Quantitative Biomarkers of Diabetic Retinopathy Using Ultra-Widefield Fluorescein Angiography.

Introduction: Diabetic retinopathy (DR) is a leading cause of blindness. Retinal imaging is an important tool to monitor the progression of DR. While seven-standard retinal fields are the traditional method for evaluating DR, ultra-widefield (UWF) imaging allows for improved visualization of peripheral areas of nonperfusion (NP) and neovascularization (NV), which could be used as biomarkers to monitor and predict progression of DR. Methods: A retrospective, cross-sectional study was conducted on 651 eyes from 363 patients diagnosed with type 1 or type 2 diabetes who received UWF-FA over 10 years. Fluorescein Angiography (FA) images were segmented, and surface areas of NP and NV were analyzed using multivariate regression to determine if biomarkers of DR and DR severity are associated with increasing areas of NP and NV. Results: Each additional year with a diagnosis of DR was associated with a 10.75 mm2 increase in the total NP (95% CI, 1.94-19.56; P = 0.02) and 7.87 mm2 increase in NP far-periphery (95% CI, 1.62-14.13; P = 0.01). A one-unit change in severity as defined by the Early Treatment of Diabetic Retinopathy Study (ETDRS) classification was associated with a 25.75 mm2 increase in total NP (95% CI, 11.16-40.33; P = 0.001), a 13.15 mm2 increase in mid-periphery NP (95% CI, 6.93-19.38; P < 0.0001), and a 12.29 mm2 increase in far-periphery NP (95% CI, 3.62-20.97; P = 0.01). Discussion: Biomarkers identified through UWF imaging such as total and regional areas of NP can be used to monitor and predict the progression of DR. This may provide a quantitative method for prognostication in patients with DR.

Impact of PTSD treatment on postconcussive symptoms in veterans: A comparison of sertraline, prolonged exposure, and their combination.

Many Veterans who served in Iraq and Afghanistan struggle with posttraumatic stress disorder (PTSD) and the effects of traumatic brain injuries (TBI). Some people with a history of TBI report a constellation of somatic, cognitive, and emotional complaints that are often referred to as postconcussive symptoms (PCS). Research suggests these symptoms may not be specific to TBI. This study examined the impact of PTSD treatment on PCS in combat Veterans seeking treatment for PTSD. As part of a larger randomized control trial, 198 Operation Iraqi Freedom, Operation Enduring Freedom, Operation New Dawn (OIF/OEF/OND) Veterans with PTSD received Prolonged Exposure Therapy, sertraline, or the combination. Potential deployment related TBI, PCS, PTSD and depression symptoms were assessed throughout treatment. Linear mixed models were used to predict PCS change over time across the full sample and treatment arms, and the association of change in PTSD and depression symptoms on PCS was also examined. Patterns of change for the full sample and the subsample of those who reported a head injury were examined. Results showed that PCS decreased with treatment. There were no significant differences across treatments. No significant differences were found in the pattern of symptom change based on TBI screening status. Shifts in PCS were predicted by change PTSD and depression. Results suggest that PCS reduced with PTSD treatment in this population and are related to shift in depression and PTSD severity, further supporting that reported PCS symptoms may be better understood as non-specific symptoms.

Circulating Ectonucleotidases Signal Impaired Myocardial Perfusion at Rest and Stress.

Background Ectonucleotidases maintain vascular homeostasis by metabolizing extracellular nucleotides, modulating inflammation and thrombosis, and potentially, myocardial flow through adenosine generation. Evidence implicates dysfunction or deficiency of ectonucleotidases CD39 or CD73 in human disease; the utility of measuring levels of circulating ectonucleotidases as plasma biomarkers of coronary artery dysfunction or disease has not been previously reported. Methods and Results A total of 529 individuals undergoing clinically indicated positron emission tomography stress testing between 2015 and 2019 were enrolled in this single-center retrospective analysis. Baseline demographics, clinical data, nuclear stress test, and coronary artery calcium score variables were collected, as well as a blood sample. CD39 and CD73 levels were assessed as binary (detectable, undetectable) or continuous variables using ELISAs. Plasma CD39 was detectable in 24% of White and 8% of Black study participants (P=0.02). Of the clinical history variables examined, ectonucleotidase levels were most strongly associated with underlying liver disease and not other traditional coronary artery disease risk factors. Intriguingly, detection of circulating ectonucleotidase was inversely associated with stress myocardial blood flow (2.3±0.8 mL/min per g versus 2.7 mL/min per g±1.1 for detectable versus undetectable CD39 levels, P<0.001) and global myocardial flow reserve (Pearson correlation between myocardial flow reserve and log(CD73) -0.19, P<0.001). A subanalysis showed these differences held true independent of liver disease. Conclusions Vasodilatory adenosine is the expected product of local ectonucleotidase activity, yet these data support an inverse relationship between plasma ectonucleotidases, stress myocardial blood flow (CD39), and myocardial flow reserve (CD73). These findings support the conclusion that plasma levels of ectonucleotidases, which may be shed from the endothelial surface, contribute to reduced stress myocardial blood flow and myocardial flow reserve.

