been successfully used for numerous overlapping pain conditions, but few studies have investigated NET for migraine. OBJECTIVE:We sought to 1) review the literature on NET used for the treatment of various pain conditions to assess how NET has been studied thus far and 2) recommend considerations for future research of NET for the treatment of migraine. DESIGN/METHODS:Following the PRISMA guideline for scoping reviews, co-author (TR), a medical librarian, searched the MEDLINE, PsychInfo, Embase, and Cochrane Central Clinical Trials Registry databases for peer-reviewed articles describing NET to treat migraine and other chronic pain conditions. Each citation was reviewed by two trained independent reviewers. Conflicts were resolved through consensus. RESULTS:Overall, a NET curriculum consists of the following topics: pain does not equate to injury, pain is generated in the brain, perception, genetics, reward systems, fear, brain plasticity, and placebo/nocebo effects. Delivered through individual, group, or a combination of individual and group sessions, NET treatments often incorporate exercise programs and/or components of other evidence-based behavioral treatments. NET has significantly reduced catastrophizing, kinesiophobia, pain intensity, and disability in overlapping pain conditions. In migraine-specific studies, when implemented together with traditional pharmacological treatments, NET has emerged as a promising therapy by reducing migraine days, pain intensity and duration, and acute medication intake. CONCLUSION:NET is an established treatment for pain conditions, and future research should focus on refining NET for migraine, examining delivery modality, dosage, components of other behavioral therapies to integrate, and migraine-specific NET curricula.

BACKGROUND:Epidemiological studies have suggested positive associations for iron and red meat intake with risk of pancreatic ductal adenocarcinoma (PDAC). Inherited pathogenic variants in genes involved in the hepcidin-regulating iron metabolism pathway are known to cause iron overload and hemochromatosis. OBJECTIVES/OBJECTIVE:The objective of this study was to determine whether common genetic variation in the hepcidin-regulating iron metabolism pathway is associated with PDAC. METHODS:We conducted a pathway analysis of the hepcidin-regulating genes using single nucleotide polymorphism (SNP) summary statistics generated from 4 genome-wide association studies in 2 large consortium studies using the summary data-based adaptive rank truncated product method. Our population consisted of 9253 PDAC cases and 12,525 controls of European descent. Our analysis included 11 hepcidin-regulating genes [bone morphogenetic protein 2 (BMP2), bone morphogenetic protein 6 (BMP6), ferritin heavy chain 1 (FTH1), ferritin light chain (FTL), hepcidin (HAMP), homeostatic iron regulator (HFE), hemojuvelin (HJV), nuclear factor erythroid 2-related factor 2 (NRF2), ferroportin 1 (SLC40A1), transferrin receptor 1 (TFR1), and transferrin receptor 2 (TFR2)] and their surrounding genomic regions (±20 kb) for a total of 412 SNPs. RESULTS:The hepcidin-regulating gene pathway was significantly associated with PDAC (P = 0.002), with the HJV, TFR2, TFR1, BMP6, and HAMP genes contributing the most to the association. CONCLUSIONS:Our results support that genetic susceptibility related to the hepcidin-regulating gene pathway is associated with PDAC risk and suggest a potential role of iron metabolism in pancreatic carcinogenesis. Further studies are needed to evaluate effect modification by intake of iron-rich foods on this association.