BACKGROUND Insulin resistance of the brain can unfavorably affect long-term weight maintenance and body fat distribution. Little is known if and how brain insulin sensitivity can be restored in humans. We aimed to evaluate the effects of an exercise intervention on insulin sensitivity of the brain and how this relates to exercise-induced changes in whole-body metabolism and behavior.METHODS In this clinical trial, sedentary participants who were overweight and obese underwent an 8-week supervised aerobic training intervention. Brain insulin sensitivity was assessed in 21 participants (14 women, 7 men; age range 21–59 years; BMI range 27.5–45.5 kg/m2) using functional MRI, combined with intranasal administration of insulin, before and after the intervention.RESULTS The exercise program resulted in enhanced brain insulin action to the level of a person of healthy weight, demonstrated by increased insulin-induced striatal activity and strengthened hippocampal functional connectivity. Improved brain insulin action correlated with increased mitochondrial respiration in skeletal muscle, reductions in visceral fat and hunger, as well as improved cognition. Mediation analyses suggest that improved brain insulin responsiveness helps mediate the peripheral exercise effects leading to healthier body fat distribution and reduced perception of hunger.CONCLUSION Our study demonstrates that an 8-week exercise intervention in sedentary individuals can restore insulin action in the brain. Hence, the ameliorating benefits of exercise toward brain insulin resistance may provide an objective therapeutic target in humans in the challenge to reduce diabetes risk factors.TRIAL REGISTRATION ClinicalTrials.gov (NCT03151590).FUNDING BMBF/DZD 01GI0925.
Stephanie Kullmann, Thomas Goj, Ralf Veit, Louise Fritsche, Lore Wagner, Patrick Schneeweiss, Miriam Hoene, Christoph Hoffmann, Jürgen Machann, Andreas Niess, Hubert Preissl, Andreas L. Birkenfeld, Andreas Peter, Hans-Ulrich Häring, Andreas Fritsche, Anja Moller, Cora Weigert, Martin Heni
BACKGROUND. Alcohol use disorder (AUD) is a chronic, relapsing brain disorder that accounts for 5% of deaths annually, and there is an urgent need to develop new targets for therapeutic intervention. The glucagon-like peptide-1 receptor agonist exenatide reduces alcohol consumption in rodents and non-human primates, but its efficacy in patients with AUD is unknown. METHODS. In a randomized, double-blinded, placebo-controlled clinical trial, treatment-seeking AUD patients were assigned to receive exenatide (2 mg subcutaneously) or placebo once weekly for 26-weeks, in addition to standard cognitive-behavioral therapy. The primary outcome was reduction in number of heavy drinking days. A subgroup also completed fMRI and SPECT brain scans. RESULTS. A total of 127 patients were enrolled. Our data revealed that although exenatide did not significantly reduce the number of heavy drinking days compared to placebo, it significantly attenuated fMRI alcohol cue-reactivity in the ventral striatum and septal area, which are crucial brain areas for drug reward and addiction. In addition, the dopamine transporter availability was lower in the exenatide group compared to the placebo group. Exploratory analyses revealed that exenatide significantly reduced heavy drinking days and total alcohol intake in a subgroup of obese patients (BMI>30 kg/m2). Adverse events were mainly gastrointestinal. CONCLUSIONS. This first RCT on the effects of a GLP-1 receptor agonist in AUD provides new important knowledge on the effects of GLP-1 receptor agonists as a novel treatment target in addiction. TRIAL REGISTRATION. EudraCT: 2016-003343-11 and ClinicalTrials.gov: NCT03232112 FUNDING. The Novavi Foundation; The Research Foundation, Mental Health Services, Capital Region of Denmark; The Research Foundation, Capital Region of Denmark; The Ivan Nielsen Foundation; The A.P. Moeller and wife Chastine Mc-Kinney Moellers Family Foundation; The Augustinus Foundation; The Woerzner Foundation; Grosserer L.F Foghts Foundation; The Hartmann Foundation; The Aase and Ejnar Danielsen Foundation; The P.A. Messerschmidt and wife foundation and The Lundbeck Foundation. The funding sources and the manufacturer of exenatide once weekly (Bydureon®, AstraZeneca), had no influence on the trial design or data analysis.