Patient-Centered Outcomes With a Multidisciplinary CKD Care Team Approach: An Observational Study.

Rationale & Objective: Multidisciplinary chronic kidney disease (CKD) care has been associated with improved clinical outcomes in comparison to general nephrology care. However, there is little research examining the impact of multidisciplinary care on patient-centered outcomes. We examined if a multidisciplinary approach to CKD care was associated with 4 patient-centered outcomes. Study Design: Cross-sectional study design using previously established surveys to assess patient-centered outcomes in participants with nondialysis CKD. Setting & Participants: Adults with CKD stages 1-5 who had not undergone transplant or were not on dialysis. Exposures: General nephrology care or multidisciplinary care. Patients receiving multidisciplinary care were seen by a pharmacist, social worker, dietitian, and nephrologist, whereas patients receiving general nephrology care only saw a nephrologist. Outcomes: Four patient-centered outcomes: CKD-specific knowledge, disease-related stress, perception of overall health, and perception of health status compared to 1 year ago. Analytical Approach: Differences were examined using a Welch 2-sample t test and linear regression model. Results: Mean age of participants was 60 years with standard deviation of 17 years. 182 (77%) patients were White, and 230 (96%) had formal education greater than or equal to high school. 121 (49%) were women, and 215 (88%) had CKD stage 3-5. 77 (31%) received multidisciplinary care. We did not identify any significant differences in patient knowledge, stress, or perception of health between multidisciplinary and general nephrology care. However, notably, patients in multidisciplinary care were older and had more advanced CKD than those in general nephrology care. Limitations: Cross-sectional study designs only identify associations. Study was conducted at clinics located within 30 miles of each other, limiting generalizability. Conclusions: Our results suggest that a team-based approach to care can better support sicker, more vulnerable patients so that they can achieve similar patient-centered outcomes compared to patients who are younger and with less advanced CKD.

Retinal neovascularization as self-organized criticality on ultra-widefield fluorescein angiography imaging of diabetic retinopathy.

BACKGROUND/OBJECTIVES: Do the distributions of surface area of non-perfusion (NP) and neovascularization (NV) on ultra-widefield fluorescein angiography (UWF FA) in patients with diabetic retinopathy (DR) differ significantly? SUBJECTS/METHODS: Inclusion criteria were patients who had a UWF FA taken for DR at the Kellogg Eye Center from January 2009 to May 2018. Exclusion criteria included previous panretinal photocoagulation and significant media opacity (e.g., vitreous haemorrhage or significant cataract). UWF FAs were manually segmented for surface areas of NP and NV. The total areas per patient were organized in a histogram, and logarithmically binned to test against power law and exponential distributions. Then, a computational model was constructed in Python 3.7 to suggest a mechanistic explanation for the observed distributions. RESULTS: Analysis of areas of NV across 189 images demonstrated a superior fit by the least squares method to a power law distribution (p = 0.014) with an R2 fit of 0.9672. Areas of NP over 794 images demonstrated a superior fit with an exponential distribution instead (p = 0.011). When the far periphery was excluded, the R2 fit for the exponential distribution was 0.9618. A computational model following the principles of self-organized criticality (SOC), akin to earthquake and forest fire models, matched these datasets. CONCLUSIONS: These distributions inform what useful statistics may be applied to study of these imaging characteristics. Further, the difference in event distribution between NV and NP suggests that the two phenomena are mechanistically distinct. NV may follow SOC, propagating as a catastrophic event in an unpredictable manner.

Extent of Extranodal Extension in Oral Cavity Squamous Cell Carcinoma is Not Independently Associated With Overall or Disease-Free Survival at a 2.0-mm Threshold.

