Catalytic activity of human indoleamine 2,3-dioxygenase (hIDO1) at low oxygen.

A cytokine-inducible extrahepatic human indoleamine 2,3-dioxygenase (hIDO1) catalyzes the first step of the kynurenine pathway. Immunosuppressive activity of hIDO1 in tumor cells weakens host T-cell immunity, contributing to the progression of cancer. Here we report on enzyme kinetics and catalytic mechanism of hIDO1, studied at varied levels of dioxygen (O2) and L-tryptophan (L-Trp). Using a cytochrome b5-based activating system, we measured the initial rates of O2 decay with a Clark-type oxygen electrode at physiologically-relevant levels of both substrates. Kinetics was also studied in the presence of two substrate analogs: 1-methyl-L-tryptophan and norharmane. Quantitative analysis supports a steady-state rather than a rapid equilibrium kinetic mechanism, where the rates of individual pathways, leading to a ternary complex, are significantly different, and the overall rate of catalysis depends on contributions of both routes. One path, where O2 binds to ferrous hIDO1 first, is faster than the second route, which starts with the binding of L-Trp. However, L-Trp complexation with free ferrous hIDO1 is more rapid than that of O2. As the level of L-Trp increases, the slower route becomes a significant contributor to the overall rate, resulting in observed substrate inhibition.

Development of an Electronic Health Record-Based Algorithm for Predicting Lung Cancer Screening Eligibility in the Population-Based Research to Optimize the Screening Process Lung Research Consortium.

PURPOSE: Lung cancer screening (LCS) guidelines in the United States recommend LCS for those age 50-80 years with at least 20 pack-years smoking history who currently smoke or quit within the last 15 years. We tested the performance of simple smoking-related criteria derived from electronic health record (EHR) data and developed and tested the performance of a multivariable model in predicting LCS eligibility. METHODS: Analyses were completed within the Population-based Research to Optimize the Screening Process Lung Consortium (PROSPR-Lung). In our primary validity analyses, the reference standard LCS eligibility was based on self-reported smoking data collected via survey. Within one PROSPR-Lung health system, we used a training data set and penalized multivariable logistic regression using the Least Absolute Shrinkage and Selection Operator to select EHR-based variables into the prediction model including demographics, smoking history, diagnoses, and prescription medications. A separate test data set assessed model performance. We also conducted external validation analysis in a separate health system and reported AUC, sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy metrics associated with the Youden Index. RESULTS: There were 14,214 individuals with survey data to assess LCS eligibility in primary analyses. The overall performance for assigning LCS eligibility status as measured by the AUC values at the two health systems was 0.940 and 0.938. At the Youden Index cutoff value, performance metrics were as follows: accuracy, 0.855 and 0.895; sensitivity, 0.886 and 0.920; specificity, 0.896 and 0.850; PPV, 0.357 and 0.444; and NPV, 0.988 and 0.992. CONCLUSION: Our results suggest that health systems can use an EHR-derived multivariable prediction model to aid in the identification of those who may be eligible for LCS.

Application of team science best practices to the project management of a large, multi-site lung cancer screening research consortium.

Research is increasingly conducted through multi-institutional consortia, and best practices for establishing multi-site research collaborations must be employed to ensure efficient, effective, and productive translational research teams. In this manuscript, we describe how the Population-based Research to Optimize the Screening Process Lung Research Center (PROSPR-Lung) utilized evidence-based Science of Team Science (SciTS) best practices to establish the consortium's infrastructure and processes to promote translational research in lung cancer screening. We provide specific, actionable examples of how we: (1) developed and reinforced a shared mission, vision, and goals; (2) maintained a transparent and representative leadership structure; (3) employed strong research support systems; (4) provided efficient and effective data management; (5) promoted interdisciplinary conversations; and (6) built a culture of trust. We offer guidance for managing a multi-site research center and data repository that may be applied to a variety of settings. Finally, we detail specific project management tools and processes used to drive collaboration, efficiency, and scientific productivity.

Evaluating and Improving Cancer Screening Process Quality in a Multilevel Context: The PROSPR II Consortium Design and Research Agenda.

