Ryan S Sprissler

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• Hollister, J., Porter, C., Sprissler, R., Beitel, S. C., Romine, J. K., Uhrlaub, J. L., Grant, L., Yoo, Y. M., Fowlkes, A., Britton, A., Olsho, L. E., Newes-Adeyi, G., Fuller, S., Zheng, P. Q., Gaglani, M., Rose, S., Dunnigan, K., Naleway, A. L., Gwynn, L., , Caban-Martinez, A., et al. (2024). Risk reduction in SARS-CoV-2 infection and reinfection conferred by humoral antibody levels among essential workers during Omicron predominance. PloS one, 19(12), e0306953.
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  The extent to which semi-quantitative antibody levels confer protection against SARS-CoV-2 infection in populations with heterogenous immune histories is unclear. Two nested case-control studies were designed within the multisite HEROES/RECOVER prospective cohort of frontline workers to study the relationship between antibody levels and protection against first-time post-vaccination infection and reinfection with SARS-CoV-2 from December 2021 to January 2023. All participants submitted weekly nasal swabs for rRT-PCR testing and blood samples quarterly and following infection or vaccination. Cases of first-time post-vaccination infection following a third dose of monovalent (origin strain WA-1) mRNA vaccine (n = 613) and reinfection (n = 350) were 1:1 matched to controls based on timing of blood draw and other potential confounders. Conditional logistic regression models were fit to estimate infection risk reductions associated with 3-fold increases in end titers for receptor binding domain (RBD). In first-time post-vaccination and reinfection study samples, most were female (67%, 57%), non-Hispanic (82%, 68%), and without chronic conditions (65%, 65%). The odds of first-time post-vaccination infection were reduced by 21% (aOR = 0.79, 95% CI = [0.66-0.96]) for each 3-fold increase in RBD end titers. The odds of reinfection associated with a 3-fold increase in RBD end titers were reduced by 23% (aOR = 0.77, 95% CI = [0.65-0.92] for unvaccinated individuals and 58% (aOR = 0.42, 95% CI = [0.22-0.84]) for individuals with three mRNA vaccine doses following their first infection. Frontline workers with higher antibody levels following a third dose of mRNA COVID-19 vaccine were at reduced risk of SARS-CoV-2 during Omicron predominance. Among those with previous infections, the point estimates of risk reduction associated with antibody levels was greater for those with three vaccine doses compared to those who were unvaccinated.
• Porter, C., Lyski, Z., Uhrlaub, J., Ellingson, K., Jeddy, Z., Gwynn, L., Rivers, P., Sprissler, R., Hegmann, K., Coughlin, M., Fowlkes, A., Hollister, J., LeClair, L., Mak, J., Beitel, S., Fuller, S., Zheng, P., Vaughan, M., Rai, R., , Grant, L., et al. (2024). Evaluating Immunologic and Illness Outcomes of SARS-CoV-2 Infection in Vaccinated and Unvaccinated Children Aged ≥ 5 Years, in a Multisite Longitudinal Cohort. Diseases, 12(8). doi:10.3390/diseases12080171
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  Hybrid immunity, as a result of infection and vaccination to SARS-CoV-2, has been well studied in adults but limited evidence is available in children. We evaluated the antibody responses to primary SARS-CoV-2 infection among vaccinated and unvaccinated children aged ≥ 5 years. Methods: A longitudinal cohort study of children aged ≥ 5 was conducted during August 2021–August 2022, at sites in Arizona, Texas, Utah, and Florida. Children submitted weekly nasal swabs for PCR testing and provided sera 14–59 days after PCR-confirmed SARS-CoV-2 infection. Antibodies were measured by ELISA against the receptor-binding domain (RBD) and S2 domain of ancestral Spike (WA1), in addition to Omicron (BA.2) RBD, following infection in children, with and without prior monovalent ancestral mRNA COVID-19 vaccination. Results: Among the 257 participants aged 5 to 18 years, 166 (65%) had received at least two mRNA COVID-19 vaccine doses ≥ 14 days prior to infection. Of these, 53 occurred during Delta predominance, with 37 (70%) unvaccinated at the time of infection. The remaining 204 infections occurred during Omicron predominance, with 53 (26%) participants unvaccinated. After adjusting for weight, age, symptomatic infection, and gender, significantly higher mean RBD AUC values were observed among the vaccinated group compared to the unvaccinated group for both WA1 and Omicron (p < 0.0001). A smaller percentage of vaccinated children reported fever during illness, with 55 (33%) reporting fever compared to 44 (48%) unvaccinated children reporting fever (p = 0.021). Conclusions: Children with vaccine-induced immunity at the time of SARS-CoV-2 infection had higher antibody levels during convalescence and experienced less fever compared to unvaccinated children during infection.
• Romine, J. K., Li, H., Coughlin, M. M., Jones, J. M., Britton, A., Tyner, H. L., Fuller, S. B., Bloodworth, R., Edwards, L. J., Etoule, J. N., Morrill, T. C., Newes-Adeyi, G., Olsho, L. E., Gaglani, M., Fowlkes, A., Hollister, J., Bedrick, E. J., Uhrlaub, J. L., Beitel, S., , Sprissler, R. S., et al. (2024). Hybrid immunity and SARS-CoV-2 antibodies: results of the HEROES-RECOVER prospective cohort study. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.
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  There are limited data on whether hybrid immunity differs by count and order of immunity-conferring events (SARS-CoV-2 infection or COVID-19 vaccination). From a cohort of health care personnel, first responders, and other frontline workers in six US states, we examined heterogeneity of the effect of hybrid immunity on SARS-CoV-2 antibody levels.
• Sprissler, R., Hammer, M., Labiner, D., Joshi, N., Alan, A., & Weinand, M. (2024). Leukocyte differential gene expression prognostic value for high versus low seizure frequency in temporal lobe epilepsy. BMC neurology, 24(1), 16.
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  This study was performed to test the hypothesis that systemic leukocyte gene expression has prognostic value differentiating low from high seizure frequency refractory temporal lobe epilepsy (TLE).
• Herring, M. K., Romine, J. K., Wesley, M. G., Ellingson, K. D., Yoon, S. K., Caban-Martinez, A. J., Meece, J., Gaglani, M., Grant, L., Olsho, L. E., Tyner, H. L., Naleway, A. L., Khan, S. M., Phillips, A. L., Solle, N. S., Rose, S., Mak, J., Fuller, S. B., Hunt, A., , Kuntz, J. L., et al. (2023). Severe Acute Respiratory Syndrome Coronavirus 2 Infection History and Antibody Response to 3 Coronavirus Disease 2019 Messenger RNA Vaccine Doses. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 76(10), 1822-1831.
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  Data on antibody kinetics are limited among individuals previously infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). From a cohort of healthcare personnel and other frontline workers in 6 US states, we assessed antibody waning after messenger RNA (mRNA) dose 2 and response to dose 3 according to SARS-CoV-2 infection history.
• Hollister, J., Caban-Martinez, A. J., Ellingson, K. D., Beitel, S., Fowlkes, A. L., Lutrick, K., Tyner, H. L., Naleway, A. L., Yoon, S. K., Gaglani, M., Hunt, D., Meece, J., Mayo Lamberte, J., Schaefer Solle, N., Rose, S., Dunnigan, K., Khan, S. M., Kuntz, J. L., Fisher, J. M., , Coleman, A., et al. (2023). Serum per- and polyfluoroalkyl substance concentrations and longitudinal change in post-infection and post-vaccination SARS-CoV-2 antibodies. Environmental research, 239(Pt 1), 117297.
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  Per- and polyfluoroalkyl substances (PFAS) are ubiquitous throughout the United States. Previous studies have shown PFAS exposure to be associated with a reduced immune response. However, the relationship between serum PFAS and antibody levels following SARS-CoV-2 infection or COVID-19 vaccination has not been examined. We examined differences in peak immune response and the longitudinal decline of antibodies following SARS-CoV-2 infection and COVID-19 vaccination by serum PFAS levels in a cohort of essential workers in the United States. We measured serum antibodies using an in-house semi-quantitative enzyme-linked immunosorbent assay (ELISA). Two cohorts contributed blood samples following SARS-CoV-2 infection or COVID-19 vaccination. We used linear mixed regression models, adjusting for age, race/ethnicity, gender, presence of chronic conditions, location, and occupation, to estimate differences in immune response with respect to serum PFAS levels. Our study populations included 153 unvaccinated participants that contributed 316 blood draws over a 14-month period following infection, and 860 participants and 2451 blood draws over a 12-month period following vaccination. Higher perfluorooctane sulfonic acid (PFOS), perfluorohexane sulfonic acid (PFHxS), and perfluorononanoic acid (PFNA) concentrations were associated with a lower peak antibody response after infection (p = 0.009, 0.031, 0.015). Higher PFOS, perfluorooctanoic acid (PFOA), PFHxS, and PFNA concentrations were associated with slower declines in antibodies over time after infection (p = 0.003, 0.014, 0.026, 0.025). PFOA, PFOS, PFHxS, and PFNA serum concentrations prior to vaccination were not associated with differences in peak antibody response after vaccination or with differences in decline of antibodies over time after vaccination. These results suggest that elevated PFAS may impede potential immune response to SARS-CoV-2 infection by blunting peak antibody levels following infection; the same finding was not observed for immune response to vaccination.
• Lafleur, B. J., White, L., Dake, M. D., Nikolich, J. Z., Sprissler, R., & Bhattacharya, D. (2023). No Evidence That Analgesic Use after COVID-19 Vaccination Negatively Impacts Antibody Responses. ImmunoHorizons, 7(12), 834-841.
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  Uptake of mRNA vaccines, especially booster immunizations, against COVID-19 has been lower than hoped, perhaps in part due to their reactogenicity. Analgesics might alleviate symptoms associated with vaccination, but they might also impact immune responses. We semiquantitatively measured Ab responses following COVID-19 vaccination in 2354 human participants surveyed about analgesic use after vaccination. Participants who used nonsteroidal anti-inflammatory drugs or acetaminophen after vaccination showed elevated Ab levels against the receptor-binding domain of Spike protein relative to those who did not use analgesics. This pattern was observed for both mRNA-1273 and BNT162b2 and across age groups. Participants who used analgesics more frequently reported fatigue, muscle aches, and headaches than did those who did not use painkillers. Among participants who reported these symptoms, we observed no statistically significant differences in Ab levels irrespective of analgesic use. These data suggest that elevated Ab levels are associated with symptoms and inflammatory processes rather than painkiller use per se. Taken together, we find no evidence that analgesic use reduces Ab responses after COVID-19 vaccination. Recommendation of their use to alleviate symptoms might improve uptake of booster immunizations.
• Lyski, Z. L., Porter, C., Uhrlaub, J. L., Ellingson, K. D., Jeddy, Z., Gwynn, L., Rivers, P., Sprissler, R., Hegmann, K. T., Coughlin, M., Fowlkes, A., Hollister, J., LeClair, L., Mak, J., Beitel, S. C., Fuller, S., Grant, L., Newes-Adeyi, G., Yoo, Y. M., , Olsho, L., et al. (2023).