PURPOSE: The presence of extranodal extension (ENE) conveys a poor prognosis in oral cavity squamous cell carcinoma (OSCC); however, there is no consensus regarding whether the histopathologic extent of ENE (e-ENE) may be a more discriminating prognostic indicator. The purpose of this study was to assess the impact of minor ENE (<2.0 mm) versus major ENE (≥ 2.0 mm) on overall survival (OS) and disease-free survival (DFS) in OSCC. MATERIALS AND METHODS: A single-institution, retrospective cohort study was designed using an electronic medical record review. Inclusion criteria included patients with OSCC and cervical node metastasis. All subjects were treated between the years 2009 and 2017 in the Michigan Medicine Department of Oral and Maxillofacial Surgery (Ann Arbor, Michigan). The primary predictor variable was e-ENE, measured as the maximum distance of tumor invasion into extranodal tissue from the outer aspect of the nodal capsule. Primary outcome variables were OS and DFS. Other covariates included demographic data, tumor staging, and histopathologic data. Descriptive statistics were performed. Kaplan-Meier survival plots for OS and DFS were performed. The data were mined for an alternative threshold at which e-ENE may impact survival using Cox proportional hazards models. RESULTS: One hundred sixty eight subjects were included (91 ENE-negative, 48 minor ENE, and 29 major ENE). Most subjects were male (62%) and the mean age was 62.9 years. Mean follow-up time was 2.97 +/- 2.76 years. There was no statistically significant difference in OS or DFS between minor and major ENE. Five-year OS for minor ENE was 30.4% versus 20.7% for major ENE (P = .28). Five-year DFS for minor ENE was 26.7% versus 18.1% for major ENE (P = .30). Five-year OS and DFS was worse for subjects with ENE-positive disease versus ENE-negative disease (OS: 26.9% vs 63.1%, hazard ratio [HR]: 2.70, 95% confidence interval [CI]: [1.77, 4.10], P < .001; DFS: 23.7% vs 59.7%, HR = 2.55, 95% CI [1.71, 3.79], P < .001). At an alternative threshold of 0.9 mm e-ENE, there was greater DFS in subjects with e-ENE 0.1-0.9 mm versus e-ENE > 0.9 (40.6% vs 18.9%, respectively) (HR = 0.49, 95% CI [0.24, 0.99], P = .047). CONCLUSION: There was no independent association between survival and e-ENE at a 2.0-mm threshold.

Evaluation of a clinical decision support tool to predict permanence of retrievable inferior vena cava filters.

OBJECTIVE: To evaluate the usefulness of a published clinical decision support tool to predict the likelihood of a retrievable inferior vena cava (IVC) filter being maintained as a permanent device. METHODS: This multicenter retrospective cohort study included 1498 consecutive patients (852 men and 646 women; median age, 60 years; range, 18-98 years) who underwent retrievable IVC filter insertion between January 2012 and December 2019. The indications for IVC filtration, baseline neurologic disease, history of venous thromboembolism (VTE), and underlying malignancy were recorded. Accuracy, sensitivity, and specificity of a published clinical support tool were calculated to determine the usefulness of the tool. RESULTS: The majority of filters (1271/1498 [85%]) were placed for VTE with a contraindication to anticoagulation. A history of VTE was present in 811 of 1498 patients (54%) patients; underlying malignancy in 531 of 1498 patients (35%), and neurological disease in 258 of 1498 patients (17%). Of the 1498 filters, 456 (30%) were retrieved, 276 (18%) were maintained as permanent devices on follow-up, and 766 (51%) filters were not retrieved. The accuracy of the clinical prediction model was 61%, sensitivity was 60%, and specificity was 62%. CONCLUSIONS: A previously published clinical decision support tool to predict permanence of IVC filters had modest usefulness in the examined population; this factor should be taken into account when using this clinical decision support tool outside of the original study population. Future studies are required to refine the predictive capability of IVC filter decision support tools for broader use across different patient populations.

Multisite Retrospective Review of Outcomes in Renal Replacement Therapy for Neonates with Inborn Errors of Metabolism.

