Featured
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| Open AccessRespiratory distress in SARS-CoV-2 exposed uninfected neonates followed in the COVID Outcomes in Mother-Infant Pairs (COMP) Study
Unusually high rates of respiratory distress were observed in infants following in utero exposure to SARS-CoV-2. Here the authors find, in a longitudinal cohort of infants born to persons infected with SARS-CoV-2 during pregnancy, that maternal vaccination is associated with a lower odds of infant respiratory distress.
- Olivia M. Man
- , Tamiris Azamor
- & Karin Nielsen-Saines
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Article
| Open AccessPangenome graphs improve the analysis of structural variants in rare genetic diseases
A pangenomic approach, where genome sequences are related to each other in a graph, facilitates analysis of genomic variation between individuals. Here, the authors explore the benefits of using such an approach to characterize structural variation (e.g., deletions or duplications of more than 50 base pairs) in a rare disease cohort.
- Cristian Groza
- , Carl Schwendinger-Schreck
- & Tomi Pastinen
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| Open AccessDiscovery of a peripheral 5HT2A antagonist as a clinical candidate for metabolic dysfunction-associated steatohepatitis
Metabolic Dysfunction-Associated Steatohepatitis (MASH), an advanced form of Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD), can progress to liver fibrosis. Here, the authors develop a peripheral 5HT2A antagonist for the treatment of MASLD and MASH.
- Haushabhau S. Pagire
- , Suvarna H. Pagire
- & Jin Hee Ahn
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Article
| Open AccessShifting patterns of dengue three years after Zika virus emergence in Brazil
Dengue virus circulation was unusually low in Brazil in 2015-2018 following the emergence of Zika virus, but subsequently resurged causing large outbreaks with a lower mean age of infection. Here, the authors use mathematical modelling to investigate the links between dengue dynamics and prior Zika infection.
- Francesco Pinotti
- , Marta Giovanetti
- & José Lourenço
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Article
| Open AccessHHV-6B detection and host gene expression implicate HHV-6B as pulmonary pathogen after hematopoietic cell transplant
Lower respiratory tract disease is a common complication after allogeneic hematopoietic cell transplant (HCT), but underlying reasons remain unclear. Here the authors show that HHV-6B detection in the lungs of allogeneic HCT recipients is associated with increased risk for death and distinct host gene expression profiles, implicating HHV-6B as a pulmonary pathogen in these patients.
- Joshua A. Hill
- , Yeon Joo Lee
- & Michael Boeckh
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Article
| Open AccessGeneration and optimization of off-the-shelf immunotherapeutics targeting TCR-Vβ2+ T cell malignancy
Clonal Vb2 usage is common among patients with mature T cell lymphoma. Here the authors report the generation of allogeneic CAR-T cells selectively targeting TCR Vb2+ on malignant T cells, with limited normal T cell destruction.
- Jingjing Ren
- , Xiaofeng Liao
- & Michael Girardi
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Article
| Open AccessLarge scale plasma proteomics identifies novel proteins and protein networks associated with heart failure development
The pathobiology of heart failure (HF) is incompletely understood. The authors identify 37 circulating proteins and 5 protein modules associated with HF risk, with several demonstrating causal effects on HF, risk factors, or cardiac dysfunction by Mendelian randomization analysis.
- Amil M. Shah
- , Peder L. Myhre
- & Bing Yu
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Article
| Open AccessDermatologist-like explainable AI enhances trust and confidence in diagnosing melanoma
Artificial intelligence has become popular as a cancer classification tool, but there is distrust of such systems due to their lack of transparency. Here, the authors develop an explainable AI system which produces text- and region-based explanations alongside its classifications which was assessed using clinicians’ diagnostic accuracy, diagnostic confidence, and their trust in the system.
- Tirtha Chanda
- , Katja Hauser
- & Titus J. Brinker
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Article
| Open AccessPersonalising intravenous to oral antibiotic switch decision making through fair interpretable machine learning
The decision to switch patients from intravenous to oral antibiotic therapy is important for the individual and wider society. Here, authors show a machine learning model using routine clinical data can predict when a patient could switch.
