Master of Science

thesisWe present a framework for detecting possible adverse drug reactions (ADRs) using Utah Medicaid administrative data. We examined four classes of ADRs associated with treatment of dementia by acetylcholinesterase inhibitors (AChEIs): known reactions (gastrointestinal, psychological disturbances), potential reactions (respiratory disturbance), novel reactions (hepatic, hematological disturbances), and death. Our cohort design linked drug utilization data to medical claims from Utah Medicaid recipients. We restricted the analysis to beneficiaries 50 years and older who had a dementia-related diagnosis. We compared patients treated with AChEIs to patients untreated with antidementia medication therapy. We attempted to remove confounding by establishing propensity-score-matched cohorts for each outcome investigated; we then evaluated effects of drug treatment by conditional multivariable Cox-proportional-hazard regression. Acute and transient effects were evaluated by a crossover design using conditional logistic regression. Propensity-matched analysis of expected reactions found that AChEI treatment was associated with gastrointestinal episodes (hazards ratio [HR]: 2.02; 95% confidence interval [CI]: 1.28-3.2) but not psychological episodes, respiratory disturbance, or death. Among the tested unexpected reactions, the risk was higher with hematological episodes (HR: 2.32; 95% CI: 1.47-3.6) but not hepatic episodes. We also noted a trend towards an increase in the odds of experiencing acute hematological events in the treated group (odds ratio [OR]: 3.0; 95% CI: 0.97-9.3). We observed an expected association between AChEIs and gastrointestinal disturbances and detected a signal of hematological adverse drug events (ADEs) after treatment with AChEIs in this pilot study. Using our analytic framework may raise awareness of potential ADEs and generate hypotheses for future investigations

Factors associated with screening or treatment initiation among male United States veterans at risk for osteoporosis fracture

Male osteoporosis continues to be under-recognized and undertreated in men. An understanding of which factors cue clinicians about osteoporosis risk in men, and which do not, is needed to identify areas for improvement. This study sought to measure the association of a provider\u27s recognition of osteoporosis with patient information constructs that are available at the time of each encounter. Using clinical and administrative data from the Veterans Health Administration system, we used a stepwise procedure to construct prognostic models for a combined outcome of osteoporosis diagnosis, treatment, or a bone mineral density (BMD) test order using time-varying covariates and Cox regression. We ran separate models for patients with at least one primary care visit and patients with only secondary care visits in the pre-index period. Some of the strongest predictors of clinical osteoporosis identification were history of gonadotropin-releasing hormone (GnRH) agonist exposure, fragility fractures, and diagnosis of rheumatoid arthritis. Other characteristics associated with a higher likelihood of having osteoporosis risk recognized were underweight or normal body mass index, cancer, fall history, and thyroid disease. Medication exposures associated with osteoporosis risk recognition included opioids, glucocorticoids, and antidepressants. Several known clinical risk factors for fracture were not correlated with osteoporosis risk including smoking and alcohol abuse. Results suggest that clinicians are relying on some, but not all, clinical risk factors when assessing osteoporosis risk

Learning to detect and understand drug discontinuation events from clinical narratives

OBJECTIVE: Identifying drug discontinuation (DDC) events and understanding their reasons are important for medication management and drug safety surveillance. Structured data resources are often incomplete and lack reason information. In this article, we assessed the ability of natural language processing (NLP) systems to unlock DDC information from clinical narratives automatically. MATERIALS AND METHODS: We collected 1867 de-identified providers\u27 notes from the University of Massachusetts Medical School hospital electronic health record system. Then 2 human experts chart reviewed those clinical notes to annotate DDC events and their reasons. Using the annotated data, we developed and evaluated NLP systems to automatically identify drug discontinuations and reasons at the sentence level using a novel semantic enrichment-based vector representation (SEVR) method for enhanced feature representation. RESULTS: Our SEVR-based NLP system achieved the best performance of 0.785 (AUC-ROC) for detecting discontinuation events and 0.745 (AUC-ROC) for identifying reasons when testing this highly imbalanced data, outperforming 2 state-of-the-art non-SEVR-based models. Compared with a rule-based baseline system for discontinuation detection, our system improved the sensitivity significantly (57.75% vs 18.31%, absolute value) while retaining a high specificity of 99.25%, leading to a significant improvement in AUC-ROC by 32.83% (absolute value). CONCLUSION: Experiments have shown that a high-performance NLP system can be developed to automatically identify DDCs and their reasons from providers\u27 notes. The SEVR model effectively improved the system performance showing better generalization and robustness on unseen test data. Our work is an important step toward identifying reasons for drug discontinuation that will inform drug safety surveillance and pharmacovigilance

HIV-1/HSV-2 Co-Infected Adults in Early HIV-1 Infection Have Elevated CD4+ T Cell Counts