OBJECTIVE: To assess the outcomes of neonates in a contemporary multi-institutional cohort who receive renal replacement therapy (RRT) for hyperammonemia. STUDY DESIGN: We performed a retrospective analysis of 51 neonatal patients with confirmed inborn errors of metabolism that were treated at 9 different children's hospitals in the US between 2000 and 2015. RESULTS: Twenty-nine patients received hemodialysis (57%), 21 patients received continuous renal replacement therapy (41%), and 1 patient received peritoneal dialysis (2%). The median age at admission of both survivors (n = 33 [65%]) and nonsurvivors (n = 18) was 3 days. Peak ammonia and ammonia at admission were not significantly different between survivors and nonsurvivors. Hemodialysis, having more than 1 indication for RRT in addition to hyperammonemia, and complications during RRT were all risk factors for mortality. After accounting for multiple patient factors by multivariable analyses, hemodialysis was associated with a higher risk of death compared with continuous renal replacement therapy. When clinical factors including evidence of renal dysfunction, number of complications, concurrent extracorporeal membrane oxygenation, vasopressor requirement, and degree of hyperammonemia were held constant in a single Cox regression model, the hazard ratio for death with hemodialysis was 4.07 (95% CI 0.908-18.2, P value = .067). To help providers caring for neonates with hyperammonemia understand their patient's likelihood of survival, we created a predictive model with input variables known at the start of RRT. CONCLUSIONS: Our large, multicenter retrospective review supports the use of continuous renal replacement therapy for neonatal hyperammonemia.

Safety and Effectiveness of Advanced Retrieval Techniques for Inferior Vena Cava Filters Compared with Standard Retrieval Techniques: A Systematic Review of the Literature and Meta-Analysis.

PURPOSE: To investigate the pooled safety and effectiveness of advanced retrieval techniques for inferior vena cava (IVC) filters compared with standard retrieval techniques through a systematic review of the literature and meta-analysis. MATERIALS AND METHODS: A systematic search of retrievable IVC filters between 1980 and 2020 was conducted. Studies were included if both standard and advanced retrieval techniques were utilized in the same cohort, retrieval success rates and adverse event rates were described for each technique, and advanced techniques were employed after the failure of standard techniques. Study heterogeneity was assessed by the I2 statistic. The outcomes included retrieval success rates and adverse event rates for standard and advanced retrieval techniques. RESULTS: Of 1,631 articles, 21 (1%) studies met inclusion criteria. The study heterogeneity was high with an I2 of 98%. The pooled random-effects outcomes included an overall standard retrieval success rate of 76% (95% confidence interval [CI], 65%-84%), with minor and major adverse event rates of 1% (95% CI, 0%-1%) and 1% (95% CI, 0%-1%), respectively. The overall pooled advanced retrieval success rates were 90% (95% CI, 82%-94%), with minor and major adverse event rates of 5% (95% CI, 2%-9%) and 4% (95% CI, 2%-6%), respectively. The standard retrievals were 16% less likely (risk ratio) to be successful (95% CI, 32% less likely to 4% more likely; P = .11). The major and minor adverse event rates were 88% and 84% less likely in standard retrievals compared with advanced retrievals, respectively (95% CI, 86%-94%; P < .0001; 95% CI, 70%-91%; P < .0001). CONCLUSIONS: Advanced retrieval techniques for IVC filters permit a higher retrieval success rate with low adverse event rates in cases of standard retrieval failure.

Change in posttraumatic stress disorder-related thoughts during treatment: Do thoughts drive change when pills are involved?

Posttraumatic negative thoughts about one's self and the world are related to posttraumatic stress disorder (PTSD) symptom severity and change in cognitive behavioral treatment (CBT), but little is known about this association when CBT is delivered with medication. The current study presents a planned comparison of changes in negative posttraumatic thoughts during (a) prolonged exposure (PE) plus pill placebo (PE+PLB), (b) sertraline plus enhanced medication management (SERT+EMM), and (c) PE plus sertraline (PE+SERT) as part of a randomized clinical trial in a sample of 176 veterans. Lagged regression modeling revealed that change in posttraumatic negative thoughts was associated with PTSD symptom change in the conditions in which participants received sertraline, ds = 0.14-0.25, ps = 0.04-.001). However, contrary to previous research, the models that started with symptom change were also statistically significant, d = 0.23, p < .001, for the lagged effect of symptoms on negative thoughts about self in the SERT+EMM condition, indicating a bidirectional association between such thoughts and PTSD symptoms. In the PE+PLB condition, no significant association between posttraumatic thoughts and PTSD symptoms emerged in either direction. These results suggest that the previously demonstrated role of change in posttraumatic thoughts leading to PTSD symptom reduction in PE may be altered when combined with pill administration, either active or placebo.

Virtual Externship Programs Can Serve as a Viable Alternative to In-Person Externship Experiences in Oral and Maxillofacial Surgery.