- William J. Bolton
- , Richard Wilson
- & Timothy M. Rawson
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Article
| Open AccessThe HER2-directed antibody-drug conjugate DHES0815A in advanced and/or metastatic breast cancer: preclinical characterization and phase 1 trial results
Antibody drug conjugates (ADCs) with pyrrolobenzodiazepine (PBD) payloads are promising cancer therapeutics but are limited by toxicity. Here, the authors develop a HER2-targeted ADC (DHES0815A) with a reduced potency PBD payload that demonstrated promising preclinical efficacy and nonhuman primate tolerability, but culminated in a phase I clinical trial in patients with metastatic breast cancer which was terminated due to toxicity.
- Gail D. Lewis
- , Guangmin Li
- & Eunpi Cho
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Article
| Open AccessAutonomous artificial intelligence increases screening and follow-up for diabetic retinopathy in youth: the ACCESS randomized control trial
Diabetic retinopathy is a complication of diabetes that can be prevented through screening, yet adherence is low. Here, the authors show that autonomous AI increases diabetic eye exam completion in a diverse cohort of youth with diabetes.
- Risa M. Wolf
- , Roomasa Channa
- & Michael D. Abramoff
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Article
| Open AccessLevels of complement factor H-related 4 protein do not influence susceptibility to age-related macular degeneration or its course of progression
Complement factor H-related 4 protein (FHR-4) has been implicated in the pathophysiology of age-related macular degeneration (AMD). Here, in contrast, the authors find that levels of FHR-4 in plasma or ocular tissue do not appear to influence susceptibility to AMD or its course of progression, questioning whether modulation of FHR-4 is likely to be an effective therapeutic strategy.
- M. A. Zouache
- , B. T. Richards
- & G. S. Hageman
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Article
| Open AccessROCK1/2 signaling contributes to corticosteroid-refractory acute graft-versus-host disease
Steroid-refractory acute graft-versus-host disease (aGVHD) is associated with a low one-year survival rate. Here, the authors show that ROCK1 is upregulated in leukocytes from patients with steroid-refractory aGVHD and that ROCK1/2 inhibition reduces the severity of aGVHD in mice by interfering with activation of multiple immune cell types.
- Kristina Maas-Bauer
- , Anna-Verena Stell
- & Robert Zeiser
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Article
| Open AccessSingle-sided magnetic resonance-based sensor for point-of-care evaluation of muscle
Magnetic resonance imaging is a useful clinical tool, but its widespread use is constrained by size, cost, and time. Here, the authors report the development of a magnetic resonance sensor for the clinical detection of muscle tissue, allowing for new point-of-care quantitative diagnostic measurements
- Sydney E. Sherman
- , Alexa S. Zammit
- & Michael J. Cima
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Article
| Open AccessProtection against symptomatic dengue infection by neutralizing antibodies varies by infection history and infecting serotype
There is still a need to improve understanding of dengue-specific immunity. Here, by analyzing the antibody response in a pediatric cohort the authors show that the protective capacity of neutralizing antibodies depends on infection history and serotype, but its estimation varies by assay condition and virion maturation.
- Sandra Bos
- , Aaron L. Graber
- & Eva Harris
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Article
| Open AccessNeutrophil activation and clonal CAR-T re-expansion underpinning cytokine release syndrome during ciltacabtagene autoleucel therapy in multiple myeloma
Chimeric antigen receptor T cell (CAR-T) therapy has revolutionized the treatment of hematological cancers, however, immune related adverse effects, such as cytokine release syndrome (CRS) may limit therapeutic success. Here authors show that CRS is preceded by a latent stage, characterized by neutrophil activation and distinct cytokine signatures, and that CAR-T re-expansion might associate with severe CRS.
