Background: Serological tools for the accurate detection of recent malaria exposure are needed to guide and monitor malaria control efforts. IgG responses against P. vivax and P. falciparum merozoite surface protein-10 (MSP10) were measured as a potential way to identify recent malaria exposure in the Peruvian Amazon. Methods: A field-based study included 470 participants in a longitudinal cohort who completed a comprehensive evaluation: light microscopy and PCR on enrollment; at least one monthly follow-up by light microscopy; a second PCR; and serum and dried blood spots for serological analysis at the end of the follow-up. IgG titers against novel mammalian cell-produced recombinant PvMSP10 and PfMSP10 were determined by ELISA. Results: During the follow-up period, 205 participants were infected, including 171 with P. vivax, 26 with P. falciparum, 6 with infections by both species but at different times, and 2 with mixed infections. Exposure to P. vivax was more accurately identified when serological responses to PvMSP10 were obtained from serum (sensitivity, 58.1%; specificity, 81.8%; AUC: 0.76) than from dried blood spots (sensitivity, 35.2; specificity, 83.5%; AUC: 0.64) (PAUC < 0.001). Sensitivity was highest (serum, 82.9%; dried blood spot, 45.7%) with confirmed P. vivax infections occurring 7-30 days before sample collection; sensitivity decreased significantly in relation to time since last documented infection. PvMSP10 serological data did not show evidence of inter-species cross-reactivity. Anti-PfMSP10 responses poorly discriminated between P. falciparum exposed- and non-exposed individuals (AUC = 0.59, P > 0.05). Conclusions: Anti-PvMSP10 IgG indicates recent exposure to P. vivax at the population level in the Amazon region. Serum, not dried blood spots, should be used for such serological tests.
Angel Rosas-Aguirre, Kailash P. Patra, Maritza Calderón, Katherine Torres, Dionicia Gamboa, Edith Arocutipa, Edith Málaga, Katherine Garro, Carlos Fernández, Grace Trompeter, Yossef Alnasser, Alejandro Llanos-Cuentas, Robert H. Gilman, Joseph M. Vinetz
Background: Hepatic encephalopathy (HE) is associated with poor outcomes. A prior randomized, pilot trial demonstrated safety after oral capsular FMT in HE with favorable changes in microbial composition and cognition. However, microbial functional changes are unclear. Aim: Determine impact of FMT on gut-brain axis compared to placebo using microbial function based on bile acids (BA), inflammation (serum IL-6, lipopolysaccharide-binding protein,LBP), and EncephalApp. Methods: 20 cirrhotic patients were randomized 1:1 into receiving one-time FMT capsules from a donor enriched in Lachnospiraceae and Ruminococcaceae, or placebo capsules with 5-month follow-up for safety outcomes. Stool microbiota and BA, serum IL-6, BA and LBP, and EncephalApp were analyzed at baseline and 4-weeks post-FMT/placebo. Correlation networks between microbiota, BAs, EncephalApp, IL-6 and LBP were performed pre/post-FMT. Results: FMT-assigned participants had one HE recurrence and 2 unrelated infections. Six placebo-assigned participants developed negative outcomes. FMT, but not placebo, was associated with reduced serum IL-6 and LBP and improved EncephalApp. FMT-assigned participants demonstrated higher deconjugation and secondary BA formation in feces and serum compared to baseline. No change was seen in placebo. Correlation networks showed greater complexity post-FMT compared to baseline. Beneficial taxa such as Ruminococcaceae, Verrucomicrobiaceae and Lachnospiraceae were correlated with cognitive improvement and decrease in inflammation post-FMT. Fecal/serum secondary/primary ratios and PiCRUST secondary BA pathways did not increase in participants who developed poor outcomes. Conclusions: Gut microbial function in cirrhosis is beneficially affected by capsular FMT with improved inflammation and cognition. Lower secondary BAs in FMT recipients could select for participants who develop negative outcomes.