PURPOSE: The purpose of this study is to describe a model for a virtual externship program in oral-maxillofacial surgery (OMS); to quantify the value of a virtual externship in increasing understanding of the program structure, scope, and commitment to diversity; and to offer qualitative feedback on structural components. METHODS: A retrospective study was completed comparing dental student perceptions of an OMS program and the virtual externship experience prior to and following an OMS residency virtual externship event. An electronic survey was distributed to registrants and included 25 questions: 5 related to demographics, 17 ascertaining understanding of various components of the residency and perception of virtual externships, and 3 text-based response queries. RESULTS: Of the 167 attendees, 125 individuals completed the pre-externship survey and 50 completed the postexternship survey for a response rate of 74.8 and 29.9% respectively. Respondents of both surveys included 30 men and 20 women, aged 18 to 34, at various stages of dental school training and of various ethnic backgrounds. All externs reported an interest in participating in virtual externships if offered by OMS programs. Understanding of scope of practice, daily activities of the program and residents, living in Ann Arbor, relationship between residents and with faculty, and program structure demonstrated a significant increase (P < .001). Perceived commitment to diversity and respect for people of different races, cultures, and backgrounds also showed a significant increase following the event (P < .001). CONCLUSIONS: A virtual externship can successfully duplicate many of the most valuable components of an in-person externship to allow enhanced understanding and interest in the residency program and can incorporate novel components otherwise not possible in an-person externship.

Patient Electronic Health Record Portal Use and Patient-Centered Outcomes in CKD.

RATIONALE & OBJECTIVE: Electronic health record portals are increasingly emphasized in chronic kidney disease (CKD). However, associations of portal use with clinical and patient-centered outcomes remain unknown. STUDY DESIGN: Cross-sectional survey (April 2015 to March 2018). SETTING & PARTICIPANTS: Nondialysis patients with CKD from nephrology clinics within 1 academic medical center. EXPOSURES: Patient demographics (age, sex, race, ethnicity, education, and income), kidney function. OUTCOMES: Association between portal use as an outcome and exposures. Additionally, associations of portal use and patient demographics with 4 patient-centered outcomes (CKD-specific knowledge, stress, and 2 self-ratings of health). ANALYTIC APPROACH: Logistic regression to examine associations between patient portal use, demographics, and kidney function. Linear regression to examine associations between portal use and patient-centered outcomes. RESULTS: Of 245 participants, mean age was 60 ± 17 (SD) years, 182 (77%) were White, 121 (49%) were women, 230 (96%) had a high school education or higher, and 96 (45%) had <$50,000 annual income. Examining portal use, 159 (65%) used the portal as follows: checking laboratory test results, 157 (99%); managing appointments, 133 (84%); messaging providers, 131 (82%); viewing medical history, 127 (80%); reviewing educational resources, 113 (71%); and renewing prescriptions, 98 (62%). African Americans (OR, 0.34; 95% CI, 0.16-0.72 vs White patients), patients with less formal education (OR, 0.06; 95% CI, 0.01-0.36), and those with lower income (OR, 0.28; 95% CI, 0.13-0.60; and OR, 0.26; 95% CI, 0.12-0.54 comparing income < $25,000 and $25,000-$50,000, respectively, with ≥$50,000) had lower odds of using the portal. In adjusted analysis, only lower income predicted lower portal use. Examining patient-centered outcomes in univariable analysis, portal users had higher knowledge (ß = 4.89; P = 0.02), higher ratings of current health (ß = 0.28; P = 0.03), and lower CKD-related stress (ß = -0.18; P = 0.05). In adjusted analysis, only patient demographics and/or kidney function remained independent predictors of patient-centered outcomes. LIMITATIONS: Cross-sectional study design, cannot determine causality. CONCLUSIONS: Interventions are needed to ensure that all patients have access to portals to mitigate disparities in care.

Outcomes of cystic fibrosis pulmonary exacerbations treated with antibiotics with activity against anaerobic bacteria.