  Humoral Immune Response to Messenger RNA Coronavirus Disease 2019 Vaccination Among Children Aged 5–11 Years in a Multisite Prospective Cohort Study, September 2021–September 2022

  . Open Forum Infectious Diseases, 10(8). doi:10.1093/ofid/ofad431
• Lyski, Z. L., Porter, C., Uhrlaub, J. L., Ellingson, K. D., Jeddy, Z., Gwynn, L., Rivers, P., Sprissler, R., Hegmann, K. T., Coughlin, M., Fowlkes, A., Hollister, J., LeClair, L., Mak, J., Beitel, S. C., Fuller, S., Grant, L., Newes-Adeyi, G., Yoo, Y. M., , Olsho, L., et al. (2023). Humoral Immune Response to Messenger RNA Coronavirus Disease 2019 Vaccination Among Children Aged 5-11 Years in a Multisite Prospective Cohort Study, September 2021-September 2022. Open forum infectious diseases, 10(8), ofad431.
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  The PROTECT study is a longitudinal cohort study initiated in July 2021 with weekly testing for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in 4 states: Arizona, Florida, exas, and Utah. This study aims to examine vaccine-elicited antibody response against postvaccination SARS-CoV-2 infections.
• Quirk, G. E., Schoenle, M. V., Peyton, K. L., Uhrlaub, J. L., Lau, B., Burgess, J. L., Ellingson, K., Beitel, S., Romine, J., Lutrick, K., Fowlkes, A., Britton, A., Tyner, H. L., Caban-Martinez, A. J., Naleway, A., Gaglani, M., Yoon, S., Edwards, L., Olsho, L., , Dake, M., et al. (2023). Determinants of B cell responses to drifted epitopes in post-vaccination SARS-CoV-2 infections. medRxiv : the preprint server for health sciences.
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  Vaccine-induced immunity may impact subsequent responses to drifted epitopes in SARS-CoV-2 variants, but this has been difficult to quantify due to the challenges in recruiting unvaccinated control groups whose first exposure to SARS-CoV-2 is a primary infection. Through local, statewide, and national SARS-CoV-2 testing programs, we were able to recruit cohorts of individuals who had recovered from either primary or post-vaccination infections by either the Delta or Omicron BA.1 variants. Regardless of variant, we observed greater Spike-specific and neutralizing antibody responses in post-vaccination infections than in those who were infected without prior vaccination. Through analysis of variant-specific memory B cells as markers of responses, we observed that Delta and Omicron BA.1 infections led to a marked shift in immunodominance in which some drifted epitopes elicited minimal responses, even in primary infections. Prior immunity through vaccination had a small negative impact on these responses, but this did not correlate with cross-reactive memory B cells, arguing against competitive inhibition of naïve B cells. We conclude that dampened B cell responses against drifted epitopes are mostly a function of altered immunodominance hierarchies that are apparent even in primary infections, with a more modest contribution from pre-existing immunity, perhaps due to accelerated antigen clearance.
• Sprissler, R. S. (2023). Leukocyte gene expression predicts human temporal lobe epilepsy seizure frequency. BMC Neurology. doi:10.21203/rs.3.rs-2070618/v1
• Arani, G., Beitel, S., Burgess, J. L., Caban-Martinez, A. J., Edwards, T., Ellingson, K. D., Fowlkes, A. L., Fuller, S. B., Gaglani, M., Grant, L., Herring, M. K., Hunt, A., Khan, S. M., Kuntz, J. L., Lamberte, J. M., Lowe, A. A., Lutrick, K., Mak, J., Meece, J., , Naleway, A. L., et al. (2022).

  Severe Acute Respiratory Syndrome Coronavirus 2 Infection History and Antibody Response to 3 Coronavirus Disease 2019 Messenger RNA Vaccine Doses