Jasmohan S. Bajaj, Nita Salzman, Chathur Acharya, Hajime Takei, Genta Kakiyama, Andrew Fagan, Melanie B. White, Edith A. Gavis, Mary L. Holtz, Michael Hayward, Hiroshi Nittono, Philip B. Hylemon, I. Jane Cox, Roger Williams, Simon D. Taylor-Robinson, Richard K. Sterling, Scott C. Matherly, Michael Fuchs, Hannah Lee, Puneet Puri, R. Todd Stravitz, Arun J. Sanyal, Lola Ajayi, Adrien Le Guennec, R. Andrew Atkinson, Mohammad S. Siddiqui, Velimir A. Luketic, William M. Pandak, Masoumeh Sikaroodi, Patrick M. Gillevet
Background: Bacille Calmette-Guérin (BCG) vaccine is protective in children but its efficacy wanes with age. Consequently, determining if BCG revaccination augments anti-TB immunity in young adults in TB endemic regions is vital. Methods: 200 healthy adults, BCG vaccinated at birth were tested for their IGRA status. Of these, 28 IGRA+ and 30 IGRA- were BCG revaccinated and 24 IGRA+ and 23 IGRA- subjects served as unvaccinated controls. T and innate cell responses to mycobacterial antigens were analyzed by 14-colour flow cytometry over 34 weeks. Results: IFN-γ and/or IL-2 Ag85A and BCG-specific CD4+ and CD8+ T-cell responses were boosted by revacciantion at 4 and 34 weeks respectively and were >2-fold higher in IGRA+ compared to IGRA- vaccinees. Polyfunctional Ag85A, BCG and Mtb latency Ag (LTAg)-specific CD4+ T-cells expressing up to 8 cytokines were also significantly enhanced in both IGRA+ and IGRA- vaccinees relative to unvaccinated controls, most markedly in IGRA+ vaccinees. A focussed analysis of Th17 responses revealed expansion of Ag85A, BCG and LTAg-specific total IL-17A+IL-17F+IL-22+ and IL-10+ CD4+ T-cell effectors in both IGRA+ and IGRA- subjects. Also, innate IFN-γ+ NK/γδ/NKT responses were higher in both IGRA+ and IGRA- vaccinees compared to controls. This is the first evidence that BCG revaccination significantly boosts anti-mycobacterial Th1/Th17 responses in IGRA+ and IGRA- subjects. Summary: These data show that BCG revaccination is immunogenic in IGRA- and IGRA+ subjects implying that Mtb pre-infection in IGRA+ subjects does not impact immunogenicity. This has implications for public health and vaccine development strategies. Funding: This work was funded principally by DBT-NIH (BT/MB/Indo-US/HIPC/2013).
Srabanti Rakshit, Asma Ahmed, Vasista Adiga, Bharath K. Sundararaj, Pravat Nalini Sahoo, John Kenneth, George D'Souza, Wesley Bonam, Christina Johnson, Kees L.M.C. Franken, Tom H.M. Ottenhoff, Greg Finak, Raphael Gottardo, Kenneth D. Stuart, Stephen C. De Rosa, M. Juliana McElrath, Annapurna Vyakarnam
BACKGROUND Bilateral loss of vestibular (inner ear inertial) sensation causes chronically blurred vision during head movement, postural instability, and increased fall risk. Individuals who fail to compensate despite rehabilitation therapy have no adequate treatment options. Analogous to hearing restoration via cochlear implants, prosthetic electrical stimulation of vestibular nerve branches to encode head motion has garnered interest as a potential treatment, but prior studies in humans have not included continuous long-term stimulation or 3D binocular vestibulo-ocular reflex (VOR) oculography, without which one cannot determine whether an implant selectively stimulates the implanted ear’s 3 semicircular canals.METHODS We report binocular 3D VOR responses of 4 human subjects with ototoxic bilateral vestibular loss unilaterally implanted with a Labyrinth Devices Multichannel Vestibular Implant System vestibular implant, which provides continuous, long-term, motion-modulated prosthetic stimulation via electrodes in 3 semicircular canals.RESULTS Initiation of prosthetic stimulation evoked nystagmus that decayed within 30 minutes. Stimulation targeting 1 canal produced 3D VOR responses approximately aligned with that canal’s anatomic axis. Targeting multiple canals yielded responses aligned with a vector sum of individual responses. Over 350–812 days of continuous 24 h/d use, modulated electrical stimulation produced stable VOR responses that grew with stimulus intensity and aligned approximately with any specified 3D head rotation axis.CONCLUSION These results demonstrate that a vestibular implant can selectively, continuously, and chronically provide artificial sensory input to all 3 implanted semicircular canals in individuals disabled by bilateral vestibular loss, driving reflexive VOR eye movements that approximately align in 3D with the head motion axis encoded by the implant.TRIAL REGISTRATION ClinicalTrials.gov: NCT02725463.FUNDING NIH/National Institute on Deafness and Other Communication Disorders: R01DC013536 and 2T32DC000023; Labyrinth Devices, LLC; and Med-El GmbH.