Mette K. Klausen, Mathias E. Jensen, Marco Møller, Nina le Dous, Anne-Marie Ø Jensen, Victoria A. Zeeman, Claas-Frederik Johannsen, Alycia M. Lee, Gerda K. Thomsen, Julian Macoveanu, Patrick M Fisher, Matthew P. Gillum, Niklas R. Jørgensen, Marianne L. Bergmann, Henrik Enghusen Poulsen, Ulrik Becker, Jens Juul Holst, Helene Benveniste, Nora D. Volkow, Sabine Vollstädt-Klein, Kamilla W. Miskowiak, Claus T. Ekstrøm, Gitte M. Knudsen, Tina Visboll, Anders Fink-Jensen
BACKGROUND. Metabolomic profiling in individuals with chronic kidney disease (CKD) has the potential to identify novel biomarkers and provide insight into disease pathogenesis. Methods: We examined the association between blood metabolites and CKD progression, defined as the subsequent development of end-stage renal disease (ESRD) or estimated glomerular filtrate rate (eGFR) halving, in 1773 participants of the Chronic Renal Insufficiency Cohort (CRIC) study, 962 participants of the African American Study of Kidney Disease and Hypertension (AASK), and 5305 participants of the Atherosclerosis Risk in Communities (ARIC) study. RESULTS. In CRIC, more than half of measured metabolites were associated with CKD progression in minimally adjusted Cox proportional hazards models, but the number and strength of associations were markedly attenuated by serial adjustment for covariates, particularly eGFR. Ten metabolites were significantly associated with CKD progression in fully-adjusted models in CRIC; three of these metabolites were also significant in fully-adjusted models in AASK and ARIC, highlighting potential markers of glomerular filtration (pseudouridine), histamine metabolism (methylimidazoleacetate), and azotemia (homocitrulline). Our findings also nominate N-acetylserine as a potential marker of kidney tubular function, with significant associations with CKD progression observed in CRIC and ARIC. CONCLUSION. Together, our findings demonstrate the application of metabolomics to identify potential biomarkers and causal pathways in CKD progression. TRIAL REGISTRATION. Not applicable FUNDING. This study was supported by the NIH (U01 DK106981, U01 DK106982, U01 DK085689, R01 DK108803, R01 DK124399)
Donghai Wen, Zihe Zheng, Aditya Surapaneni, Bing Yu, Linda Zhou, Wen Zhou, Dawei Xie, Haochang Shou, Julian Avila-Pacheco, Sahir Kalim, Jiang He, Chi-yuan Hsu, Afshin Parsa, Panduranga Rao, James Sondheimer, Raymond Townsend, Sushrut S. Waikar, Casey M. Rebholz, Michelle R. Denburg, Paul L. Kimmel, Ramachandran S. Vasan, Clary B. Clish, Josef Coresh, Harold I. Feldman, Morgan E. Grams, Eugene P. Rhee
BACKGROUND. Increased reinfection rates with SARS-CoV-2 have recently been reported, with some locations basing reinfection on a second positive PCR test at least 90 days after initial infection. In this study, we used the Johns Hopkins SARS-CoV-2 genomic surveillance data to evaluate the frequency of sequencing validated, confirmed and inferred reinfections between March 2020 and July 2022. METHODS. Patients who had two or more positive SARS-CoV-2 tests in our system with samples sequenced as a part of our surveillance efforts were identified as the cohort for our study. SARS-CoV-2 genomes of patients’ initial and later samples were compared. RESULTS. A total of 755 patients (920 samples) had a positive test at least 90 days after the initial test with a median time between tests of 377 days. Sequencing was attempted on 231 samples and was successful in 127. Successful sequencing spiked during the Omicron surge and showed higher median days from initial infection compared to failed sequences. A total of 122 (98%) patients showed evidence of reinfection, 45 of which had sequence validated reinfection and 77 had inferred reinfections (later sequence showed a clade that was not circulating when the patient was initially infected). Of 45 sequence validated reinfections, 43 (96%) were caused by the Omicron variant, 41 (91%) were symptomatic, 32 (71%) were vaccinated prior to the second infection, 6 (13%) were Immunosuppressed, and only 2 (4%) were hospitalized. CONCLUSIONS. Sequence validated reinfections increased with the Omicron variant but were generally associated with mild infections.