BACKGROUND: Obligate and facultative anaerobic bacteria are prevalent in cystic fibrosis (CF) airways. Increases in anaerobe relative abundance have been associated with CF pulmonary exacerbations (PEx); however, the impact of antibiotic treatment of anaerobes during PEx is unknown. We hypothesized that PEx treated with antibiotics with activity against anaerobes would improve outcomes compared to antibiotics without anaerobic activity. METHODS: This was a single-center, retrospective study of people with CF, ages 6 years and older, treated with intravenous (IV) antibiotics for PEx. IV antibiotics were classified as either broad or minimal anaerobic activity. PEx treated with broad anaerobe coverage were propensity-score matched to PEx treated with minimal anaerobic coverage. The primary outcome, % of baseline % predicted forced expiratory volume in one second (ppFEV1) recovered, was compared between antibiotic categories with a linear mixed model. The secondary outcome, time to next PEx, was assessed using a Prentice Williams Petersen model. RESULTS: 514 PEx from 182 patients were included. Broad anaerobe coverage was used in 27% of PEx, and was used more often for older patients (p < 0.001) with worse baseline ppFEV1 (p < 0.001), and with Achromobacter (p < 0.001) or Burkholderia infections (p = 0.002). In the matched PEx, broad anaerobe coverage was not a significant predictor of % of baseline ppFEV1 recovered (∆ppFEV1 = -2.4, p = 0.09). Broad anaerobe coverage was also not a significant predictor of time to next PEx (HR 0.89, 95% CI 0.7-1.13, p = 0.35). CONCLUSIONS: In this single center, retrospective study, antibiotics with broad activity against anaerobes were not associated with improved outcomes of CF PEx.

An In-House Computer-Aided Design and Computer-Aided Manufacturing Workflow for Maxillofacial Free Flap Reconstruction is Associated With a Low Cost and High Accuracy.

PURPOSE: In-house computer-aided surgical design and computer-aided manufacturing (CAD/CAM) can be used in oral and maxillofacial surgery for virtual surgical planning and 3-dimensional printing of patient-specific models. The purpose of this study was to measure the cost and accuracy of an in-house CAD/CAM workflow for maxillofacial free flap reconstruction. MATERIALS AND METHODS: A retrospective cohort study of patients undergoing mandibular resection and free flap reconstruction was performed between July 2017 and March 2018 in which in-house CAD/CAM was used. The predictor variable was the in-house CAD/CAM workflow. The outcome variables were in-house workflow cost, as measured by the material expenses, and accuracy, as measured by comparative distance, osteotomy angle, and surfaced overlay measurements and the root mean square (RMS) between the preoperative virtual reconstructive plan and the postoperative computed tomography scan. Additional variables evaluated were time required for in-house CAD/CAM workflow, and clinical and radiographic outcomes. RESULTS: In-house CAD/CAM was used for 26 patients undergoing mandibular resection for benign or malignant disease and free flap reconstruction with fibula (n = 24) or scapula free flap (n = 2). Overall flap success rate was 95%. The mean in-house workflow cost per case was $3.87 USD. There were no significant differences between the mean comparative distance and osteotomy angle measurements between the planned and actual mandibular reconstructions with an RMS ranging from 5.11 to 9.00 mm for distance measurements and 17.41° for the osteotomy angle measurements. The mean surface overlay difference was 1.90 mm with an RMS of 3.72 mm. CONCLUSIONS: The in-house CAD/CAM workflow is a low cost and accurate option for maxillofacial free flap reconstruction. The in-house workflow should be considered as an alternative to current practices using proprietary systems in select cases.

Quality improvement initiative to improve pulmonary function in pediatric cystic fibrosis patients.

BACKGROUND: Our Cystic Fibrosis (CF) Center initiated a Quality Improvement (QI) project in November 2017 with the goal of improving our patients' forced expiratory volume in 1 second (FEV1) percent predicted (pp) and continued for 1 year. Our specific aim was to increase the relative mean FEV1 pp by 5% in 12 months for CF patients 6 to 21 years old with FEV1 ≤ 80 pp. METHODS: We identified patients with FEV1 ≤ 80 pp, developed cause and effect diagrams (fishbones) to identify contributing factors to FEV1 ≤ 80 pp, and created flowcharts to address barriers. The barriers to adherence that may result in FEV1 ≤ 80 pp were studied using a fishbone. A standardized approach across providers was implemented to individualize care for each patient. Each discipline developed a flowchart to address barriers to improving FEV1. RESULTS: Forty patients were identified (43% male). Their mean age was 16.8 years (range 8.2-21.5 years). Mean FEV1 pp at baseline was 58.6 (range 30-80). The fishbone identified needs for continuing education for patients/families, and providing a treatment plan at each clinic visit. After 6 months of implementation, patients had an improvement in mean FEV1 pp by 6.4% (CI, 0.4%-12.9%). At 12 months, mean FEV1 pp had improved by 14% (CI, 6.5%-21.4%), which exceeded our goal of 5%. CONCLUSION: Through this ongoing project, team members, patients, and families partnered to improve lung function in pediatric CF patients. Flowcharts facilitated a standardized approach across providers to develop individualized treatment plans for patients, which resulted in improved lung function.