Peter J. Boutros, Desi P. Schoo, Mehdi Rahman, Nicolas S. Valentin, Margaret R. Chow, Andrianna I. Ayiotis, Brian J. Morris, Andreas Hofner, Aitor Morillo Rascon, Andreas Marx, Ross Deas, Gene Y. Fridman, Natan S. Davidovics, Bryan K. Ward, Carolina Treviño, Stephen P. Bowditch, Dale C. Roberts, Kelly E. Lane, Yoav Gimmon, Michael C. Schubert, John P. Carey, Andreas Jaeger, Charles C. Della Santina
BACKGROUND IL-33, found in high levels in participants with allergic disorders, is thought to mediate allergic reactions. Etokimab, an anti–IL-33 biologic, has previously demonstrated a good safety profile and favorable pharmacodynamic properties in many clinical studies.METHODS In this 6-week placebo-controlled phase 2a study, we evaluated the safety and the ability of a single dose of etokimab to desensitize peanut-allergic adults. Participants received either etokimab (n = 15) or blinded placebo (n = 5). Clinical tests included oral food challenges and skin prick tests at days 15 and 45. Blood samples were collected for IgE levels and measurement of ex vivo peanut-stimulated T cell cytokine production.RESULTS Efficacy measurements for active vs. placebo participants at the day 15 and 45 food challenge (tolerating a cumulative 275 mg of peanut protein, which was the food challenge outcome defined in this paper) demonstrated, respectively, 73% vs. 0% (P = 0.008) to 57% vs. 0% (ns). The etokimab group had fewer adverse events compared with placebo. IL-4, IL-5, IL-9, IL-13, and ST2 levels in CD4+ T cells were reduced in the active vs. placebo arm upon peanut-induced T cell activation (P = 0.036 for IL-13 and IL-9 at day 15), and peanut-specific IgE was reduced in active vs. placebo (P = 0.014 at day 15).CONCLUSION The phase 2a results suggest etokimab is safe and well tolerated and that a single dose of etokimab could have the potential to desensitize peanut-allergic participants and possibly reduce atopy-related adverse events.TRIAL REGISTRATION ClinicalTrials.gov NCT02920021.FUNDING This work was supported by NIH grant R01AI140134, AnaptysBio, the Hartman Vaccine Fund, and the Sean N. Parker Center for Allergy and Asthma Research at Stanford University.
Sharon Chinthrajah, Shu Cao, Cherie Liu, Shu-Chen Lyu, Sayantani B. Sindher, Andrew Long, Vanitha Sampath, Daniel Petroni, Marco Londei, Kari C. Nadeau
Introduction: The airways of obese asthmatics have been shown to be nitric oxide (NO) deficient, which contributes to airway dysfunction and reduced response to inhaled corticosteroids (ICS). In cultured airway epithelial cells, L-citrulline, a precursor of L-arginine recycling and NO formation, has been shown to prevent asymmetric di-methyl arginine (ADMA)-mediated NO synthase (NOS2) uncoupling, restoring NO and reducing oxidative stress. Methods: In a proof of concept, pre – post open label pilot study, we hypothesized that 15g/day of L-citrulline for two weeks would: a) increase the fractional excretion of NO (FeNO); b) improve asthma control and c) improve lung function. To do this, we recruited obese (body mass index [BMI] >30) asthmatics on controller therapy with a baseline fractional exhaled nitric oxide (FeNO) ≤ 30 ppb from the University of Colorado Medical Center and Duke University Health System. Results: A total of 41 subjects with an average FeNO of 17 ppb (95% 19 - 20) and poorly controlled asthma (average asthma control questionnaire [ACQ] 1.5 [95% 1.2 – 1.8) completed the study. Compared to baseline, L-citrulline increased (values represent the mean delta and 95%CI): plasma L-citrulline (190uM, 84 – 297), plasma L-arginine (67uM, 38 – 95), plasma L-arginine/ADMA (117, 67 - 167), but not ADMA or arginase concentration. FeNO increased by 4.2ppb (1.7 – 6.7); ACQ decreased by -0.46 (-0.67 – -0.27); the forced vital capacity (FVC) and forced exhalation volume in one second (FEV1) respectively changed by 86 ml (10 – 161), and 52 ml (-11 – 132). In a secondary analysis, the greatest FEV1 increments occurred in those subjects with late onset asthma (>12 years) (63 ml [95%CI 1 – 137]), in females (80 ml [95%CI 5 – 154]), with a greater change seen in late onset females (100ml, [95%CI 2 – 177]). The changes in lung function or asthma control were not significantly associated with the pre-post changes in L-arginine/ADMA or FeNO. Conclusion: Short-term L-citrulline treatment improved asthma control and FeNO levels in obese asthmatics with low or normal FeNO. Larger FEV1 increments were observed in those with late onset asthma and in females.