- Shuangshuang Yang
- , Jie Xu
- & Sai-Juan Chen
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Article
| Open AccessGene-SGAN: discovering disease subtypes with imaging and genetic signatures via multi-view weakly-supervised deep clustering
Many diseases can display distinct brain imaging phenotypes across individuals, potentially reflecting disease subtypes. However, biological interpretability is limited if the derived subtypes are not associated with genetic drivers or susceptibility factors. Here, the authors describe a deep-learning method that links imaging phenotypes with genetic factors, thereby conferring genetic correlations to the disease subtypes.
- Zhijian Yang
- , Junhao Wen
- & Christos Davatzikos
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Article
| Open AccessBlood DNA methylation profiling identifies cathepsin Z dysregulation in pulmonary arterial hypertension
Pulmonary arterial hypertension is a complex disease characterised by high morbidity and mortality. Here, the authors report methylation profiling of patients, finding disease associations in genes CTSZ, COG6 and ZNF678.
- Anna Ulrich
- , Yukyee Wu
- & Christopher J. Rhodes
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Article
| Open AccessRedirecting antibody responses from egg-adapted epitopes following repeat vaccination with recombinant or cell culture-based versus egg-based influenza vaccines
Here the authors report an exploratory analysis of a clinical trial that tested different influenza virus vaccination platforms. The results show that multiple seasons of recombinant or cell-based influenza vaccinations may be needed to redirect antibody responses away from immune memory to egg-adapted epitopes and refocus on epitopes on the circulating viruses.
- Feng Liu
- , F. Liaini Gross
- & Min Z. Levine
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Comment
| Open AccessFrom lab to life: how wearable devices can improve health equity
Wearable devices can provide personalised medicine at the point of need, potentially increasing access to health services and therefore improving health equity. Here the authors discuss their experiences developing wearable devices for vulnerable patient populations, including neonates and pregnant individuals.
- Jessica R. Walter
- , Shuai Xu
- & John A. Rogers
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| Open AccessThe antibiotic resistance reservoir of the lung microbiome expands with age in a population of critically ill patients
Here, by performing tracheal aspirate RNA sequencing of critically ill patients, the authors find that older age associates with a greater number of detectably expressed antimicrobial resistance genes in the lower respiratory tract microbiome.
- Victoria T. Chu
- , Alexandra Tsitsiklis
- & Charles R. Langelier
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Article
| Open AccessBCG vaccination-induced acquired control of mycobacterial growth differs from growth control preexisting to BCG vaccination
Bacillus Calmette-Guèrin vaccination prevents tuberculosis but some individuals control infection without immunization. Here the authors employ functional assessment of effector responses against mycobacteria to find that distinct gene expression profiles for pre-existing capacity to control and control induced by BCG vaccination.
- Krista E. van Meijgaarden
- , Wenchao Li
- & Simone A. Joosten
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| Open AccessIntegrative genotyping of cancer and immune phenotypes by long-read sequencing
Single-cell transcriptomics excel in cell subset classification and can be augmented by suitable genotype information. Here the authors devise a long-read sequencing workflow, termed nanoranger, for detection of molecular barcodes from single-cell cDNA and apply this to clonal tracking of acute myeloid leukemia and identification of complex immune phenotypes.
- Livius Penter
- , Mehdi Borji
- & Catherine J. Wu
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Article
| Open AccessDistinct gene expression signatures comparing latent tuberculosis infection with different routes of Bacillus Calmette-Guérin vaccination
The ability of BCG vaccination to prevent pulmonary tuberculosis could be improved by targeting mucosal immunity within the lung. Here the authors compare latent Mtb-infected donors with intradermal or oral BCG vaccine recipients to show distinct systemic and pulmonary immune responses are induced by differing routes of natural infection or vaccination.