  . Clinical Infectious Diseases, 76(10), 1822-1831. doi:10.1093/cid/ciac976
• Jergović, M., Uhrlaub, J. L., Watanabe, M., Bradshaw, C. M., White, L. M., LaFleur, B. J., Edwards, T., Sprissler, R., Worobey, M., Bhattacharya, D., & Nikolich-Žugich, J. (2022). Competent immune responses to SARS-CoV-2 variants in older adults following two doses of mRNA vaccination. Nature communications, 13(1), 2891.
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  Aging is associated with a reduced magnitude of primary immune responses to vaccination. mRNA-based SARS-CoV-2 vaccines have shown efficacy in older adults but virus variant escape is still unclear. Here we analyze humoral and cellular immunity against an early-pandemic viral isolate and compare that to the P.1 (Gamma) and B.1.617.2 (Delta) variants in two cohorts (55 age) of mRNA vaccine recipients. We further measure neutralizing antibody titers for B.1.617.1 (Kappa) and B.1.595, with the latter SARS-CoV-2 isolate bearing the spike mutation E484Q. Robust humoral immunity is measured following second vaccination, and older vaccinees manifest cellular immunity comparable to the adult group against early-pandemic SARS-CoV-2 and more recent variants. More specifically, the older cohort has lower neutralizing capacity at 7-14 days following the second dose but equilibrates with the younger cohort after 2-3 months. While long-term vaccination responses remain to be determined, our results implicate vaccine-induced protection in older adults against SARS-CoV-2 variants and inform thinking about boost vaccination.
• Kang, H., Allison, S., Spangenberg, A., Carr, T., Sprissler, R., Halonen, M., & Cusanovich, D. A. (2022). Evaluation of Swab-Seq as a scalable, sensitive assay for community surveillance of SARS-CoV-2 infection. Scientific reports, 12(1), 3047.
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  The ongoing SARS-CoV-2 pandemic and subsequent demand for viral testing has led to issues in scaling diagnostic lab efforts and in securing basic supplies for collection and processing of samples. This has motivated efforts by the scientific community to establish improved protocols that are more scalable, less resource intensive, and less expensive. One such developmental effort has resulted in an assay called "Swab-Seq", so named because it was originally developed to work with dry nasal swab samples. The existing gold standard test consists of RNA extracted from a nasopharyngeal (NP) swab that is subjected to quantitative reverse transcription polymerase chain reaction (qRT-PCR). Swab-Seq adapts this method to a next-generation sequencing readout. By pairing this modification with extraction-free sampling techniques, Swab-Seq achieves high scalability, low cost per sample, and a reasonable turnaround time. We evaluated the effectiveness of this assay in a community surveillance setting by testing samples collected from both symptomatic and asymptomatic individuals using the traditional NP swab. In addition, we evaluated extraction-free sampling techniques (both saliva and saline mouth gargle samples). We found the assay to be as clinically sensitive as the qRT-PCR assay, adaptable to multiple sample types, and able to easily accommodate hundreds of samples at a time. We thus provide independent validation of Swab-Seq and extend its utility regarding sample type and sample stability. Assays of this type greatly expand the possibility of routine, noninvasive, repeated testing of asymptomatic individuals suitable for current and potential future needs.
• Snyder, E. M., Sprissler, R., & Olson, T. P. (2022). Data at 36 months for the Symplicity SPYRAL HTN-ON MED pilot. Lancet (London, England), 400(10351), 491-492.
• Betancourt, W. Q., Schmitz, B. W., Innes, G. K., Prasek, S. M., Pogreba Brown, K. M., Stark, E. R., Foster, A. R., Sprissler, R. S., Harris, D. T., Sherchan, S. P., Gerba, C. P., & Pepper, I. L. (2021). COVID-19 containment on a college campus via wastewater-based epidemiology, targeted clinical testing and an intervention. The Science of the total environment, 779, 146408.
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  Wastewater-based epidemiology has potential as an early-warning tool for determining the presence of COVID-19 in a community. The University of Arizona (UArizona) utilized WBE paired with clinical testing as a surveillance tool to monitor the UArizona community for SARS-CoV-2 in near real-time, as students re-entered campus in the fall. Positive detection of virus RNA in wastewater lead to selected clinical testing, identification, and isolation of three infected individuals (one symptomatic and two asymptomatic) that averted potential disease transmission. This case study demonstrated the value of WBE as a tool to efficiently utilize resources for COVID-19 prevention and response. Thus, WBE coupled with targeted clinical testing was further conducted on 13 dorms during the course of the Fall semester (Table 3). In total, 91 wastewater samples resulted in positive detection of SARS-CoV-2 RNA that successfully provided an early-warning for at least a single new reported case of infection (positive clinical test) among the residents living in the dorm. Overall, WBE proved to be an accurate diagnostic for new cases of COVID-19 with an 82.0% positive predictive value and an 88.9% negative predictive value. Increases in positive wastewater samples and clinical tests were noted following holiday-related activities. However, shelter-in-place policies proved to be effective in reducing the number of daily reported positive wastewater and clinical tests. This case study provides evidence for WBE paired with clinical testing and public health interventions to effectively contain potential outbreaks of COVID-19 in defined communities.
• Harris, D. T., Badowski, M., Jernigan, B., Sprissler, R., Edwards, T., Cohen, R., Paul, S., Merchant, N., Weinkauf, C. C., Bime, C., Erickson, H. E., Bixby, B., Parthasarathy, S., Chaudhary, S., Natt, B., Cristan, E., El Aini, T., Rischard, F., Campion, J., , Chopra, M., et al. (2021). SARS-CoV-2 Rapid Antigen Testing of Symptomatic and Asymptomatic Individuals on the University of Arizona Campus. Biomedicines, 9(5).
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  SARS-CoV-2, the cause of COVID19, has caused a pandemic that has infected more than 80 M and killed more than 1.6 M persons worldwide. In the US as of December 2020, it has infected more than 32 M people while causing more than 570,000 deaths. As the pandemic persists, there has been a public demand to reopen schools and university campuses. To consider these demands, it is necessary to rapidly identify those individuals infected with the virus and isolate them so that disease transmission can be stopped. In the present study, we examined the sensitivity of the Quidel Rapid Antigen test for use in screening both symptomatic and asymptomatic individuals at the University of Arizona from June to August 2020. A total of 885 symptomatic and 1551 asymptomatic subjects were assessed by antigen testing and real-time PCR testing. The sensitivity of the test for both symptomatic and asymptomatic persons was between 82 and 90%, with some caveats.
• Shroff, R. T., Chalasani, P., Wei, R., Pennington, D., Quirk, G., Schoenle, M. V., Peyton, K. L., Uhrlaub, J. L., Ripperger, T. J., Jergović, M., Dalgai, S., Wolf, A., Whitmer, R., Hammad, H., Carrier, A., Scott, A. J., Nikolich-Žugich, J., Worobey, M., Sprissler, R., , Dake, M., et al. (2021). Immune responses to two and three doses of the BNT162b2 mRNA vaccine in adults with solid tumors. Nature medicine, 27(11), 2002-2011.
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  Vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have shown high efficacy, but immunocompromised participants were excluded from controlled clinical trials. In this study, we compared immune responses to the BNT162b2 mRNA Coronavirus Disease 2019 vaccine in patients with solid tumors (n = 53) who were on active cytotoxic anti-cancer therapy to a control cohort of participants without cancer (n = 50). Neutralizing antibodies were detected in 67% of patients with cancer after the first immunization, followed by a threefold increase in median titers after the second dose. Similar patterns were observed for spike protein-specific serum antibodies and T cells, but the magnitude of each of these responses was diminished relative to the control cohort. In most patients with cancer, we detected spike receptor-binding domain and other S1-specific memory B cell subsets as potential predictors of anamnestic responses to additional immunizations. We therefore initiated a phase 1 trial for 20 cancer cohort participants of a third vaccine dose of BNT162b2 ( NCT04936997 ); primary outcomes were immune responses, with a secondary outcome of safety. At 1 week after a third immunization, 16 participants demonstrated a median threefold increase in neutralizing antibody responses, but no improvement was observed in T cell responses. Adverse events were mild. These results suggest that a third dose of BNT162b2 is safe, improves humoral immunity against SARS-CoV-2 and could be immunologically beneficial for patients with cancer on active chemotherapy.