Quantification of Retinal Nonperfusion and Neovascularization With Ultrawidefield Fluorescein Angiography in Patients With Diabetes and Associated Characteristics of Advanced Disease.

Importance: Quantification of nonperfusion (NP) and neovascularization (NV) in diabetic retinopathy (DR) may identify better biomarkers of disease progression. Objective: To identify demographic risk factors and markers of advanced DR that are associated with increased areas of NP and NV in eyes with disease ranging from no DR but diagnosed as having diabetes to proliferative DR (PDR) and to calculate a threshold total area of NP that may be associated with an increased risk of PDR. Design, Setting, and Participants: This retrospective case series was performed on ultrawidefield fluorescein angiography (UWF FA) images from January 2009 to May 2018 at the University of Michigan Kellogg Eye Center. A total of 363 participants (651 eyes) diagnosed as having type 1 or 2 diabetes receiving UWF FA were included. Exclusion criteria included previous panretinal photocoagulation (PRP) and poor-quality images (eg, vitreous hemorrhage and significant cataract). Main Outcomes and Measures: The surface areas in millimeters squared of the foveal avascular zone; total NP; NP at posterior pole, midperiphery, and far periphery; total NV; NV at posterior pole, midperiphery, and far periphery were measured. Results: Of 363 patients, most were male (205 patients [56.5%]) and white (247 [68%]) or black (77 [21.2%]). The mean (SD) age was 59.4 (13.7) years. Seventy-six eyes with no DR, 92 with mild NPDR, 144 with moderate NPDR, 101 with severe NPDR, 220 with PDR, and 18 with DR of unknown severity were included. Male sex had a positive association with total NP (difference, 15.72; 95% CI, 4.83-26.61; P = .005); black race/ethnicity with total NV (difference, 2.32; 95% CI, 0.09-4.55; P = .04); and vitreous hemorrhage with total NP (difference, 30.00; 95% CI, 5.26-54.75; P = .02). A threshold total NP area of 77.48 mm2 (95% CI, 54.24-92.66 mm2) was identified, at greater than which patients may have an increased risk of developing PDR (sensitivity of 59.5% and specificity of 73.6%). Conclusions and Relevance: Our results indicate NP and NV can be quantified on UWF FA. These biomarkers interpreted with demographic risk factors may help predict disease progression. Conclusions are limited by ascertainment and information biases because the results are from retrospective data.

Cortisol awakening response in PTSD treatment: Predictor or mechanism of change.

PTSD is associated with abnormalities in hypothalamic-pituitary-adrenal (HPA) axis activity. This includes enhanced HPA axis negative feedback, attenuated cortisol awakening response, and attenuated cortisol response to personal trauma script. Whether HPA axis function predicts treatment response or treatment related symptom reduction in PTSD remains unclear. In addition, the relative effects of different treatment modalities (i.e., medication and psychotherapy) on HPA axis is unclear. To address this gap in knowledge, the PROGrESS study examined cortisol awakening response across treatment in Veterans with chronic PTSD randomized to receive Prolonged Exposure + Placebo (PE + PLB), Sertraline + PE (SERT + PE) or Sertraline + Enhanced Medication Management (SERT + EMM). Salivary cortisol awakening response (CAR) was assessed at baseline, mid-treatment (week 6 and 12), post-treatment (week 24) and follow-up (week 36 and 52). Among males at baseline, combat veterans with PTSD showed lower CAR Area Under the Curve Increase (AUCi; M = 3.15, SD = 9.57) than Combat controls (M = 7.63, SD = 9.07; p = .02), demonstrating combat veterans with PTSD have a less responsive system than combat controls. Higher PTSD severity was also related to lower CAR AUCi (r = -0.52, p = .03). When controlling for PTSD severity, higher baseline CAR AUCi was related to attenuated reduction in PTSD and lower likelihood of high treatment response over treatment (z = -2.06, p = .04).

Oral Lichen Planus-Associated Oral Cavity Squamous Cell Carcinoma Is Associated With Improved Survival and Increased Risk of Recurrence.