- Richard F. Silver
- , Mei Xia
- & Daniel F. Hoft
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Article
| Open AccessBACH1 controls hepatic insulin signaling and glucose homeostasis in mice
Hepatic insulin resistance plays a central role in metabolic syndrome. Here, the authors show that transcription factor BACH1 acts as a negative regulator of insulin signaling and that hepatic BACH1 deficiency ameliorates hyperglycemia and insulin resistance in high-fat diet-fed or diabetic mice
- Jiayu Jin
- , Yunquan He
- & Dan Meng
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| Open AccessRevealing hidden patterns in deep neural network feature space continuum via manifold learning
Existing feature visualisation methods are not well-suited for regression tasks. Here, authors introduce a method to learn the manifold topology related to deep neural network output and target labels and provide insightful visualisations of the high-dimensional features while preserving the local geometry.
- Md Tauhidul Islam
- , Zixia Zhou
- & Lei Xing
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Article
| Open AccessCyclosporine A-resistant CAR-T cells mediate antitumour immunity in the presence of allogeneic cells
Although allogeneic chimaeric antigen receptor (CAR)-T cells can overcome manufacturing bottlenecks for cancer immunotherapy, immune rejection reduces the persistence and efficacy of allogeneic cells. Here, the authors demonstrate that CAR-T cells engineered to be resistant to cyclosporin A show improved engraftment and mediate robust tumour-specific responses in allogeneic recipients.
- Yixi Zhang
- , Hongyu Fang
- & Xun Zeng
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Article
| Open AccessAlveolar epithelial progenitor cells require Nkx2-1 to maintain progenitor-specific epigenomic state during lung homeostasis and regeneration
Alveolar epithelial progenitors in the lungs can regenerate the epithelial surface after acute injury. Here they generate lung organoids that can be used to study lung regeneration after injury and identify Nkx2-1 as a key regulator of alveolar progenitor activation.
- Andrea Toth
- , Paranthaman Kannan
- & William J. Zacharias
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Article
| Open AccessOptimal timing of nirmatrelvir/ritonavir treatment after COVID-19 symptom onset or diagnosis: target trial emulation
Nirmatrelvir/ritonavir can reduce COVID-19 severity when initiated within five days of symptom onset but the optimal timing within this window is unknown. Here, the authors emulate a randomised trial using electronic health records from Hong Kong and find evidence for a benefit of early treatment initiation.
- Carlos K. H. Wong
- , Jonathan J. Lau
- & Joseph T. Wu
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Article
| Open AccessA pilot study of alternative substrates in the critically Ill subject using a ketogenic feed
Critical illness leads to altered metabolic states and bioenergetic failure caused by impaired utilisation of glucose, fatty acids and amino acids. Here the authors show ketogenic diets may provide a safe and acceptable alternative metabolic fuel enabling energy production and maintaining tissue homeostasis.
- Angela McNelly
- , Anne Langan
- & Zudin A. Puthucheary
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| Open AccessIdentification of 5-HT2A receptor signaling pathways associated with psychedelic potential
Serotonin 5-HT2A receptor signaling mechanisms associated with predicting psychedelic potential remain elusive. Using 5-HT2A-selective β-arrestin-biased ligands, here the authors show that a threshold level of 5-HT2A-Gq efficacy and not β-arrestin recruitment is associated with psychedelic potential.
- Jason Wallach
- , Andrew B. Cao
- & John D. McCorvy
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Article
| Open AccessRepurposed drugs and their combinations prevent morbidity-inducing dermonecrosis caused by diverse cytotoxic snake venoms
Three drugs initially developed for other conditions, 2,3-dimercapto-1-propanesulfonic acid (DMPS), marimastat and varespladib, have shown promise in preventing the lethality of snakebite envenoming. Here, Hall et al., show that a combination of these drugs can combat the local dermonecrotic effects caused by diverse cytotoxic venoms.
- Steven R. Hall
- , Sean A. Rasmussen
- & Nicholas R. Casewell
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| Open AccessA phase 2 randomised controlled trial of mazdutide in Chinese overweight adults or adults with obesity
Mazdutide is a once-weekly glucagon-like peptide-1 (GLP-1) and glucagon receptor dual agonist. Here, the authors show mazdutide was well tolerated over 24 weeks and demonstrated significant and clinically meaningful body weight loss, compared with placebo, in Chinese overweight adults or adults with obesity.