• Snider, J. M., You, J. K., Wang, X., Snider, A. J., Hallmark, B., Zec, M. M., Seeds, M. C., Sergeant, S., Johnstone, L., Wang, Q., Sprissler, R., Carr, T. F., Lutrick, K., Parthasarathy, S., Bime, C., Zhang, H. H., Luberto, C., Kew, R. R., Hannun, Y. A., , Guerra, S., et al. (2021). Group IIA secreted phospholipase A2 is associated with the pathobiology leading to COVID-19 mortality. The Journal of clinical investigation, 131(19).
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  There is an urgent need to identify the cellular and molecular mechanisms responsible for severe COVID-19 that results in death. We initially performed both untargeted and targeted lipidomics as well as focused biochemical analyses of 127 plasma samples and found elevated metabolites associated with secreted phospholipase A2 (sPLA2) activity and mitochondrial dysfunction in patients with severe COVID-19. Deceased COVID-19 patients had higher levels of circulating, catalytically active sPLA2 group IIA (sPLA2-IIA), with a median value that was 9.6-fold higher than that for patients with mild disease and 5.0-fold higher than the median value for survivors of severe COVID-19. Elevated sPLA2-IIA levels paralleled several indices of COVID-19 disease severity (e.g., kidney dysfunction, hypoxia, multiple organ dysfunction). A decision tree generated by machine learning identified sPLA2-IIA levels as a central node in the stratification of patients who died from COVID-19. Random forest analysis and least absolute shrinkage and selection operator-based (LASSO-based) regression analysis additionally identified sPLA2-IIA and blood urea nitrogen (BUN) as the key variables among 80 clinical indices in predicting COVID-19 mortality. The combined PLA-BUN index performed significantly better than did either one alone. An independent cohort (n = 154) confirmed higher plasma sPLA2-IIA levels in deceased patients compared with levels in plasma from patients with severe or mild COVID-19, with the PLA-BUN index-based decision tree satisfactorily stratifying patients with mild, severe, or fatal COVID-19. With clinically tested inhibitors available, this study identifies sPLA2-IIA as a therapeutic target to reduce COVID-19 mortality.
• Ripperger, T. J., Uhrlaub, J. L., Watanabe, M., Wong, R., Castaneda, Y., Pizzato, H. A., Thompson, M. R., Bradshaw, C., Weinkauf, C. C., Bime, C., Erickson, H. L., Knox, K., Bixby, B., Parthasarathy, S., Chaudhary, S., Natt, B., Cristan, E., Aini, T. E., Rischard, F., , Campion, J., et al. (2020). Detection, prevalence, and duration of humoral responses to SARS-CoV-2 under conditions of limited population exposure. medRxiv : the preprint server for health sciences.
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  We conducted an extensive serological study to quantify population-level exposure and define correlates of immunity against SARS-CoV-2. We found that relative to mild COVID-19 cases, individuals with severe disease exhibited elevated authentic virus-neutralizing titers and antibody levels against nucleocapsid (N) and the receptor binding domain (RBD) and the S2 region of spike protein. Unlike disease severity, age and sex played lesser roles in serological responses. All cases, including asymptomatic individuals, seroconverted by 2 weeks post-PCR confirmation. RBD- and S2-specific and neutralizing antibody titers remained elevated and stable for at least 2-3 months post-onset, whereas those against N were more variable with rapid declines in many samples. Testing of 5882 self-recruited members of the local community demonstrated that 1.24% of individuals showed antibody reactivity to RBD. However, 18% (13/73) of these putative seropositive samples failed to neutralize authentic SARS-CoV-2 virus. Each of the neutralizing, but only 1 of the non-neutralizing samples, also displayed potent reactivity to S2. Thus, inclusion of multiple independent assays markedly improved the accuracy of antibody tests in low seroprevalence communities and revealed differences in antibody kinetics depending on the viral antigen. In contrast to other reports, we conclude that immunity is durable for at least several months after SARS-CoV-2 infection.
• Ripperger, T. J., Uhrlaub, J. L., Watanabe, M., Wong, R., Castaneda, Y., Pizzato, H. A., Thompson, M. R., Bradshaw, C., Weinkauf, C. C., Bime, C., Erickson, H. L., Knox, K., Bixby, B., Parthasarathy, S., Chaudhary, S., Natt, B., Cristan, E., El Aini, T., Rischard, F., , Campion, J., et al. (2020). Orthogonal SARS-CoV-2 Serological Assays Enable Surveillance of Low-Prevalence Communities and Reveal Durable Humoral Immunity. Immunity, 53(5), 925-933.e4.
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  We conducted a serological study to define correlates of immunity against SARS-CoV-2. Compared to those with mild coronavirus disease 2019 (COVID-19) cases, individuals with severe disease exhibited elevated virus-neutralizing titers and antibodies against the nucleocapsid (N) and the receptor binding domain (RBD) of the spike protein. Age and sex played lesser roles. All cases, including asymptomatic individuals, seroconverted by 2 weeks after PCR confirmation. Spike RBD and S2 and neutralizing antibodies remained detectable through 5-7 months after onset, whereas α-N titers diminished. Testing 5,882 members of the local community revealed only 1 sample with seroreactivity to both RBD and S2 that lacked neutralizing antibodies. This fidelity could not be achieved with either RBD or S2 alone. Thus, inclusion of multiple independent assays improved the accuracy of antibody tests in low-seroprevalence communities and revealed differences in antibody kinetics depending on the antigen. We conclude that neutralizing antibodies are stably produced for at least 5-7 months after SARS-CoV-2 infection.
• Sprissler, R. S., Perkins, B., Babiker, H. M., Chalasani, P., Johnstone, L., Lau, B., Ramos, K., Placencia, C., Gutenkunst, R. N., Mannakee, B. K., Hammer, M. F., & Mahadevan, D. (2020). Whole exome sequencing of rare tumor and matched germline DNA identifies somatic and inherited variants of clinical significance. Cancers.
• Sprissler, R., Perkins, B., Johnstone, L., Babiker, H. M., Chalasani, P., Lau, B., Hammer, M., & Mahadevan, D. (2020). Rare Tumor-Normal Matched Whole Exome Sequencing Identifies Novel Genomic Pathogenic Germline and Somatic Aberrations. Cancers, 12(6).
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  Whole exome sequencing (WES) of matched tumor-normal pairs in rare tumors has the potential to identify genome-wide mutations and copy number alterations (CNAs). We evaluated 27 rare cancer patients with tumor-normal matching by WES and tumor-only next generation sequencing (NGS) as a comparator. Our goal was to: 1) identify known and novel variants and CNAs in rare cancers with comparison to common cancers; 2) examine differences between germline and somatic variants and how that functionally impacts rare tumors; 3) detect and characterize alleles in biologically relevant genes-pathways that may be of clinical importance but not represented in classical cancer genes. We identified 3343 germline single nucleotide variants (SNVs) and small indel variants-1670 in oncogenes and 1673 in tumor suppressor genes-generating an average of 124 germline variants/case. The number of somatic SNVs and small indels detected in all cases was 523:306 in oncogenes and 217 in tumor suppressor genes. Of the germline variants, six were identified to be pathogenic or likely pathogenic. In the 27 analyzed rare cancer cases, CNAs are variable depending on tumor type, germline pathogenic variants are more common. Cell fate pathway mutations (e.g., Hippo, Notch, Wnt) dominate pathogenesis and double hit (mutation + CNV) represent ~18% cases.
• Babiker, H. M., Chalasani, P., Gutenkunst, R., Hammer, M., Johnstone, L., Lau, B., Mahadevan, D., Perkins, B., Placencia, C., Ramos, K., & Sprissler, R. (2019).