C. Paul Morris, Raghda E. Eldesouki, Amary Fall, David C. Gaston, Julie M. Norton, Nicholas D. Gallagher, Chun Huai Luo, Omar Abdullah, Eili Y. Klein, Heba H. Mostafa
BACKGROUND. Apolipoprotein CIII is a regulator of triglyceride (TG) metabolism, and due to its association with risk of cardiovascular disease, is an emergent target for pharmacological intervention. The impact of substantially lowering apoC-III on lipoprotein metabolism is not clear. METHODS. We investigated the kinetics of apolipoproteins B48 and B100 in chylomicrons, VLDL1, VLDL2, IDL and LDL in subjects heterozygous for a loss-of-function (LOF) mutation in the APOC3 gene. Studies were conducted in the post-prandial state to provide a more comprehensive view of the influence of this protein on TG transport. RESULTS. Compared to non-LOF subjects, a genetically-determined decrease in apoC-III resulted in marked acceleration of lipolysis of triglyceride-rich lipoproteins (TRL), increased removal of VLDL remnants from the bloodstream, and a substantial decrease in circulating levels of VLDL1, VLDL2 and IDL particles. Production rates for apolipoprotein B48-containing chylomicrons and apoB100-containing VLDL1 and VLDL2 were not different between LOF carriers and non-carriers. Likewise, the rate of production of LDL was not affected by the lower apoC-III level, nor was the concentration of LDL-apoB100 or its clearance rate. CONCLUSION. These findings indicate that apoC-III lowering will have a marked effect on TRL and remnant metabolism, with possibly significant consequences for cardiovascular disease prevention. TRIAL REGISTRATIONS. Clinical Trials NCT04209816 and NCT01445730 FUNDING. This project was funded by grants from Swedish Heart-Lung Foundation, Swedish Research Council, ALF grant from the Sahlgrenska University Hospital, Novo Nordisk Foundation, Sigrid Juselius Foundation, Helsinki University Hospital Government Research funds, Finnish Heart Foundation, and Finnish Diabetes Research Foundation.
Marja-Riitta Taskinen, Elias Björnson, Niina Matikainen, Sanni Söderlund, Joel Rämo, Mari-Mia Ainola, Antti Hakkarainen, Carina Sihlbom, Annika Thorsell, Linda Andersson, Per-Olof Bergh, Marcus Henricsson, Stefano Romeo, Martin Adiels, Samuli Ripatti, Markku Laakso, Chris J. Packard, Jan Borén
BACKGROUND. During ageing there is a functional decline in the pool of muscle stem cells (MuSCs) which influences the functional and regenerative capacity of skeletal muscle. Preclinical evidence have suggested that Nicotinamide Riboside (NR) and Pterostilbene (PT) can improve muscle regeneration e.g. by increasing MuSC function. The objective of the present study was to investigate if NRPT-supplementation promotes skeletal muscle regeneration after muscle injury in elderly humans by improved recruitment of MuSCs. METHODS. 32 elderly men and women (55-80 yr) were randomized to daily supplementation with either NRPT (1000 mg NR + 200 mg PT) or matched placebo. Two weeks after initiation of supplementation, a skeletal muscle injury was induced by electrically-induced eccentric muscle work. Skeletal muscle biopsies were obtained pre, 2h, 2, 8, and 30 days post injury. RESULTS. A substantial skeletal muscle injury was induced by the protocol and associated with release of myoglobin and creatine kinase, muscle soreness, tissue edema, and a decrease in muscle strength. MuSC content, proliferation and cell size revealed a large demand for recruitment post injury but was not affected by NRPT. Furthermore, histological analyses of muscle fiber area, internal nuclei and embryonic Myosin Heavy Chain showed no effect of NRPT supplementation. CONCLUSION. Daily supplementation with 1000 mg NR+200 mg PT is safe but does not improve recruitment of the MuSC pool or other measures of muscle recovery in response to injury or subsequent regeneration in elderly subjects. TRIAL REGISTRATION. NCT03754842. FUNDING. Novo Nordisk Foundation (Ref. NNF17OC0027242) given to JTT and NJ. JTT, ED, SC, MVD, KT, and TM are supported by the Novo Nordisk Foundation Center for Basic Metabolic Research (CBMR). CBMR is an independent Research Center at the University of Copenhagen that is partially funded by an unrestricted donation from the Novo Nordisk Foundation (NNF18CC0034900).