Fernando Holguin, Hartmut Grasemann, Sunita Sharma, Daniel Winnica, Karen Wasil, Vong Smithphone, Margaret H. Cruse, Nancy Perez, Erika Coleman, Timothy J. Scialla, Loretta Que
BACKGROUND Insulin resistance results from impaired skeletal muscle glucose transport/phosphorylation, linked to augmented lipid availability. Despite greater intramuscular lipids, athletes are highly insulin sensitive, which could result from higher rates of insulin-stimulated glycogen synthesis or glucose transport/phosphorylation and oxidation. Thus, we examined the time course of muscle glycogen and glucose-6-phosphate concentrations during low and high systemic lipid availability.METHODS Eight endurance-trained and 9 sedentary humans (VO2 peak: 56 ± 2 vs. 33 ± 2 mL/kg/min, P < 0.05) underwent 6-hour hyperinsulinemic-isoglycemic clamp tests with infusions of triglycerides or saline in a randomized crossover design. Glycogen and glucose-6-phosphate concentrations were monitored in vastus lateralis muscles using 13C/31P magnetic resonance spectroscopy.RESULTS Athletes displayed a 25% greater (P < 0.05) insulin-stimulated glucose disposal rate (Rd) than sedentary participants. During Intralipid infusion, insulin sensitivity remained higher in the athletes (ΔRd: 25 ± 3 vs. 17 ± 3 μmol/kg/min, P < 0.05), supported by higher glucose transporter type 4 protein expression than in sedentary humans. Compared to saline infusion, AUC of glucose-6-phosphate remained unchanged during Intralipid infusion in athletes (1.6 ± 0.2 mmol/L vs. 1.4 ± 0.2 [mmol/L] × h, P = n.s.) but tended to decrease by 36% in sedentary humans (1.7 ± 0.4 vs. 1.1 ± 0.1 [mmol/L] × h, P < 0.059). This drop was accompanied by a 72% higher rate of net glycogen synthesis in the athletes upon Intralipid infusion (47 ± 9 vs. 13 ± 3 μmol/kg/min, P < 0.05).CONCLUSION Athletes feature higher skeletal muscle glucose disposal and glycogen synthesis during increased lipid availability, which primarily results from maintained insulin-stimulated glucose transport with increased myocellular glucose-6-phosphate levels for subsequent glycogen synthesis.TRIAL REGISTRATION ClinicalTrials.gov NCT01229059.FUNDING German Federal Ministry of Health (BMG).
Esther Phielix, Paul Begovatz, Sofiya Gancheva, Alessandra Bierwagen, Esther Kornips, Gert Schaart, Matthijs K. C. Hesselink, Patrick Schrauwen, Michael Roden
Background: Innate immune activation impacts lung transplant outcomes. Dectin-1 is an innate receptor important for pathogen recognition. We hypothesized that genotypes reducing dectin-1 activity would be associated with infection, graft dysfunction, and death in lung transplant recipients. Methods: We assessed the rs16910526 CLEC7A gene polymorphism Y238X, which results in dectin-1 truncation, in 321 lung allograft recipients at a single institution and in 1,129 lung allograft recipients in the multi-center lung transplant outcomes group (LTOG) cohort. Differences in dectin-1 mRNA, cytokines, protein levels, immunophenotypes, and clinical factors were assessed. Results: Y238X carriers had decreased dectin-1 mRNA expression (P = 0.0001), decreased soluble dectin-1 protein concentrations in BAL (P = 0.008) and plasma (P = 0.04), and decreased monocyte surface dectin-1 (P = 0.01) compared to wild type subjects. Y238X carriers had an increased risk of fungal pathogens (HR 1.17, CI 1.0 – 1.4), an increased risk of graft dysfunction or death (HR 1.6, CI 1.0 – 2.6), as well increased mortality in the UCSF cohort (HR 1.8, CI 1.1 – 3.8) and in the LTOG cohort (HR 1.3, CI 1.1 – 1.6), compared to CLEC7A wildtype subjects. Conclusion: Increased rates of graft dysfunction and death associated with this dectin-1 polymorphism may be amplified by immunosuppression that drives higher fungal burden from compromised pathogen recognition. Funding: Project funding came from the UCSF Nina Ireland Program for Lung Health (NIPLH) Innovative Grant program, award number IK2CX001034 from the Clinical Sciences Research & Development Service of the VA Office of Research and Development, and the Joel D. Cooper Career Development Award from the International Society for Heart and Lung Transplantation.