Introduction. HIV-1 is often acquired in the presence of pre-existing co-infections, such as Herpes Simplex Virus 2 (HSV-2). We examined the impact of HSV-2 status at the time of HIV-1 acquisition for its impact on subsequent clinical course, and total CD4+ T cell phenotypes. Methods. We assessed the relationship of HSV-1/HSV-2 co-infection status on CD4+ T cell counts and HIV-1 RNA levels over time prior in a cohort of 186 treatment naive adults identified during early HIV-1 infection. We assessed the activation and differentiation state of total CD4+ T cells at study entry by HSV-2 status. Results. of 186 recently HIV-1 infected persons, 101 (54%) were sero-positive for HSV-2. There was no difference in initial CD8+ T cell count, or differences between the groups for age, gender, or race based on HSV-2 status. Persons with HIV-1/HSV-2 co-infection sustained higher CD4+ T cell counts over time (+69 cells/ul greater (SD = 33.7, p = 0.04) than those with HIV-1 infection alone (Figure 1), after adjustment for HIV-1 RNA levels (-57 cells per 1 log(10) higher HIV-1 RNA, p<0.0001). We did not observe a relationship between HSV-2 infection status with plasma HIV-1 RNA levels over time. HSV-2 acquistion after HIV-1 acquisition had no impact on CD4+ count or viral load. We did not detect differences in CD4+ T cell activation or differentiation state by HSV-2+ status. Discussion. We observed no effect of HSV-2 status on viral load. However, we did observe that treatment naive, recently HIV-1 infected adults co-infected with HSV-2+ at the time of HIV-1 acquisition had higher CD4+ T cell counts over time. If verified in other cohorts, this result poses a striking paradox, and its public health implications are not immediately clear.Brazilian Program for STD and AIDS, Ministry of HealthSão Paulo City Health DepartmentFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)NIAID/NIHJohn E. Fogarty International CenterAIDS Research Institute of the AIDS Biology Program at UCSFCoordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Brazilian Ministry of EducationUniversidade Federal de São Paulo, Div Infect Dis, São Paulo, BrazilUniv Calif San Francisco, San Francisco Gen Hosp, Div HIV AIDS, San Francisco, CA USAUniv Calif San Francisco, Dept Expt Med, San Francisco, CA USASao Paula City Hlth Syst, São Paulo, BrazilUniversidade Federal de São Paulo, Div Infect Dis, São Paulo, BrazilBrazilian Program for STD and AIDS, Ministry of Health: 914/BRA/3014 UNESCO/KallasSão Paulo City Health Department: 2004-0.168.922-7/KallasFAPESP: 04/15856-9/KallasNIAID/NIH: AI066917/BarbourNIAID/NIH: AI064520/NixonJohn E. Fogarty International Center: D43 TW00003Web of Scienc

Solar Neutrino Constraints on the BBN Production of Li

Using the recent WMAP determination of the baryon-to-photon ratio, 10^{10} \eta = 6.14 to within a few percent, big bang nucleosynthesis (BBN) calculations can make relatively accurate predictions of the abundances of the light element isotopes which can be tested against observational abundance determinations. At this value of \eta, the Li7 abundance is predicted to be significantly higher than that observed in low metallicity halo dwarf stars. Among the possible resolutions to this discrepancy are 1) Li7 depletion in the atmosphere of stars; 2) systematic errors originating from the choice of stellar parameters - most notably the surface temperature; and 3) systematic errors in the nuclear cross sections used in the nucleosynthesis calculations. Here, we explore the last possibility, and focus on possible systematic errors in the He3(\alpha,\gamma)Be7 reaction, which is the only important Li7 production channel in BBN. The absolute value of the cross section for this key reaction is known relatively poorly both experimentally and theoretically. The agreement between the standard solar model and solar neutrino data thus provides additional constraints on variations in the cross section (S_{34}). Using the standard solar model of Bahcall, and recent solar neutrino data, we can exclude systematic S_{34} variations of the magnitude needed to resolve the BBN Li7 problem at > 95% CL. Additional laboratory data on He3(\alpha,\gamma)Be7 will sharpen our understanding of both BBN and solar neutrinos, particularly if care is taken in determining the absolute cross section and its uncertainties. Nevertheless, it already seems that this ``nuclear fix'' to the Li7 BBN problem is unlikely; other possible solutions are briefly discussed.Comment: 21 pages, 3 ps figure

Selective Deletion of PTEN in Dopamine Neurons Leads to Trophic Effects and Adaptation of Striatal Medium Spiny Projecting Neurons