  Rare tumor with matched germline whole exome sequencing to identify somatic and inherited variants of clinical significance.

  . Journal of Clinical Oncology, 37(15_suppl), 1523-1523. doi:10.1200/jco.2019.37.15_suppl.1523
• Curry, T. B., Kelley, E. F., Olson, T. P., Snyder, E. M., & Sprissler, R. (2019).

  The Effect of Genetically Guided Mathematical Prediction and the Blood Pressure Response to Pharmacotherapy in Hypertension Patients

  . Clinical Medicine Insights: Cardiology, 13, 117954681984588. doi:10.1177/1179546819845883
• Hammer, M. F., Sprissler, R., Bina, R. W., Lau, B., Johnstone, L., Walter, C. M., Labiner, D. M., & Weinand, M. E. (2019). Altered expression of signaling pathways regulating neuronal excitability in hippocampal tissue of temporal lobe epilepsy patients with low and high seizure frequency. Epilepsy research, 155, 106145.
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  Despite recent advances in our understanding of synaptic transmission associated with epileptogenesis, the molecular mechanisms that control seizure frequency in patients with temporal lobe epilepsy (TLE) remain obscure. RNA-Seq was performed on hippocampal tissue resected from 12 medically intractable TLE patients with pre-surgery seizure frequencies ranging from 0.33 to 120 seizures per month. Differential expression (DE) analysis of individuals with low (LSF, mean = 4 seizure/month) versus high (HSF, mean = 60 seizures/month) seizure frequency identified 979 genes with ≥2-fold change in transcript abundance (FDR-adjusted p-value ö0.05). Comparisons with post-mortem controls revealed a large number of downregulated genes in the HSF (1676) versus LSF (399) groups. More than 50 signaling pathways were inferred to be deactivated or activated, with Signal Transduction as the central hub in the pathway network. While neuroinflammation pathways were activated in both groups, key neuronal system pathways were systematically deactivated in the HSF group, including calcium, CREB and Opioid signaling. We also infer that enhanced expression of a signaling cascade promoting synaptic downscaling may have played a key role in maintaining a higher seizure threshold in the LSF cohort. These results suggest that therapeutic approaches targeting synaptic scaling pathways may aid in the treatment of seizures in TLE.
• Kelley, E. F., Olson, T. P., Snyder, E. M., & Sprissler, R. (2019).

