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Item Alzheimer disease brain atrophy subtypes are associated with cognition and rate of decline(American Academy of Neurology, 2017-11-21) Risacher, Shannon L.; Anderson, Wesley H.; Charil, Arnaud; Castelluccio, Peter F.; Shcherbinin, Sergey; Saykin, Andrew J.; Schwarz, Adam J.; Radiology and Imaging Sciences, School of MedicineOBJECTIVE: To test the hypothesis that cortical and hippocampal volumes, measured in vivo from volumetric MRI (vMRI) scans, could be used to identify variant subtypes of Alzheimer disease (AD) and to prospectively predict the rate of clinical decline. METHODS: Amyloid-positive participants with AD from the Alzheimer's Disease Neuroimaging Initiative (ADNI) 1 and ADNI2 with baseline MRI scans (n = 229) and 2-year clinical follow-up (n = 100) were included. AD subtypes (hippocampal sparing [HpSpMRI], limbic predominant [LPMRI], typical AD [tADMRI]) were defined according to an algorithm analogous to one recently proposed for tau neuropathology. Relationships between baseline hippocampal volume to cortical volume ratio (HV:CTV) and clinical variables were examined by both continuous regression and categorical models. RESULTS: When participants were divided categorically, the HpSpMRI group showed significantly more AD-like hypometabolism on 18F-fluorodeoxyglucose-PET (p < 0.05) and poorer baseline executive function (p < 0.001). Other baseline clinical measures did not differ across the 3 groups. Participants with HpSpMRI also showed faster subsequent clinical decline than participants with LPMRI on the Alzheimer's Disease Assessment Scale, 13-Item Subscale (ADAS-Cog13), Mini-Mental State Examination (MMSE), and Functional Assessment Questionnaire (all p < 0.05) and tADMRI on the MMSE and Clinical Dementia Rating Sum of Boxes (CDR-SB) (both p < 0.05). Finally, a larger HV:CTV was associated with poorer baseline executive function and a faster slope of decline in CDR-SB, MMSE, and ADAS-Cog13 score (p < 0.05). These associations were driven mostly by the amount of cortical rather than hippocampal atrophy. CONCLUSIONS: AD subtypes with phenotypes consistent with those observed with tau neuropathology can be identified in vivo with vMRI. An increased HV:CTV ratio was predictive of faster clinical decline in participants with AD who were clinically indistinguishable at baseline except for a greater dysexecutive presentation.Item Are Pain Management Questions in Patient Satisfaction Surveys Driving the Opioid Epidemic?(American Public Health Association, 2016-06) Adams, Jerome; Bledsoe, Gregory H.; Armstrong, John H.; Anesthesia, School of MedicineItem Computer-facilitated review of electronic medical records reliably identifies emergency department interventions in older adults(Society for Academic Emergency Medicine, 2013-06) Biese, Kevin J.; Forbach, Cory R.; Medlin, Richard P.; Platts- Mills, Timothy F.; Scholer, Matthew J.; McCall, Brenda; Shofer, Frances S.; LaMantia, Michael; Hobgood, Cherri; Kizer, J. S.; Busby-Whitehead, Jan; Cairns, Charles B.; Emergency Medicine, School of MedicineOBJECTIVES: An estimated 14% to 25% of all scientific studies in peer-reviewed emergency medicine (EM) journals are medical records reviews. The majority of the chart reviews in these studies are performed manually, a process that is both time-consuming and error-prone. Computer-based text search engines have the potential to enhance chart reviews of electronic emergency department (ED) medical records. The authors compared the efficiency and accuracy of a computer-facilitated medical record review of ED clinical records of geriatric patients with a traditional manual review of the same data and describe the process by which this computer-facilitated review was completed. METHODS: Clinical data from consecutive ED patients age 65 years or older were collected retrospectively by manual and computer-facilitated medical record review. The frequency of three significant ED interventions in older adults was determined using each method. Performance characteristics of each search method, including sensitivity and positive predictive value, were determined, and the overall sensitivities of the two search methods were compared using McNemar's test. RESULTS: For 665 patient visits, there were 49 (7.4%) Foley catheters placed, 36 (5.4%) sedative medications administered, and 15 (2.3%) patients who received positive pressure ventilation. The computer-facilitated review identified more of the targeted procedures (99 of 100, 99%), compared to manual review (74 of 100 procedures, 74%; p < 0.0001). CONCLUSIONS: A practical, non-resource-intensive, computer-facilitated free-text medical record review was completed and was more efficient and accurate than manually reviewing ED records.Item Factors Associated With Posthospital Nursing Facility Discharge for Patients