The widespread distribution of the tumor suppressor PTEN in the nervous system suggests a role in a broad range of brain functions. PTEN negatively regulates the signaling pathways initiated by protein kinase B (Akt) thereby regulating signals for growth, proliferation and cell survival. Pten deletion in the mouse brain has revealed its role in controlling cell size and number. In this study, we used Cre-loxP technology to specifically inactivate Pten in dopamine (DA) neurons (Pten KO mice). The resulting mutant mice showed neuronal hypertrophy, and an increased number of dopaminergic neurons and fibers in the ventral mesencephalon. Interestingly, quantitative microdialysis studies in Pten KO mice revealed no alterations in basal DA extracellular levels or evoked DA release in the dorsal striatum, despite a significant increase in total DA tissue levels. Striatal dopamine receptor D1 (DRD1) and prodynorphin (PDyn) mRNA levels were significantly elevated in KO animals, suggesting an enhancement in neuronal activity associated with the striatonigral projection pathway, while dopamine receptor D2 (DRD2) and preproenkephalin (PPE) mRNA levels remained unchanged. In addition, PTEN inactivation protected DA neurons and significantly enhanced DA-dependent behavioral functions in KO mice after a progressive 6OHDA lesion. These results provide further evidence about the role of PTEN in the brain and suggest that manipulation of the PTEN/Akt signaling pathway during development may alter the basal state of dopaminergic neurotransmission and could provide a therapeutic strategy for the treatment of Parkinson's disease, and other neurodegenerative disorders

Loss of apical monocilia on collecting duct principal cells impairs ATP secretion across the apical cell surface and ATP-dependent and flow-induced calcium signals

Renal epithelial cells release ATP constitutively under basal conditions and release higher quantities of purine nucleotide in response to stimuli. ATP filtered at the glomerulus, secreted by epithelial cells along the nephron, and released serosally by macula densa cells for feedback signaling to afferent arterioles within the glomerulus has important physiological signaling roles within kidneys. In autosomal recessive polycystic kidney disease (ARPKD) mice and humans, collecting duct epithelial cells lack an apical central cilium or express dysfunctional proteins within that monocilium. Collecting duct principal cells derived from an Oak Ridge polycystic kidney (orpkTg737) mouse model of ARPKD lack a well-formed apical central cilium, thought to be a sensory organelle. We compared these cells grown as polarized cell monolayers on permeable supports to the same cells where the apical monocilium was genetically rescued with the wild-type Tg737 gene that encodes Polaris, a protein essential to cilia formation. Constitutive ATP release under basal conditions was low and not different in mutant versus rescued monolayers. However, genetically rescued principal cell monolayers released ATP three- to fivefold more robustly in response to ionomycin. Principal cell monolayers with fully formed apical monocilia responded three- to fivefold greater to hypotonicity than mutant monolayers lacking monocilia. In support of the idea that monocilia are sensory organelles, intentionally harsh pipetting of medium directly onto the center of the monolayer induced ATP release in genetically rescued monolayers that possessed apical monocilia. Mechanical stimulation was much less effective, however, on mutant orpk collecting duct principal cell monolayers that lacked apical central monocilia. Our data also show that an increase in cytosolic free Ca2+ primes the ATP pool that is released in response to mechanical stimuli. It also appears that hypotonic cell swelling and mechanical pipetting stimuli trigger release of a common ATP pool. Cilium-competent monolayers responded to flow with an increase in cell Ca2+ derived from both extracellular and intracellular stores. This flow-induced Ca2+ signal was less robust in cilium-deficient monolayers. Flow-induced Ca2+ signals in both preparations were attenuated by extracellular gadolinium and by extracellular apyrase, an ATPase/ADPase. Taken together, these data suggest that apical monocilia are sensory organelles and that their presence in the apical membrane facilitates the formation of a mature ATP secretion apparatus responsive to chemical, osmotic, and mechanical stimuli. The cilium and autocrine ATP signaling appear to work in concert to control cell Ca2+. Loss of a cilium-dedicated autocrine purinergic signaling system may be a critical underlying etiology for ARPKD and may lead to disinhibition and/or upregulation of multiple sodium (Na+) absorptive mechanisms and a resultant severe hypertensive phenotype in ARPKD and, possibly, other diseases

Characterizing Emerging Canine H3 Influenza Viruses.

The continual emergence of novel influenza A strains from non-human hosts requires constant vigilance and the need for ongoing research to identify strains that may pose a human public health risk. Since 1999, canine H3 influenza A viruses (CIVs) have caused many thousands or millions of respiratory infections in dogs in the United States. While no human infections with CIVs have been reported to date, these viruses could pose a zoonotic risk. In these studies, the National Institutes of Allergy and Infectious Diseases (NIAID) Centers of Excellence for Influenza Research and Surveillance (CEIRS) network collaboratively demonstrated that CIVs replicated in some primary human cells and transmitted effectively in mammalian models. While people born after 1970 had little or no pre-existing humoral immunity against CIVs, the viruses were sensitive to existing antivirals and we identified a panel of H3 cross-reactive human monoclonal antibodies (hmAbs) that could have prophylactic and/or therapeutic value. Our data predict these CIVs posed a low risk to humans. Importantly, we showed that the CEIRS network could work together to provide basic research information important for characterizing emerging influenza viruses, although there were valuable lessons learned