  The importance and challenges of developing a pharmacogenetics test for hypertension

  . Pharmacogenomics, 20(8), 563-566. doi:10.2217/pgs-2019-0056
• Phelps, P. K., Snyder, E. M., Walla, D. M., Ross, J. K., Simmons, J. J., Bulock, E. K., Ayres, A., Akre, M. K., Sprissler, R., & Olson, T. P. (2019). Relationship Between a Weighted Multi‐Gene Algorithm and Blood Pressure Control in Hypertension. The FASEB Journal, 33(S1). doi:10.1096/fasebj.2019.33.1_supplement.819.6
• Phelps, P., Kelley, E., Walla, D., Ross, J., Simmons, J., Bulock, E., Ayres, A., Akre, M., Sprissler, R., Olson, T., & Snyder, E. (2019). Relationship between a weighted multi-gene algorithm and blood pressure controlin hypertension. Journal of Clinical Medicine, 8(3). doi:10.3390/jcm8030289
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  Hypertension (HTN) is a complex disease with interactions among multiple organ systems, including the heart, vasculature, and kidney with a strong heritable component. Despite the multifactorial nature of HTN, no clinical guidelines utilize a multi-gene approach to guide blood pressure (BP) therapy. Non-smokers with a family history of HTN were included in the analysis (n = 384; age = 61.0 ± 0.9, 11% non-white). A total of 17 functional genotypes were weighted according to the previous effect size in the literature and entered into an algorithm. Pharmacotherapy was ranked from 1–4 as most to least likely to respond based on the algorithmic assessment of individual patient’s genotypes. Three-years of data were assessed at six-month intervals for BP and medication history. There was no difference in BP at diagnosis between groups matching the top drug recommendation using the multi-gene weighted algorithm (n = 92) vs. those who did not match (n = 292). However, from diagnosis to nadir, patients who matched the primary recommendation had a significantly greater drop in BP when compared to patients who did not. Further, the difference between diagnosis to current 1-year average BP was lower in the group that matched the top recommendation. These data suggest an association between a weighted multi-gene algorithm on the BP response to pharmacotherapy.
• Sprissler, R., Bina, R., Kasoff, W., Witte, M., Bernas, M., Walter, C., Labiner, D., Lau, B., Hammer, M., & Weinand, M. (2019). Leukocyte expression profiles reveal gene sets with prognostic value for seizure-free outcome following stereotactic laser amygdalohippocampotomy. Scientific Reports, 9(1). doi:10.1038/s41598-018-37763-5
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  Among patients with intractable epilepsy, the most commonly performed surgical procedure is craniotomy for amygdalohippocampectomy (AH). Stereotactic laser amygdalohippocampotomy (SLAH) has also been recently employed as a minimally invasive treatment for intractable temporal lobe epilepsy (TLE). Among patients treated with AH and SLAH approximately 65% and 54% of patients become seizure-free, respectively. Therefore, selection criteria for surgical candidates with improved prognostic value for post-operative seizure-free outcome are greatly needed. In this study, we perform RNA sequencing (RNA-Seq) on whole blood leukocyte samples taken from 16 patients with intractable TLE prior to SLAH to test the hypothesis that pre-operative leukocyte RNA expression profiles are prognostic for post-operative seizure outcome. Multidimensional scaling analysis of the RNA expression data indicated separate clustering of patients with seizure free (SF) and non-seizure-free (NSF) outcomes. Differential expression (DE) analysis performed on SF versus NSF groups revealed 24 significantly differentially expressed genes (≥2.0-fold change, p-value < 0.05, FDR
• Abraham, I., Akre, M. K., Alkhatib, N. S., Kelley, E. F., Olson, T. P., Snyder, S. C., Snyder, E. M., & Sprissler, R. (2018).

  Economic evaluation of a pharmacogenomic multi-gene panel test to optimize anti-hypertension therapy: simulation study