PURPOSE: We investigated the overall survival (OS), disease-specific survival (DSS), and disease-free survival among patients with oral lichen planus-associated oral cavity squamous cell carcinoma (OLP-OCSCC). The secondary objective was to assess the annual risk of tumor recurrence or second primary tumor (SPT). MATERIALS AND METHODS: A comparative retrospective study was performed of patients with OLP-OCSCC presenting between June 2007 and December 2018 to the Department of Oral and Maxillofacial Surgery, Michigan Medicine (Ann Arbor, MI) and patients with OCSCC in the National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) database (1973 to 2015). RESULTS: A total of 87 patients with OLP-OCSCC met the inclusion criteria, and 55,165 patients with OCSCC from the SEER database were included. The proportion of women was greater in the OLP group than in the SEER group (56.3 vs 38.0%; P < .001). In the OLP group, 47.1% had no smoking history and 43.7% had no alcohol history. Most patients in the OLP group had presented with stage I disease (46.0%) compared with 31.7% in the SEER group (P = .004). Overall, the OS and DSS were significantly greater in the OLP group than in the SEER group at all points from 1 to 5 years (P ≤ .01). In the OLP group, 46 patients (52.9%) had at least 1 recurrence or SPT. At 10 years, the predicted mean number of recurrences was 1.93 per patient (95% confidence interval, 1.56 to 2.39). CONCLUSIONS: OLP-OCSCC frequently affects women, nonsmokers, and nondrinkers and presents with localized disease at a high frequency. Patients with OLP-OCSCC have increased OS and DSS and a greater risk of tumor recurrence or SPT compared with OCSCC in the general population. Lifelong, frequent surveillance is recommended for patients with OLP-OCSCC owing to the risk of late recurrence. Future studies are needed to understand the pathophysiology of OLP-OCSCC.

Efficacy of Prolonged Exposure Therapy, Sertraline Hydrochloride, and Their Combination Among Combat Veterans With Posttraumatic Stress Disorder: A Randomized Clinical Trial.

Importance: Meta-analyses of treatments for posttraumatic stress disorder (PTSD) suggest that trauma-focused psychotherapies produce greater benefits than antidepressant medications alone. Objective: To determine the relative efficacy of prolonged exposure therapy plus placebo, prolonged exposure therapy plus sertraline hydrochloride, and sertraline plus enhanced medication management in the treatment of PTSD. Design, Setting, and Participants: The Prolonged Exposure and Sertraline Trial was a randomized, multisite, 24-week clinical trial conducted at the Veterans Affairs Ann Arbor Healthcare System, Veterans Affairs San Diego Healthcare System, Ralph H. Johnson Veterans Affairs Medical Center, and Massachusetts General Hospital Home Base Veterans Program between January 26, 2012, and May 9, 2016. Participants and clinicians were blinded to pill condition, and outcome evaluators were blinded to assignment. Participants completed assessments at weeks 0 (intake), 6, 12, 24, and 52 (follow-up). Participants (N = 223) were service members or veterans of the Iraq and/or Afghanistan wars with combat-related PTSD and significant impairment (Clinician-Administered PTSD Scale score, ≥50) of at least 3 months' duration. Analyses were on an intent-to-treat basis. Intervention: Participants completed up to thirteen 90-minute sessions of prolonged exposure therapy by week 24. Sertraline dosage was titrated during a 10-week period and continued until week 24; medication management was manualized. Main Outcomes and Measures: The primary outcome was symptom severity of PTSD in the past month as assessed by the Clinician-Administered PTSD Scale score at week 24. Results: Of 223 randomized participants, 149 completed the study at 24 weeks, and 207 (180 men and 27 women; mean [SD] age, 34.5 [8.3 years]) were included in the intent-to-treat analysis. Modified intent-to-treat analysis using a mixed model of repeated measures showed that PTSD symptoms decreased significantly during the 24 weeks (sertraline plus enhanced medication management, 33.8 points; prolonged exposure therapy plus sertraline, 32.7 points; and prolonged exposure therapy plus placebo, 29.4 points; ß,-9.39; 95% CI, -11.62 to -7.16; P < .001); however, slopes did not differ by treatment group (prolonged exposure therapy plus placebo group, -9.39; sertraline plus enhanced medication management group, -10.37; and prolonged exposure therapy plus sertraline group, -9.99; P = .81). Conclusions and Relevance: No difference in change in PTSD symptoms or symptom severity at 24 weeks was found between sertraline plus enhanced medication management, prolonged exposure therapy plus placebo, and prolonged exposure therapy plus sertraline. Trial Registration: ClinicalTrials.gov Identifier: NCT01524133.