- Linong Ji
- , Hongwei Jiang
- & Lei Qian
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| Open AccessBinge-pattern alcohol consumption and genetic risk as determinants of alcohol-related liver disease
Deaths from alcohol-related liver disease have sharply increased following the Covid-19 pandemic. Here, the authors show that binge-pattern alcohol consumption, genetic factors and the presence of diabetes mellitus confer the greatest risk, allowing targeted interventions for high-risk individuals.
- Chengyi Ding
- , Linda Ng Fat
- & Gautam Mehta
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Article
| Open AccessTemperature-related death burden of various neurodegenerative diseases under climate warming: a nationwide modelling study
Examining non-optimal temperatures’ influence on neurodegenerative diseases amid climate warming is vital for public health. Here, the authors project a notable net increase of death burden from neurodegenerative diseases after the mid-21st century.
- Peng Yin
- , Ya Gao
- & Haidong Kan
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Comment
| Open AccessAccelerating African neuroscience to provide an equitable framework using perspectives from West and Southern Africa
Drawing on perspectives from West and Southern Africa, this Comment critically examines the current state of neuroscience progress in Africa, describing the unique landscape and ongoing challenges as embedded within wider socio-political realities. Distinct research opportunities in the African context are explored to include genetic and bio-diversity, multilingual and multicultural populations, life-course development, clinical neuroscience and neuropsychology, with applications to machine learning models, in light of complex post-colonial legacies that often impede research progress. Key determinants needed to accelerate African neuroscience are then discussed, as well as cautionary underpinnings that together create an equitable neuroscience framework.
- Sahba Besharati
- & Rufus Akinyemi
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Article
| Open AccessA lung-selective delivery of mRNA encoding broadly neutralizing antibody against SARS-CoV-2 infection
The authors use lipid nanoparticles (LNPs) that predominantly accumulate in the lung to deliver mRNA encoding for the broadly neutralizing antibody 8-9D, and achieve superior inhibition of SARS-CoV-2 infection in mice compared to control LNPs.
- Wanbo Tai
- , Kai Yang
- & Gong Cheng
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Article
| Open AccessShuttle peptide delivers base editor RNPs to rhesus monkey airway epithelial cells in vivo
Gene editing strategies for cystic fibrosis are challenging. Here the authors improve on their previously reported shuttle peptide noncovalently combined with Cas ribonucleoprotein (RNP), and derive the S315 peptide for delivery: they show base editing in the respiratory tract of the rhesus macaques.
- Katarina Kulhankova
- , Soumba Traore
- & Paul B. McCray Jr.
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Article
| Open AccessProstate cancer genetic risk and associated aggressive disease in men of African ancestry
Most genetic studies for prostate cancer have been performed outside the context of Sub-Saharan Africa. Here, the authors interrogate 247,780 exomic variants for 798 Black South African men and identify genes associated with aggressive disease.
- Pamela X. Y. Soh
- , Naledi Mmekwa
- & Vanessa M. Hayes
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Article
| Open AccessYoung infants display heterogeneous serological responses and extensive but reversible transcriptional changes following initial immunizations
Our understanding of the infant immune responses to routine vaccines remains limited. Here, the authors show that administration of routine vaccines to 2-month-old infants is associated with highly variable but limited antibody responses and mostly naïve-like immune cells with robust and transient expression of interferon genes.
- Nima Nouri
- , Raquel Giacomelli Cao
- & Octavio Ramilo
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Article
| Open AccessHealth-related quality of life is linked to the gut microbiome in kidney transplant recipients
Here, Swarte et al. use metagenomics to investigate the association between the gut microbiome and Health-Related Quality of Life (HRQoL) in kidney transplant recipients, showing evidence for the association of multiple taxonomic, metabolic and neuroactive pathways (gut brain modules) with lower HRQoL, together suggesting potential modifiable gut microbial factors to improve HRQoL.