  . Journal of Medical Economics, 21(12), 1246-1253. doi:10.1080/13696998.2018.1531011
• Bina, R. W., Kasoff, W., Sprissler, R. S., Witte, M. H., Bernas, M. J., Walter, C. M., Labiner, D. M., Hammer, M., & Weinand, M. E. (2018). Leukocyte RNA expression: Prognostic value for seizure-free outcome following stereotactic laser amygdalohippocampotomy. Neurosurgery, 65(1), 94.
• Kelley, E., Snyder, E., Alkhatib, N., Snyder, S., Sprissler, R. S., Olson, T., & Abraham, I. L. (2018). Economic evaluation of a pharmacogenomic multi-gene panel test to optimize anti-hypertension therapy: simulation study.. Journal of Medical Economics, 21, 1246-1253.
• Hammer, M., Ishii, A., Johnstone, L., Tchourbanov, A., Lau, B., Sprissler, R., Hallmark, B., Zhang, M., Zhou, J., Watkins, J., & Hirose, S. (2017). Rare variants of small effect size in neuronal excitability genes influence clinical outcome in Japanese cases of SCN1A truncation-positive Dravet syndrome. PLoS ONE, 12(7). doi:10.1371/journal.pone.0180485
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  Dravet syndrome (DS) is a rare, devastating form of childhood epilepsy that is often associated with mutations in the voltage-gated sodium channel gene, SCN1A. There is considerable variability in expressivity within families, as well as among individuals carrying the same primary mutation, suggesting that clinical outcome is modulated by variants at other genes. To identify modifier gene variants that contribute to clinical outcome, we sequenced the exomes of 22 individuals at both ends of a phenotype distribution (i.e., mild and severe cognitive condition). We controlled for variation associated with different mutation types by limiting inclusion to individuals with a de novo truncation mutation resulting in SCN1A haploinsufficiency. We performed tests aimed at identifying 1) single common variants that are enriched in either phenotypic group, 2) sets of common or rare variants aggregated in and around genes associated with clinical outcome, and 3) rare variants in 237 candidate genes associated with neuronal excitability. While our power to identify enrichment of a common variant in either phenotypic group is limited as a result of the rarity of mild phenotypes in individuals with SCN1A truncation variants, our top candidates did not map to functional regions of genes, or in genes that are known to be associated with neurological pathways. In contrast, we found a statistically-significant excess of rare variants predicted to be damaging and of small effect size in genes associated with neuronal excitability in severely affected individuals. A KCNQ2 variant previously associated with benign neonatal seizures is present in 3 of 12 individuals in the severe category. To compare our results with the healthy population, we performed a similar analysis on whole exome sequencing data from 70 Japanese individuals in the 1000 genomes project. Interestingly, the frequency of rare damaging variants in the same set of neuronal excitability genes in healthy individuals is nearly as high as in severely affected individuals. Rather than a single common gene/variant modifying clinical outcome in SCN1A-related epilepsies, our results point to the cumulative effect of rare variants with little to no measurable phenotypic effect (i.e., typical genetic background) unless present in combination with a disease-causing truncation mutation in SCN1A.
• Sprissler, R., Wagnon, J., Bunton-Stasyshyn, R., Meisler, M., & Hammer, M. (2017). Altered gene expression profile in a mouse model of SCN8A encephalopathy. Experimental Neurology, 288. doi:10.1016/j.expneurol.2016.11.002
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  SCN8A encephalopathy is a severe, early-onset epilepsy disorder resulting from de novo gain-of-function mutations in the voltage-gated sodium channel Nav1.6. To identify the effects of this disorder on mRNA expression, RNA-seq was performed on brain tissue from a knock-in mouse expressing the patient mutation p.Asn1768Asp (N1768D). RNA was isolated from forebrain, cerebellum, and brainstem both before and after seizure onset, and from age-matched wildtype littermates. Altered transcript profiles were observed only in forebrain and only after seizures. The abundance of 50 transcripts increased more than 3-fold and 15 transcripts decreased more than 3-fold after seizures. The elevated transcripts included two anti-convulsant neuropeptides and more than a dozen genes involved in reactive astrocytosis and response to neuronal damage. There was no change in the level of transcripts encoding other voltage-gated sodium, potassium or calcium channels. Reactive astrocytosis was observed in the hippocampus of mutant mice after seizures. There is considerable overlap between the genes affected in this genetic model of epilepsy and those altered by chemically induced seizures, traumatic brain injury, ischemia, and inflammation. The data support the view that gain-of-function mutations of SCN8A lead to pathogenic alterations in brain function contributing to encephalopathy.
• Johnson, M. W., Sprissler, R., Olson, T. P., Beenken, G. W., & Snyder, E. M. (2016). Multi‐Gene Pharmacogenetics and Blood Pressure Control in Patients with Hypertension. The FASEB Journal, 30(S1). doi:10.1096/fasebj.30.1_supplement.942.1
• Malanga, S., Sprissler, R., Robertson, C., & Joiner, K. (2016). A problem not yet manifest: Gaps in insurance coverage of medical interventions after genetic testing. Journal of Law and the Biosciences, 2(3). doi:10.1093/jlb/lsv043
• Herrell, A., Lyons, E., Miller, S., Pivniouk, V., Pivniouk, O., Rosenbaum, D., Sprissler, R., & Vercelli, D. (2014).

  DNA methylation profiles at the human Th2 locus in BAC transgenic mice point to novel putative regulatory elements (IRM6P.720)

  . The Journal of Immunology, 192(1_Supplement), 63.12-63.12. doi:10.4049/jimmunol.192.supp.63.12
• Anderson, K., Johansson, A., Sheehan, T., Mott, B., Corby-Harris, V., Johnstone, L., Sprissler, R., & Fitz, W. (2013). Draft genome sequences of two Bifidobacterium sp. from the honey bee (Apis mellifera). Gut Pathogens, 5(1). doi:10.1186/1757-4749-5-42
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  Background: Widely considered probiotic organisms, Bifidobacteria are common inhabitants of the alimentary tract of animals including insects. Bifidobacteria identified from the honey bee are found in larval guts and throughout the alimentary tract, but attain their greatest abundance in the adult hind gut. To further understand the role of Bifidobacteria in honey bees, we sequenced two strains of Bifidobacterium cultured from different alimentary tract environments and life stages. Results: Reflecting an oxygen-rich niche, both strains possessed catalase, peroxidase, superoxide-dismutase and respiratory chain enzymes indicative of oxidative metabolism. The strains show markedly different carbohydrate processing capabilities, with one possessing auxiliary and key enzymes of the Entner-Doudoroff pathway. Conclusions: As a result of long term co-evolution, honey bee associated Bifidobacterium may harbor considerable strain diversity reflecting adaptation to a variety of different honey bee microenvironments and hive-mediated vertical transmission between generations. © 2013 Aderson et al.; licensee BioMed Central Ltd.
• Barth-Maron, A., Erickson, R. P., Greenberg, M. E., Hammer, M. F., Jentsch, T. J., Johnstone, L., Karafet, T. M., Pazzi, M., Restifo, L. L., Salogiannis, J., Sprissler, R., Stuhlmann, T., Talwar, D., Veeramah, K. R., Weinert, S., & Wolf, D. (2013).

  Exome sequencing reveals new causal mutations in children with epileptic encephalopathies