BACKGROUND: Cancer screening is a complex process involving multiple steps and levels of influence (e.g., patient, provider, facility, health care system, community, or neighborhood). We describe the design, methods, and research agenda of the Population-based Research to Optimize the Screening Process (PROSPR II) consortium. PROSPR II Research Centers (PRC), and the Coordinating Center aim to identify opportunities to improve screening processes and reduce disparities through investigation of factors affecting cervical, colorectal, and lung cancer screening in U.S. community health care settings. METHODS: We collected multilevel, longitudinal cervical, colorectal, and lung cancer screening process data from clinical and administrative sources on >9 million racially and ethnically diverse individuals across 10 heterogeneous health care systems with cohorts beginning January 1, 2010. To facilitate comparisons across organ types and highlight data breadth, we calculated frequencies of multilevel characteristics and volumes of screening and diagnostic tests/procedures and abnormalities. RESULTS: Variations in patient, provider, and facility characteristics reflected the PROSPR II health care systems and differing target populations. PRCs identified incident diagnoses of invasive cancers, in situ cancers, and precancers (invasive: 372 cervical, 24,131 colorectal, 11,205 lung; in situ: 911 colorectal, 32 lung; precancers: 13,838 cervical, 554,499 colorectal). CONCLUSIONS: PROSPR II's research agenda aims to advance: (i) conceptualization and measurement of the cancer screening process, its multilevel factors, and quality; (ii) knowledge of cancer disparities; and (iii) evaluation of the COVID-19 pandemic's initial impacts on cancer screening. We invite researchers to collaborate with PROSPR II investigators. IMPACT: PROSPR II is a valuable data resource for cancer screening researchers.

A supervised exercise intervention fails to improve subjective and objective sleep measures among older adults with and without HIV.

BACKGROUND: Chronic sleep disruption can have significant negative health effects and prior studies suggest that people with HIV (PWH) have disproportionately higher rates of sleep problems. METHODS: We evaluated baseline sleep of sedentary, older adults (50-75 years) with (n = 28) and without HIV (n = 29) recruited into a 24-week exercise study. Subjective sleep quality was assessed with the Pittsburgh Sleep Quality Index (PSQI); objective sleep parameters were assessed using wrist-worn actigraphy. Regression models were used to investigate changes in outcomes. RESULTS: Fifty-seven participants completed the intervention. At baseline, PWH had significantly lower sleep efficiency (88.7 [95% CI 86, 91]%) compared to controls (91.8 [95% CI 91, 93]%; p = 0.02); other sleep measures indicated poorer sleep among PWH but did not reach statistical significance (p ≥ 0.12). Overall, sleep outcomes did not significantly change with the exercise intervention (all p > 0.05). In adjusted analyses, PWH demonstrated a decrease in total sleep time (-22.1 [-43.7, -0.05] p = 0.045) and sleep efficiency (-1.3 [-2.5, -.01], p = 0.03) during the 24 weeks of exercise; these differences were attenuated and no longer significant after adjusting for exercise intensity. At the completion of the intervention, compared to controls, PWH had significantly poorer sleep by PSQI score (2.2 [0.6, 3.8]; p = 0.006) and sleep efficiency (-2.8 [-5.4,-0.2]%; p = 0.04). CONCLUSIONS: In this study, sleep disturbance was more prevalent in sedentary older PWH compared to uninfected controls. An exercise intervention had minimal effect on sleep impairments among PWH nor controls. Among older adults, interventions beyond cardiovascular and resistance exercise may be needed to significantly alter subjective and objective sleep outcomes.

Transoral robotic resection of a combined laryngocele.

This case report describes the use of trans-oral robotic surgery (TORS) for the excision of a combined laryngocele. Mixed or combined laryngoceles extend from the supraglottic larynx through the thyrohyoid membrane into the neck. Surgical excision for these benign lesions often requires combined external (transcervical) and internal (transoral endoscopic) approaches which carry significant morbidity. We present the case of a 37-year-old male who was diagnosed with a large laryngopyocele and was subsequently managed with a transoral excision using the da Vinci Si surgical robot system. The procedure was without complications and the patient was discharged on the second post-operative day on a full liquid diet supplemented with a naso-gastric feeding tube. Postoperative stroboscopy performed 1 month later demonstrated a well-healed hemilarynx and a normal voice. The patient is on a regular diet and now over three years removed from surgery with no evidence of recurrence. We conclude that TORS is an effective tool in the management of benign laryngeal pathology including combined laryngoceles, resulting in reduced morbidity.