With Impaired Decision Making(Elsevier, 2018-10) Carnahan, Jennifer L.; Inger, Lev; Young, Robert S.; Slaven, James E.; Torke, Alexia M.; Medicine, School of MedicineItem Identification of TMEM230 mutations in familial Parkinson's disease(Nature Research, 2016-07) Deng, Han-Xiang; Shi, Yong; Yang, Yi; Ahmeti, Kreshnik B.; Miller, Nimrod; Huang, Cao; Cheng, Lijun; Zhai, Hong; Deng, Sheng; Nuytemans, Karen; Corbett, Nicola J.; Kim, Myung Jong; Deng, Hao; Tang, Baisha; Yang, Ziquang; Xu, Yanming; Chen, Piao; Huang, Bo; Gao, Xiao-Ping; Song, Zhi; Liu, Zhenhua; Fecto, Faisal; Siddique, Nailah; Foroud, Tatiana; Jankovic, Joseph; Ghetti, Bernardino; Nicholson, Daniel A.; Krainc, Dimitri; Melen, Onur; Vance, Jeffery M.; Pericak-Vance, Margaret A.; Ma, Yong-Chao; Rajput, Ali H.; Siddique, Teepu; Medical and Molecular Genetics, School of MedicineParkinson's disease is the second most common neurodegenerative disorder without effective treatment. It is generally sporadic with unknown etiology. However, genetic studies of rare familial forms have led to the identification of mutations in several genes, which are linked to typical Parkinson's disease or parkinsonian disorders. The pathogenesis of Parkinson's disease remains largely elusive. Here we report a locus for autosomal dominant, clinically typical and Lewy body-confirmed Parkinson's disease on the short arm of chromosome 20 (20pter-p12) and identify TMEM230 as the disease-causing gene. We show that TMEM230 encodes a transmembrane protein of secretory/recycling vesicles, including synaptic vesicles in neurons. Disease-linked TMEM230 mutants impair synaptic vesicle trafficking. Our data provide genetic evidence that a mutant transmembrane protein of synaptic vesicles in neurons is etiologically linked to Parkinson's disease, with implications for understanding the pathogenic mechanism of Parkinson's disease and for developing rational therapies.Item Prevalence and correlates of pain and pain treatment in a western Kenya referral hospital(Mary Ann Liebert, Inc., 2013-10) Huang, Kristin T. L.; Owino, Claudio; Gramelspacher, Gregory P.; Monahan, Patrick O.; Tabbey, Rebeka; Hagembe, Mildred; Strother, Robert M.; Njuguna, Festus; Vreeman, Rachel C.; Department of Medicine, IU School of MedicineBACKGROUND: Pain is often inadequately evaluated and treated in sub-Saharan Africa (SSA). OBJECTIVE: We sought to assess pain levels and pain treatment in 400 hospitalized patients at a national referral hospital in western Kenya, and to identify factors associated with pain and pain treatment. DESIGN: Using face-validated Kiswahili versions of two single-item pain assessment tools, the Numerical Rating Scale (NRS) and the Faces Pain Scale-Revised (FPS-R), we determined patients' pain levels. Additional data collected included patient demographics, prescribed analgesics, and administered analgesics. We calculated mean pain ratings and pain management index (PMI) scores. RESULTS: Averaged between the NRS and FPS-R, 80.5% of patients endorsed a nonzero level of pain and 30% of patients reported moderate to severe pain. Older patients, patients with HIV, and cancer patients had higher pain ratings. Sixty-six percent of patients had been prescribed analgesics at some point during their hospitalization, the majority of which were nonopioids. A majority of patients (66%) had undertreated pain (negative scores on the PMI). CONCLUSION: This study shows that hospitalized patients in Kenya are experiencing pain and that this pain is often undertreated.Item Race and sex differences in response to endothelin receptor antagonists for pulmonary arterial hypertension(Elsevier, 2012-01) Gabler, Nicole B.; French, Benjamin; Strom, Brian L.; Liu, Ziyue; Palevsky, Harold I.; Taichman, Darren B.; Kawut, Steven M.; Halpern, Scott D.; Biostatistics, School of Public HealthBackground Recently studied therapies for pulmonary arterial hypertension (PAH) have improved outcomes among populations of patients, but little is known about which patients are most likely to respond to specific treatments. Differences in endothelin-1 biology between sexes and between whites and blacks may lead to differences in patients' responses to treatment with endothelin receptor antagonists (ERAs). Methods We conducted pooled analyses of deidentified, patient-level data from six randomized placebo-controlled trials of ERAs submitted to the US Food and Drug Administration to elucidate heterogeneity in treatment response. We estimated the interaction between treatment assignment (ERA vs placebo) and sex and between treatment and white or black race in terms of the change in 6-min walk distance from baseline to 12 weeks. Results Trials included 1,130 participants with a mean age of 49 years; 21% were men, 74% were white, and 6% were black. The placebo-adjusted response to ERAs was 29.7 m (95% CI, 3.7-55.7 m) greater in women