- J. Casper Swarte
- , Tim J. Knobbe
- & Rinse K. Weersma
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Article
| Open AccessExplainable machine learning for profiling the immunological synapse and functional characterization of therapeutic antibodies
Therapeutic antibodies are crucial in treating severe diseases. Here, the authors introduce scifAI, an open-source explainable AI framework for analyzing imaging flow cytometry data, enabling rapid screening of therapeutic antibody candidates.
- Sayedali Shetab Boushehri
- , Katharina Essig
- & Fabian Schmich
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Article
| Open AccessUtilizing river and wastewater as a SARS-CoV-2 surveillance tool in settings with limited formal sewage systems
COVID-19 has impacted health systems unequally and widespread SARS-CoV-2 testing for community surveillance has been limited globally. This work in Malawi highlights how river and wastewater can be used to detect emerging SARS-CoV-2 waves, identify variants of concern, and provide an early warning system.
- Kayla G. Barnes
- , Joshua I. Levy
- & Nicholas Feasey
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Article
| Open AccessTransformEHR: transformer-based encoder-decoder generative model to enhance prediction of disease outcomes using electronic health records
Using AI to predict disease can improve interventions slow down or prevent disease. Here, the authors show that generative AI models built on the framework of Transformer, the model that also empowers ChatGPT, can achieve state-of-the-art performance on disease predictions based on longitudinal electronic records.
- Zhichao Yang
- , Avijit Mitra
- & Hong Yu
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Article
| Open AccessPlasma proteomic profiles predict individual future health risk
The predictive capability of future health risk using plasma proteomic profiles remains largely unexplored. Using 1461 proteins collected from 50k individuals, authors show proteins can derive much better or equivalent performance than established clinical indicators for more than 40 endpoints.
- Jia You
- , Yu Guo
- & Jin-Tai Yu
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Article
| Open AccessNR-SAFE: a randomized, double-blind safety trial of high dose nicotinamide riboside in Parkinson’s disease
Oral nicotinamide riboside (NR) at a dose of 3000 mg daily for 30 days is safe and associated with a pronounced systemic augmentation of the NAD metabolome, but no methyl donor depletion.
- Haakon Berven
- , Simon Kverneng
- & Charalampos Tzoulis
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Article
| Open AccessAdults on pre-exposure prophylaxis (tenofovir-emtricitabine) have faster clearance of anti-HIV monoclonal antibody VRC01
Small molecule drugs can affect clearance of monoclonal antibodies, but this hasn’t been assessed for oral HIV-1 pre-exposure prophylaxis. Here, the authors find that faster serum clearance of an experimental IgG1 monoclonal antibody, VRC01, is associated with use of tenofovir-emtricitabine, possibly explained by increased epithelial intestinal permeability.
- Yunda Huang
- , Lily Zhang
- & Maria P. Lemos
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Article
| Open AccessPersistent humoral immune response in youth throughout the COVID-19 pandemic: prospective school-based cohort study
Understanding the immune responses of school-aged children to SARS-CoV-2 is important for designing public health measures. Here, the authors report findings from cross-sectional and longitudinal anti-SARS-CoV-2 antibody measurements in a school-based study in Zurich, Switzerland, from 2020-2022.
- Alessia Raineri
- , Thomas Radtke
- & Susi Kriemler
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Article
| Open AccessSequential vaccinations with divergent H1N1 influenza virus strains induce multi-H1 clade neutralizing antibodies in swine
Seasonal influenza vaccines typically fail to induce cross-protective antibody responses. Here, Van Reeth et al. sequentially vaccinate pigs with diverse H1N1 viruses and show that this strategy induces antibodies against a panel of H1N1 strains from swine and humans and protects against antigenically mismatched strains.
- Kristien Van Reeth
- , Anna Parys
- & Elien Vandoorn