Rurality and determinants of hearing healthcare in adult hearing aid recipients.

OBJECTIVE: The objective of this study was to compare the timing of hearing aid (HA) acquisition between adults in rural and urban communities. We hypothesized that time of acquisition of HA after onset of hearing loss is greater in rural adults compared with urban adults. Secondary objectives included assessment of socioeconomic/educational status and impact of hearing loss and hearing rehabilitation of urban and rural HA recipients. STUDY DESIGN: Cross-sectional questionnaire survey. METHODS: We assessed demographics, timing of HA fitting from onset of hearing loss, and impact of hearing impairment in 336 adult HA recipients (273 urban, 63 rural) from a tertiary referral center. Amplification benefit was assessed using the International Outcome Inventory for Hearing Aids (IOI). RESULTS: The time to HA acquisition was greater for rural participants compared to urban participants (19.1 vs. 25.7 years, P = 0.024) for those with untreated hearing loss for at least 8 years. Age at hearing loss onset was correlated with time to HA acquisition (P = -0.54, P < 0.001). Rural HA participants experienced longer commutes to hearing specialists (68 vs. 32 minutes, P < 0.001), were less likely to achieve a degree beyond high school (P < 0.001), and were more likely to possess Medicaid coverage (P = 0.012) compared to urban participants. Hearing impairment caused job performance difficulty in 60% of all participants. CONCLUSION: Rural adults are at risk for delayed HA acquisition, which may be related to distance to hearing specialists. Further research is indicated to investigate barriers to care and expand access for vulnerable populations. LEVEL OF EVIDENCE: 4. Laryngoscope, 127:2362-2367, 2017.

Factors involved in access and utilization of adult hearing healthcare: A systematic review.

OBJECTIVE/HYPOTHESIS: Hearing loss is a public health concern, yet hearing healthcare disparities exist and influence utilization of rehabilitation services. The objective of this review was to systematically analyze the published literature on motivators, barriers, and compliance factors affecting adult patient access and utilization of hearing rehabilitation healthcare. DATA SOURCES: Pubmed, PsychINFO, CINAHL, and Web of Science were searched for relevant articles. Eligible studies were those containing original, peer-reviewed research in English pertaining to factors affecting adult hearing healthcare access and utilization of hearing aids and cochlear implantation. The search encompassed 1990 to 2015. METHODS: Two investigators independently reviewed all articles and extracted data. Specific variables regarding access to care and compliance to recommended care were extracted from each study. RESULTS: Thirty articles were reviewed. The factors affecting access and utilization of hearing rehabilitation could be classified into motivators, barriers, and compliance in treatment or device use. The key motivators to seek care include degree of hearing loss, self-efficacy, family support, and self-recognition of hearing loss. The primary barriers to care were financial limitations, stigma of hearing devices, inconvenience, competing chronic health problems, and unrealistic expectations. Compliance is most affected by self-efficacy, education level, and engagement in the rehabilitation process. CONCLUSION: Accessing hearing healthcare is complicated by multiple factors. Considering the current climate in healthcare policy and legislation toward improved access of care, a deeper understanding of motivators, barriers, and compliance factors can aid in delivery of effective and efficient hearing healthcare. Laryngoscope, 127:1187-1194, 2017.

Timing and Impact of Hearing Healthcare in Adult Cochlear Implant Recipients: A Rural-Urban Comparison.

OBJECTIVE: The purpose of this study is to compare the timing and impact of hearing healthcare of rural and urban adults with severe hearing loss who use cochlear implants (CI). STUDY DESIGN: Cross-sectional questionnaire study. SETTING: Tertiary referral center. PATIENTS: Adult cochlear implant recipients. MAIN OUTCOME MEASURES: Data collected included county of residence, socioeconomic information, impact of hearing loss on education/employment, and timing of hearing loss treatment. The benefits obtained from cochlear implantation were also evaluated. RESULTS: There were 91 participants (32 from urban counties, 26 from moderately rural counties, and 33 for extremely rural counties). Rural participants have a longer commute time to the CI center (p < 0.001), lower income (p < 0.001), and higher percentage of Medicaid coverage (p = 0.004). Compared with urban-metro participants, rural participants with gradually progressive hearing loss had a greater time interval from the onset of hearing loss to obtaining hearing aid amplification (10 yr versus 5 yr, p = 0.04). There was also a greater time interval from onset of hearing loss to the time of cochlear implantation in rural participants (p = 0.04). Reported job loss was higher in rural participants than in urban participants (p = 0.05). Both groups reported comparable benefit from cochlear implantation. CONCLUSION: Rural CI recipients differ from urban residents in socioeconomic characteristics and may be delayed in timely treatment of hearing loss. Further efforts to expand access to hearing healthcare services may benefit rural adult patients.