Jonas Brorson Jensen, Ole Lindgård Dollerup, Andreas Buch Møller, Tine B. Billeskov, Emilie Dalbram, Sabina Chubanava, Mads V. Damgaard, Ryan W. Dellinger, Kajetan Trošt, Thomas Moritz, Steffen Ringgaard, Niels Møller, Jonas T. Treebak, Jean Farup, Niels Jessen
BACKGROUND. New therapeutic combinations to improve the outcome of ovarian cancer patients are clearly needed. Preclinical studies with ribociclib (LEE-011), a CDK4/6 cell cycle checkpoint inhibitor, demonstrate a synergistic effect with platinum chemotherapy and efficacy as a maintenance therapy after chemotherapy. We tested the safety and initial efficacy of ribociclib in combination with platinum-based chemotherapy in recurrent ovarian cancer. METHODS. This phase I trial combined weekly carboplatin and paclitaxel chemotherapy with ribociclib followed by ribociclib maintenance in patients with recurrent platinum-sensitive ovarian cancer. Primary objectives were safety and maximum tolerated dose (MTD) of ribociclib when given with platinum and taxane chemotherapy. Secondary endpoints were response rate (RR) and progression-free survival (PFS). RESULTS. Thirty-five patients were enrolled. Patients had a mean 2.5 prior lines of chemotherapy, and 51% received prior maintenance therapy with Poly (ADP-ribose) polymerase inhibitors (PARPi) and/or Bevacizumab. The MTD was 400mg. The most common AEs included anemia (82.9%), neutropenia (82.9%), fatigue (82.9%), and nausea (77.1%). Overall RR was 79.3% with a stable disease (SD) rate of 18% resulting in a clinical benefit rate of 96.6%. The PFS was 11.4 months. RR and PFS did not differ based on number of lines of prior chemotherapy or prior maintenance therapy. CONCLUSIONS. This work demonstrates the combination of ribociclib with chemotherapy in ovarian cancer is feasible and safe. With a clinical benefit rate of 97%, this work provides encouraging evidence of clinical efficacy in patients with recurrent platinum-sensitive disease. TRIAL REGISTRATION. ClinicalTrials.gov NCT03056833. FUNDING. This investigator-initiated trial was supported by Novartis who provided drug and funds for trial execution.
Lan G. Coffman, Taylor J. Orellana, Tianshi Liu, Leonard G. Frisbie, Daniel Normolle, Kent Griffith, Shitanshu Uppal, Karen McLean, Jessica L. Berger, Michelle Boisen, Madeleine Courtney-Brooks, Robert P. Edwards, Jamie Lesnock, Haider Mahdi, Alexander Olawaiye, Paniti Sukumvanich, Sarah E. Taylor, Ronald Buckanovich
BACKGROUND. Systemic sclerosis (SSc) is an autoimmune, connective tissue disease characterized by vasculopathy and fibrosis of the skin and internal organs. METHODS. We randomized 15 participants with early diffuse cutaneous SSc to tofacitinib 5 mg twice a day or matching placebo in a Phase I/II double-blind, placebo-controlled trial. The primary outcome measure was safety and tolerability at or before Week 24. In order to understand the changes in gene expression associated with tofacitinib treatment in each skin cell populations, we compared single cell gene expression in punch skin biopsies obtained at baseline and 6 weeks following the initiation of treatment. RESULTS. Tofacitinib was well tolerated; there were no participants, who experienced Grade 3 or higher adverse effects (AEs) before or at Week 24. Trends in efficacy outcome measures favored tofacitnib. Baseline gene expression in fibroblast and keratinocyte subpopulations indicates interferon (IFN) activated gene expression. Tofacitinib inhibited IFN-regulated gene expression in the SFRP2/DPP4 fibroblasts (progenitors of myofibroblasts) and MYOC and CCL19, representing adventitial fibroblasts (p< 0.05), as well as in the basal and keratinized layers of the epidermis. Gene expression in macrophages and dendritic cells indicated inhibition of STAT3 by tofacitinib (p<0.05). No clinically meaningful inhibition of T cells and endothelial cells in the skin tissue was observed. CONCLUSION. These results indicate that mesenchymal and epithelial cells of a target organ in SSc, not the infiltrating lymphocytes, may be the primary focus for therapeutic effects of a janus kinase inhibitor. TRIAL REGISTRATION. clinicaltrials.gov NCT03274076. FUNDING SOURCE. This was an investigator-initiated trial designed by the Sponsor and the steering committee. The industry funder, Pfizer, had no role in collecting, analyzing, and interpreting the data. The manuscript was drafted by the authors and was reviewed by Pfizer Inc. before final submission. No medical writer was involved in creating the manuscript. DK was supported by NIH/NIAMS R01 AR070470 and NIH/NIAMS K24 AR063120. JMK, JEG, LCT are supported by the Taubman Medical Research Institute and NIH-P30 AR075043. LCT was also supported by NIH/NIAMS K01AR072129. The corresponding author had full access to all data congregates in the study and made the final decision to submit the manuscript for publication.
