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
BACKGROUND Fecal microbiota transplantation (FMT) is an effective treatment for recurrent Clostridioides difficile infection (rCDI) in adults and children, but donor stool samples are currently screened for only a limited number of potential pathogens. We sought to determine whether putative procarcinogenic bacteria (enterotoxigenic Bacteroides fragilis, Fusobacterium nucleatum, and Escherichia coli harboring the colibactin toxin) could be durably transmitted from donors to patients during FMT.METHODS Stool samples were collected from 11 pediatric rCDI patients and their respective FMT donors prior to FMT as well as from the patients at 2–10 weeks, 10–20 weeks, and 6 months after FMT. Bacterial virulence factors in stool DNA extracts and stool cultures were measured by quantitative PCR: Bacteroides fragilis toxin (bft), Fusobacterium adhesin A (fadA), and Escherichia coli colibactin (clbB).RESULTS Four of 11 patients demonstrated sustained acquisition of a procarcinogenic bacteria. Whole genome sequencing was performed on colony isolates from one of these donor/recipient pairs and demonstrated that clbB+ E. coli strains present in the recipient after FMT were identical to a strain present in the donor, confirming strain transmission. Conversely, 2 patients exhibited clearance of procarcinogenic bacteria following FMT from a negative donor.CONCLUSION Both durable transmission and clearance of procarcinogenic bacteria occurred following FMT, suggesting that additional studies on appropriate screening measures for FMT donors and the long-term consequences and/or benefits of FMT are warranted.FUNDING Crohn’s & Colitis Foundation, the Bloomberg~Kimmel Institute for Cancer Immunotherapy at Johns Hopkins University School of Medicine, the National Cancer Institute, and the Canadian Institutes of Health Research.
Julia L. Drewes, Alina Corona, Uriel Sanchez, Yunfan Fan, Suchitra K. Hourigan, Melissa Weidner, Sarah D. Sidhu, Patricia J. Simner, Hao Wang, Winston Timp, Maria Oliva-Hemker, Cynthia L. Sears
BACKGROUND Recessive dystrophic epidermolysis bullosa (RDEB) patients have mutations in the COL7A1 gene and thus lack functional type VII collagen (C7) protein; they have marked skin fragility and blistering. This single-center phase 1/2a open-label study evaluated the long-term efficacy, safety, and patient-reported outcomes in RDEB patients treated with gene-corrected autologous cell therapy.METHODS Autologous keratinocytes were isolated from participant skin biopsies. Epidermal sheets were prepared from cells transduced with a retrovirus carrying the full-length human COL7A1 gene. These gene-corrected autologous epidermal sheets measured 5 × 7 cm (35 cm2) and were transplanted onto 6 wound sites in each of 7 adult participants (n = 42 sites total) from 2013 to 2017. Participants were followed for 2 to 5 years.RESULTS No participants experienced any serious related adverse events. Wound healing of 50% or greater by Investigator Global Assessment was present in 95% (36 of 38) of treated wounds versus 0% (0 of 6) of untreated control wounds at 6 months (P < 0.0001). At year 1, 68% (26 of 38) of treated wounds had 50% or greater healing compared with 17% (1 of 6) of control wounds (P = 0.025). At year 2, 71% (27 of 38) of treated wounds had 50% or greater healing compared with 17% (1 of 6) of control wounds (P = 0.019).CONCLUSION C7 expression persisted up to 2 years after treatment in 2 participants. Treated wounds with 50% or greater healing demonstrated improvement in patient-reported pain, itch, and wound durability. This study provides additional data to support the clinically meaningful benefit of treating chronic RDEB wounds with ex vivo, C7 gene–corrected autologous cell therapy. This approach was safe and promoted wound healing that was associated with improved patient-reported outcomes.TRIAL REGISTRATION Clinicaltrials.gov identifier: NCT01263379.FUNDING Epidermolysis Bullosa Research Partnership, Epidermolysis Bullosa Medical Research Foundation, NIH R01 AR055914, Office of Research and Development at the Palo Alto Veteran’s Affairs Medical Center, and the Dermatology Foundation.
Shaundra Eichstadt, Melissa Barriga, Anusha Ponakala, Claudia Teng, Ngon T. Nguyen, Zurab Siprashvili, Jaron Nazaroff, Emily S. Gorell, Albert S. Chiou, Lisa Taylor, Phuong Khuu, Douglas R. Keene, Kerri Rieger, Rohit K. Khosla, Louise K. Furukawa, H. Peter Lorenz, M. Peter Marinkovich, Jean Y. Tang
Background: Hydroxymethyl-glutaryl-coenzyme A reductase inhibitors (‘statins’) are prescribed to millions of people. Statins are anti-inflammatory independent of their cholesterol-reducing effects. To date, most reports on the immune effects of statins have assayed a narrow array of variables and have focused on cell lines, rodent models, or patient cohorts. We sought to define the effect of rosuvastatin on the ‘immunome’ of healthy, normocholesterolemic subjects. Methods: Prospective study of rosuvastatin (20 mg/day x 28 days) in 18 statin-naïve adults with low density lipoprotein-cholesterol <130 mg/dL. A panel of >180 immune/biochemical/endocrinologic variables was measured at baseline, and days 14, 28, and 42 (14 days after drug withdrawal). Drug effect was evaluated using linear mixed effects models. Potential interactions between drug and baseline high-sensitivity C-reactive protein (hsCRP) were evaluated. Results: A wide array of immune measures changed (nominal p<0.05) during rosuvastatin treatment, although the changes were modest in magnitude and few met a false discovery rate of 0.05. Among changes noted were a concordant increase in pro-inflammatory cytokines (IFNγ, IL-1β, IL-5, IL-6, TNFα) and peripheral blood neutrophil frequency, and a decline in activated T regulatory cell frequency. Several drug effects were significantly modified by baseline hsCRP, and some did not resolve after drug withdrawal. Among other unexpected rosuvastatin effects were changes in erythrocyte indices, glucose-regulatory hormones, CD8+ T cells, and haptoglobin. Conclusion: Rosuvastatin induces modest changes in immunologic and metabolic measures in normocholesterolemic subjects, with several effects dependent upon baseline CRP. Future, larger studies are warranted to validate these changes and their physiological significance.
Peer W. F. Karmaus, Min Shi, Shira Perl, Angélique Biancotto, Julián Candia, Foo Cheung, Yuri Kotliarov, Neal Young, Michael B. Fessler
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