  . Epilepsia, 54(7), 1270-1281. doi:10.1111/epi.12201
• Baker, S., Wong, E., Wheatley, C., Foxx-Lupo, W., Martinez, M., Morgan, M., Sprissler, R., Morgan, W., & Snyder, E. (2012). Genetic variation of SCNN1A influences lung diffusing capacity in cystic fibrosis. Medicine and Science in Sports and Exercise, 44(12). doi:10.1249/mss.0b013e318266ebc3
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  INTRODUCTION: Epithelial Na channels (ENaCs) play a crucial role in ion and fluid regulation in the lung. In cystic fibrosis (CF), Na hyperabsorption results from ENaC overactivity, leading to airway dehydration. Previous work has demonstrated functional genetic variation of SCNN1A (the gene encoding the ENaC α-subunit), manifesting as an alanine (A) to threonine (T) substitution at amino acid 663, with the αT663 variant resulting in a more active channel. METHODS: We assessed the influence of genetic variation of SCNN1A on the diffusing capacity of the lungs for carbon monoxide (DLCO) and nitric oxide (DLNO), together with alveolar-capillary membrane conductance (DM), pulmonary capillary blood volume, and alveolar volume (VA) at rest and during peak exercise in 18 patients with CF (10 homozygous for αA663 (AA group) and 8 with at least one T663 allele (AT/TT group)). Because of the more active channel, we hypothesized that the AT/TT group would show a greater increase in DLCO, DLNO, and DM with exercise because of exercise-mediated ENaC inhibition and subsequent attenuation of Na hyperabsorption. RESULTS: The AT/TT group had significantly lower pulmonary function, weight, and body mass index than the AA group. Both groups had similar peak workloads, relative peak oxygen consumptions, and cardiopulmonary responses to exercise. The AT/TT group demonstrated a greater increase in DLNO, DLNO/VA, and DM in response to exercise (% increases: DLNO = 18 ± 11 vs 41 ± 38; DLNO/VA = 14 ± 21 vs 40 ± 37; DM = 15 ± 11 vs 41 ± 38, AA vs AT/TT, respectively). There were no differences between groups in absolute diffusing capacity measures at peak exercise. CONCLUSION: These results suggest that genetic variation of the α-subunit of ENaC differentially affects the diffusing capacity response to exercise in patients with CF. Copyright © 2012 by the American College of Sports Medicine.
• Baker, S., Wheatley, C., Cassuto, N., Foxx-Lupo, W., Sprissler, R., & Snyder, E. (2011). Genetic variation of αENaC influences lung diffusion during exercise in humans. Respiratory Physiology and Neurobiology, 179(2-3). doi:10.1016/j.resp.2011.08.007
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  Exercise, decompensated heart failure, and exposure to high altitude have been shown to cause symptoms of pulmonary edema in some, but not all, subjects, suggesting a genetic component to this response. Epithelial Na + Channels (ENaC) regulate Na + and fluid reabsorption in the alveolar airspace in the lung. An increase in number and/or activity of ENaC has been shown to increase lung fluid clearance. Previous work has demonstrated common functional genetic variants of the α-subunit of ENaC, including an A→T substitution at amino acid 663 (αA663T). We sought to determine the influence of the T663 variant of αENaC on lung diffusion at rest and at peak exercise in healthy humans. Thirty healthy subjects were recruited for study and grouped according to their SCNN1A genotype [n=17 vs. 13, age=25±7 years vs. 30±10 years, BMI=23±4kg/m 2 vs. 25±4kg/m 2, V̇O2 peak=95Plusminus;30%pred. vs. 100Plusminus;31%pred., mean±SD, for AA (homozygous for αA663) vs. AT/TT groups (at least one αT663), respectively]. Measures of the diffusing capacity of the lungs for carbon monoxide (DL CO), the diffusing capacity of the lungs for nitric oxide (DL NO), alveolar volume (V A), and alveolar-capillary membrane conductance (D M) were taken at rest and at peak exercise. Subjects expressing the AA polymorphism of ENaC showed a significantly greater percent increase in DL CO and DL NO, and a significantly greater decrease in systemic vascular resistance from rest to peak exercise than those with the AT/TT variant (DL CO=51±12% vs. 36±17%, DL NO=51±24% vs. 32±25%, SVR=-67±3 vs. -50±8%, p
• Traylor, B., Wheatley, C., Skrentny, T., Foxx-Lupo, W., Phan, H., Patanwala, A., Morgan, W., Daines, C., Sprissler, R., & Snyder, E. (2011). Influence of Genetic variation of the β 2-Adrenergic receptor on lung diffusion in patients with cystic fibrosis. Pulmonary Pharmacology and Therapeutics, 24(5). doi:10.1016/j.pupt.2011.06.001
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  Rationale: Cystic fibrosis (CF) is a disease that adversely affects the lung resulting in a reduction in lung diffusion. Stimulation of the β 2-adrenergic receptors mediates mucociliary clearance and bronchodilation. We sought to determine the influence of an inhaled β-agonist on the diffusing capacity of the lungs for carbon monoxide (DLCO), alveolar-capillary membrane conductance (D M), pulmonary capillary blood volume (Vc), and peripheral oxygen saturation (SaO 2) in subjects with CF, when compared to matched healthy subjects, according to genetic variation of the β 2-adrenergic receptor (ADRB2). Methods: To determine this we recruited 18 subjects with CF and 20 healthy subjects (age = 23 ± 7 vs. 24±4years; ht = 168 ± 8 vs. 174 ± 12 cm; wt = 64 ± 16 vs. 70 ± 13 kg; BMI = 23 ± 4 vs. 23±3 kg/m 2; FEV 1 = 72 ± 27 vs. 92 ± 12%pred; VO 2peak = 45 ± 25 vs. 99 ± 24%pred, p < 0.05 for FEV 1 and VO 2peak, mean ± SD, for CF and healthy, respectively). The study involved measurement of DLCO, D M, V C and SaO 2 before and 30, 60, and 90 min following the administration of inhaled albuterol. Subjects were stratified according to genetic variation of ADRB2, Gln 27Gln vs. Glu 27Glu/Gln 27Glu. Results: Within the healthy group, there were no differences in DLCO, D M, V C, D M/V C at baseline or in response to albuterol according to genetic variation of the ADRB2 at amino acid 27. Within the CF group, the Glu 27Glu/Gln 27Glu group had higher D M/V C and SaO 2 when compared to the Gln 27Gln group at baseline (p < 0.05). Both genotype groups demonstrated a significant decline in V C and an improvement in D M/V C and SaO 2 in response to albuterol. Subjects with the Glu 27 genotype experienced a greater improvement in D M/V C with albuterol when compared to subjects homozygous for Gln at amino acid 27. Conclusion: These results suggest that there are differences in lung diffusion and peripheral SaO 2 according to genetic variation of the ADRB2 at position 27 which could play a potential role in dosing options or adjustments that may be required according to genotype. © 2011 Elsevier Ltd.

Presentations

• Whitaker, M. E., Nai, V., Gupta, A., Sweitzer, N. K., Khalpey, Z. I., Tardiff, J. C., Granzier, H. L., Sotak, S., Sprissler, R. S., & Desai, A. (2015, November). dult Onset Non-Ischemic Dilated Cardiomyopathy: A Novel Titin Mutation and a Case of Complex Inheritance. American College of Physicians (Arizona Chapter) Scientific Meeting. Phoenix, AZ: American College of Physicians (Arizona Chapter).