Daniel R. Calabrese, Ping Wang, Tiffany Chong, Jonathan Hoover, Jonathan P. Singer, Dara Torgerson, Steven R. Hays, Jeffrey A. Golden, Jasleen Kukreja, Daniel Dugger, Jason D. Christie, LTOG investigators, John R. Greenland
Background: Myeloid-derived suppressor cells (MDSCs) are elevated in glioblastoma (GBM) patient circulation, present in tumor tissue, and associated with poor prognosis. While low-dose chemotherapy reduces MDSCs in preclinical models, the use of this strategy to reduce MDSCs in GBM patients has yet to be evaluated. Methods: A phase 0/1 dose-escalation clinical trial was conducted in recurrent glioblastoma patients treated 5-7 days prior to surgery with low-dose chemotherapy via capecitabine followed by concomitant low-dose capecitabine and bevacizumab. Clinical outcomes, including progression-free and overall survival, were measured, along with safety and toxicity profiles. Over the treatment time course, circulating MDSC levels were measured by multi-parameter flow cytometry, and tumor tissue immune profiles were assessed via mass cytometry time-of-flight. Results: A total of 11 patients were enrolled across escalating dose cohorts of 150, 300, and 450 mg bid. No serious adverse events related to the drug combination were observed. Compared to pre-treatment baseline, circulating MDSCs were found to be higher after surgery in the 150 mg treatment arm and lower in the 300 mg and 450 mg treatment arms. Increased cytotoxic immune infiltration was observed after low-dose capecitabine compared to untreated GBM patients in the 300 mg and 450 mg treatment arms. Conclusions: Low-dose, metronomic capecitabine in combination with bevacizumab is well tolerated in GBM patients and was associated with a reduction in circulating MDSC levels and an increase in cytotoxic immune infiltration into the tumor microenvironment. Trial registration: NCT02669173
David M. Peereboom, Tyler J. Alban, Mathew M. Grabowski, Alvaro G. Alvarado, Balint Otvos, Defne Bayik, Gustavo Roversi, Mary McGraw, Pengjing Huang, Alireza M. Mohammadi, Harley I. Kornblum, Tomas Radivoyevitch, Manmeet S. Ahluwalia, Michael A. Vogelbaum, Justin D. Lathia
Background. The presence of an early repolarization pattern (ERP) on the surface electrocardiogram (ECG) is associated with risk of ventricular fibrillation and sudden cardiac death. Family studies have shown that ERP is a highly heritable trait but molecular genetic determinants are unknown. Methods. To identify genetic susceptibility loci for ERP, we performed a GWAS and meta-analysis in 2,181 cases and 23,641 controls of European ancestry. Results. We identified a genome-wide significant (p<5E-8) locus in the KCND3 (potassium voltage gated channel subfamily D member 3) gene that was successfully replicated in additional 1,124 cases and 12,510 controls. A subsequent joint meta-analysis of the discovery and replication cohorts identified rs1545300 as the lead SNP at the KCND3 locus (OR 0.82 per minor T allele, p=7.7E-12), but did not reveal additional loci. Co-localization analyses indicate causal effects of KCND3 gene expression levels on ERP in both cardiac left ventricle and tibial artery. Conclusions. In this study we identified for the first time a genome-wide significant association of a genetic variant with ERP. Our findings of a locus in the KCND3 gene not only provide insights into the genetic determinants but also into the pathophysiological mechanism of ERP, discovering a promising candidate for functional studies. Funding. For detailed information per study, see Acknowledgments.
Alexander Teumer, Teresa Trenkwalder, Thorsten Kessler, Yalda Jamshidi, Marten E. van den Berg, Bernhard Kaess, Christopher P. Nelson, Rachel Bastiaenen, Marzia De Bortoli, Alessandra Rossini, Isabel Deisenhofer, Klaus Stark, Solmaz Assa, Peter S. Braund, Claudia Cabrera, Anna F. Dominiczak, Martin Gögele, Leanne M. Hall, M. Arfan Ikram, Maryam Kavousi, Karl J. Lackner, Christian Müller, Thomas Münzel, Matthias Nauck, Sandosh Padmanabhan, Norbert Pfeiffer, Tim D. Spector, Andre G. Uitterlinden, Niek Verweij, Uwe Völker, Helen R. Warren, Mobeen Zafar, Stephan B. Felix, Jan A. Kors, Harold Snieder, Patricia B. Munroe, Cristian Pattaro, Christian Fuchsberger, Georg Schmidt, Ilja M. Nolte, Heribert Schunkert, Peter Pramstaller, Philipp S. Wild, Pim van der Harst, Bruno H. Stricker, Renate B. Schnabel, Nilesh J. Samani, Christian Hengstenberg, Marcus Dörr, Elijah R. Behr, Wibke Reinhard
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