than in men (P = .03). The placebo-adjusted response was 42.2 m for whites and −1.4 m for blacks, a difference of 43.6 m (95% CI, −3.5-90.7 m) (P = .07). Similar results were found in sensitivity analyses and in secondary analyses using the outcome of absolute distance walked. Conclusions Women with PAH obtain greater responses to ERAs than do men, and whites may experience a greater treatment benefit than do blacks. This heterogeneity in treatment-response may reflect pathophysiologic differences between sexes and races or distinct disease phenotypes.Item A systems approach for discovering linoleic acid derivatives that potentially mediate pain and itch(American Association for the Advancement of Science, 2017-08-22) Ramsden, Christopher E.; Domenichiello, Anthony F.; Yuan, Zhi-Xin; Sapio, Matthew R.; Keyes, Gregory S.; Mishra, Santosh K.; Gross, Jacklyn R.; Majchrzak-Hong, Sharon; Zamora, Daisy; Horowitz, Mark S.; Davis, John M.; Sorokin, Alexander V.; Dey, Amit; LaPaglia, Danielle M.; Wheeler, Joshua J.; Vasko, Michael R.; Mehta, Nehal N.; Mannes, Andrew J.; Iadarola, Michael J.; Pharmacology and Toxicology, School of MedicineChronic pain and itch are common hypersensitivity syndromes that are affected by endogenous mediators. We applied a systems-based, translational approach to predict, discover, and characterize mediators of pain and itch that are regulated by diet and inflammation. Profiling of tissue-specific precursor abundance and biosynthetic gene expression predicted that inflamed skin would be abundant in four previously unknown 11-hydroxy-epoxy- or 11-keto-epoxy-octadecenoate linoleic acid derivatives and four previously identified 9- or 13-hydroxy-epoxy- or 9- or 13-keto-epoxy-octadecenoate linoleic acid derivatives. All of these mediators were confirmed to be abundant in rat and human skin by mass spectrometry. However, only the two 11-hydroxy-epoxy-octadecenoates sensitized rat dorsal root ganglion neurons to release more calcitonin gene-related peptide (CGRP), which is involved in pain transmission, in response to low pH (which mimics an inflammatory state) or capsaicin (which activates ion channels involved in nociception). The two 11-hydroxy-epoxy-octadecenoates share a 3-hydroxy-Z-pentenyl-E-epoxide moiety, thus suggesting that this substructure could mediate nociceptor sensitization. In rats, intradermal hind paw injection of 11-hydroxy-12,13-trans-epoxy-(9Z)-octadecenoate elicited C-fiber-mediated sensitivity to thermal pain. In a randomized trial testing adjunctive strategies to manage refractory chronic headaches, reducing the dietary intake of linoleic acid was associated with decreases in plasma 11-hydroxy-12,13-trans-epoxy-(9Z)-octadecenoate, which correlated with clinical pain reduction. Human psoriatic skin had 30-fold higher 9-keto-12,13-trans-epoxy-(10E)-octadecenoate compared to control skin, and intradermal injection of this compound induced itch-related scratching behavior in mice. Collectively, these findings define a family of endogenous mediators with potential roles in pain and itch.Item Tissue-specific network-based genome wide study of amygdala imaging phenotypes to identify functional interaction modules(Oxford University Press, 2017-10-15) Yao, Xiaohui; Yan, Jingwen; Liu, Kefei; Kim, Sungeun; Nho, Kwangsik; Risacher, Shannon L.; Greene, Casey S.; Moore, Jason H.; Saykin, Andrew J.; Shen, Li; Alzheimer’s Disease Neuroimaging Initiative; BioHealth Informatics, School of Informatics and ComputingMotivation: Network-based genome-wide association studies (GWAS) aim to identify functional modules from biological networks that are enriched by top GWAS findings. Although gene functions are relevant to tissue context, most existing methods analyze tissue-free networks without reflecting phenotypic specificity. Results: We propose a novel module identification framework for imaging genetic studies using the tissue-specific functional interaction network. Our method includes three steps: (i) re-prioritize imaging GWAS findings by applying machine learning methods to incorporate network topological information and enhance the connectivity among top genes; (ii) detect densely connected modules based on interactions among top re-prioritized genes; and (iii) identify phenotype-relevant modules enriched by top GWAS findings. We demonstrate our method on the GWAS of [18F]FDG-PET measures in the amygdala region using the imaging genetic data from the Alzheimer's Disease Neuroimaging Initiative, and map the GWAS results onto the amygdala-specific functional interaction network. The proposed network-based GWAS method can effectively detect densely connected modules enriched by top GWAS findings. Tissue-specific functional network can provide precise context to help explore the collective effects of genes with biologically meaningful interactions specific to the studied phenotype.