Factors influencing emergency department preference for access to healthcare.

INTRODUCTION: African-Americans are more likely than Caucasians to access healthcare through the emergency department (ED); however, the reasons behind this pattern are unclear. The objective is to investigate the effect of race, insurance, socioeconomic status, and perceived health on the preference for ED use. METHODS: This is a prospective study at a tertiary care ED from June to July 2009. Patients were surveyed to capture demographics, healthcare utilization, and baseline health status. The primary outcome of interest was patient-reported routine place of healthcare. Other outcomes included frequency of ED visits in the previous 6 months, barriers to primary care and patient perception of health using select questions from the Medical Outcomes Study Short Form 36 (SF-36). RESULTS: Two hundred and ninety-two patients completed the survey of whom 58% were African-American and 44% were uninsured. African-Americans were equally likely to report 3 or more visits to the ED, but more likely to state a preference for the ED for their usual place of care (24% vs. 13%, p < 0.01). No significant differences between groups were found for barriers to primary care, including insurance. African-Americans less often reported comorbidities or hospitalization within the previous 6 months (23% vs. 34%, p = 0.04). On logistic regression modeling, African-Americans were more than 2 times as likely to select the ED as their usual place of healthcare (OR 2.24, 95% CI 1.22 - 4.08). CONCLUSION: African-Americans, independent of health insurance, are more likely than Caucasians to designate the ED as their routine place of healthcare.

Transepithelial ion transport is suppressed in hypoxic sinonasal epithelium.

OBJECTIVES/HYPOTHESIS: Sinonasal respiratory epithelial mucociliary clearance is dependent on the transepithelial transport of ions such as Cl(-) . The objectives of the present study were to investigate the role of oxygen restriction in 1) Cl(-) transport across primary sinonasal epithelial monolayers, 2) expression of the apical Cl(-) channels cystic fibrosis transmembrane conductance regulator (CFTR) and transmembrane protein 16A (TMEM16A), and 3) the pathogenesis of chronic rhinosinusitis. STUDY DESIGN: In vitro investigation. METHODS: Murine nasal septal epithelial (MNSE), wild type, and human sinonasal epithelial (HSNE) cultures were incubated under hypoxic conditions (1% O(2) , 5% CO(2) ). Cultures were mounted in Ussing chambers for ion transport measurements. CFTR and TMEM16A expression were measured using quantitative reverse-transcription polymerase chain reaction (RT-PCR). RESULTS: The change in short-circuit current (ΔI(SC) in microamperes per square centimeter) attributable to CFTR (forskolin-stimulated) was significantly decreased due to a 12-hour hypoxia exposure in both MNSE (13.55 ± 0.46 vs. 19.23 ± 0.18) and HSNE (19.55 ± 0.56 vs. 25.49 ± 1.48 [control]; P < .05). TMEM16A (uridine triphosphate-stimulated transport) was inhibited by 48 hours of hypoxic exposure in MNSE (15.92 ± 2.87 vs. 51.44 ± 3.71 [control]; P < .05) and by 12 hours of hypoxic exposure in HSNE (16.75 ± 0.68 vs. 24.15 ± 1.35 [control]). Quantitative RT-PCR (reported as relative mRNA levels ± standard deviation) demonstrated significant reductions in both CFTR and TMEM16A mRNA expression in MNSE and HSNE owing to airway epithelial hypoxia. CONCLUSIONS: Sinonasal epithelial CFTR and TMEM16A-mediated Cl(-) transport and mRNA expression were robustly decreased in an oxygen-restricted environment. These findings indicate that persistent hypoxia may lead to acquired defects in sinonasal Cl(-) transport in a fashion likely to confer mucociliary dysfunction in chronic rhinosinusitis.