Dinesh Khanna, Cristina M. Padilla, Lam C. Tsoi, Vivek Nagaraja, Puja Khanna, Tracy Tabib, J. Michelle Kahlenberg, Amber Young, Suiyuan Huang, Johann e. Gudjonsson, David A. Fox, Robert Lafyatis
BACKGROUND Prolonged symptoms after SARS-CoV-2 infection are well documented. However, which factors influence development of long-term symptoms, how symptoms vary across ethnic groups, and whether long-term symptoms correlate with biomarkers are points that remain elusive.METHODS Adult SARS-CoV-2 reverse transcription PCR–positive (RT-PCR–positive) patients were recruited at Stanford from March 2020 to February 2021. Study participants were seen for in-person visits at diagnosis and every 1–3 months for up to 1 year after diagnosis; they completed symptom surveys and underwent blood draws and nasal swab collections at each visit.RESULTS Our cohort (n = 617) ranged from asymptomatic to critical COVID-19 infections. In total, 40% of participants reported at least 1 symptom associated with COVID-19 six months after diagnosis. Median time from diagnosis to first resolution of all symptoms was 44 days; median time from diagnosis to sustained symptom resolution with no recurring symptoms for 1 month or longer was 214 days. Anti-nucleocapsid IgG level in the first week after positive RT-PCR test and history of lung disease were associated with time to sustained symptom resolution. COVID-19 disease severity, ethnicity, age, sex, and remdesivir use did not affect time to sustained symptom resolution.CONCLUSION We found that all disease severities had a similar risk of developing post–COVID-19 syndrome in an ethnically diverse population. Comorbid lung disease and lower levels of initial IgG response to SARS-CoV-2 nucleocapsid antigen were associated with longer symptom duration.TRIAL REGISTRATION ClinicalTrials.gov, NCT04373148.FUNDING NIH UL1TR003142 CTSA grant, NIH U54CA260517 grant, NIEHS R21 ES03304901, Sean N Parker Center for Allergy and Asthma Research at Stanford University, Chan Zuckerberg Biohub, Chan Zuckerberg Initiative, Sunshine Foundation, Crown Foundation, and Parker Foundation.
Xiaolin Jia, Shu Cao, Alexandra S. Lee, Monali Manohar, Sayantani B. Sindher, Neera Ahuja, Maja Artandi, Catherine A. Blish, Andra L. Blomkalns, Iris Chang, William J. Collins, Manisha Desai, Hena Naz Din, Evan Do, Andrea Fernandes, Linda N. Geng, Yael Rosenberg-Hasson, Megan Ruth Mahoney, Abigail L. Glascock, Lienna Y. Chan, Sharon Y. Fong, CLIAHUB Consortium, Chan Zuckerberg Biohub, Maira Phelps, Olivia Raeber, Stanford COVID-19 Biobank Study Group, Natasha Purington, Katharina Röltgen, Angela J. Rogers, Theo Snow, Taia T. Wang, Daniel Solis, Laura Vaughan, Michelle Verghese, Holden Maecker, Richard Wittman, Rajan Puri, Amy Kistler, Samuel Yang, Scott D. Boyd, Benjamin A. Pinsky, Sharon Chinthrajah, Kari C. Nadeau
Serum neurofilament light chain (sNFL) is becoming an important biomarker of neuroaxonal injury. Though sNFL correlates with cerebrospinal fluid (CSF) NFL (cNFL), 40-60% of variance remains unexplained. We aimed to mathematically adjust sNFL to strengthen its clinical value. We measured NFL in blinded fashion in 1,138 matched CSF and serum samples from 571 subjects. Multiple linear regression (MLR) models constructed in the training cohort were validated in an independent cohort. MLR model that included age, blood urea nitrogen (BUN), alkaline phosphatase (AP), creatinine, and weight improved correlations of cNFL with sNFL (from R2 = 0.57 to 0.67). Covariate-adjustment significantly improved the correlation of sNFL with number of contrast-enhancing lesions (from R2 = 0.18 to 0.28; 36% improvement) in the validation cohort. Unexpectedly, only sNFL, but not cNFL, weakly but significantly correlated with cross-sectional MS severity outcomes. Investigating two non-overlapping hypotheses, we show that subjects with proportionally higher sNFL to cNFL have higher clinical and radiological evidence of spinal cord (SC) injury, and likely release NFL from peripheral axons into blood, bypassing the CSF. Thus, sNFL captures two sources of axonal injury: central and peripheral; the latter reflecting SC damage, which primarily drives disability progression in MS.
Peter Kosa, Ruturaj Masvekar, Mika Komori, Jonathan Phillips, Vighnesh Ramesh, Mihael Varosanec, Mary Sandford, Bibiana Bielekova
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