Purpose The ketogenic diet is a low-carbohydrate, moderate protein, high-fat diet that has emerged as a potential treatment for autism spectrum disorder. Autism spectrum disorder is a neurodevelopmental disorder of social communication, and restricted, repetitive behaviors and interests in need of novel therapies. An open-label clinical trial was done in Honolulu, Hawaii to test a modified ketogenic diet for improvement of core clinical impairments in children with ASD. Intervention A modified ketogenic gluten-free diet regimen with supplemental MCT was completed in 15 children ages 2 to 17 years for 3 months. Clinical (ADOS-2, CARS-2) and biochemical measures were performed at baseline and 3-months on the ketogenic diet. Main outcome Children administered a modified ketogenic gluten-free diet with supplemental MCT significantly improved core autism features assessed from the ADOS-2 after 3 months on diet (P = 0.006). No significant difference was observed in restricted and repetitive behavior score (P = 0.125) after 3 months on the diet protocol. Substantial improvement (> 30% decrease ADOS-2 total score) was observed in six participants, moderate improvement (> 3 units) in two participants, and minor/no improvement in seven participants. Ten participants assessed at a six-month time point sustained improvement in total ADOS-2 and social affect subdomain scores comparing baseline and 6 months (P = 0.019; P = 0.023), but no significant improvement in restricted and repetitive behavior scores were noted (P = 0.197). Significant improvements in CARS-2 items after 3 months of the modified ketogenic protocol were observed in imitation, body use, and fear or nervousness (P = 0.031, P = 0.008, P = 0.039). The percent change on ADOS-2 score from baseline to 3 months was associated with baseline high-density lipoprotein levels (ρ = −0.67, P = 0.007) and albumin levels (ρ = −0.60, P = 0.019). Moreover, the percent change from baseline to 3 months in ADOS-2 scores was significantly associated with percent change in high-density lipoprotein levels (ρ = 0.54, P = 0.049) and albumin levels (ρ = 0.67, P = 0.010). Conclusions A modified gluten-free ketogenic diet with supplemental MCT is a potentially beneficial treatment option to improve the core features of autism spectrum disorder and warrants further investigation. Trial registration Trial Registry: Clinicaltrials.gov Registration Number: NCT02477904URL: https://www.clinicaltrials.gov/ct2/show/NCT02477904?term=ketogenic+diet&cond=Autism&rank=1

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28Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of 29 coronavirus disease 2019 , is now pandemic with nearly three million cases 30 reported to date 1 . Although the majority of COVID-19 patients experience only mild or 31 moderate symptoms, a subset will progress to severe disease with pneumonia and acute 32 respiratory distress syndrome (ARDS) requiring mechanical ventilation 2 . Emerging results 33 indicate a dysregulated immune response characterized by runaway inflammation, 34including cytokine release syndrome (CRS), as the major driver of pathology in severe 35 -19 3,4 . With no treatments currently approved for COVID-19, therapeutics to 36 prevent or treat the excessive inflammation in severe disease caused by SARS-CoV-2 37 infection are urgently needed. Here, in 10 terminally-ill, critical COVID-19 patients we 38 report profound elevation of plasma IL-6 and CCL5 (RANTES), decreased CD8+ T cell 39 levels, and SARS-CoV-2 plasma viremia. Following compassionate care treatment with 40 the CCR5 blocking antibody leronlimab, we observed complete CCR5 receptor 41 occupancy on macrophage and T cells, rapid reduction of plasma IL-6, restoration of the 42 CD4/CD8 ratio, and a significant decrease in SARS-CoV-2 plasma viremia. Consistent 43 with reduction of plasma IL-6, single-cell RNA-sequencing revealed declines in 44 transcriptomic myeloid cell clusters expressing IL-6 and interferon-related genes. These 45 results demonstrate a novel approach to resolving unchecked inflammation, restoring 46 immunologic deficiencies, and reducing SARS-CoV-2 plasma viral load via disruption of 47 COVID MAIN TEXT 51 52Since the initial cases of COVID-19 were reported from Wuhan, China in December 53 2019 2 , SARS-CoV-2 has emerged as a global pandemic with an ever-increasing number 54 of severe cases requiring invasive external ventilation that threatens to overwhelm health 55

The global pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) is a highly pathogenic RNA virus causing coronavirus disease 2019 (COVID‐19) in humans. Although most patients with COVID‐19 have mild illness and may be asymptomatic, some will develop severe pneumonia, acute respiratory distress syndrome, multi‐organ failure, and death. RNA viruses such as SARS‐CoV‐2 are capable of hijacking the epigenetic landscape of host immune cells to evade antiviral defense. Yet, there remain considerable gaps in our understanding of immune cell epigenetic changes associated with severe SARS‐CoV‐2 infection pathology. Here, we examined genome‐wide DNA methylation (DNAm) profiles of peripheral blood mononuclear cells from 9 terminally‐ill, critical COVID‐19 patients with confirmed SARS‐CoV‐2 plasma viremia compared with uninfected, hospitalized influenza, untreated primary HIV infection, and mild/moderate COVID‐19 HIV coinfected individuals. Cell‐type deconvolution analyses confirmed lymphopenia in severe COVID‐19 and revealed a high percentage of estimated neutrophils suggesting perturbations to DNAm associated with granulopoiesis. We observed a distinct DNAm signature of severe COVID‐19 characterized by hypermethylation of IFN‐related genes and hypomethylation of inflammatory genes, reinforcing observations in infection models and single‐cell transcriptional studies of severe COVID‐19. Epigenetic clock analyses revealed severe COVID‐19 was associated with an increased DNAm age and elevated mortality risk according to GrimAge, further validating the epigenetic clock as a predictor of disease and mortality risk. Our epigenetic results reveal a discovery DNAm signature of severe COVID‐19 in blood potentially useful for corroborating clinical assessments, informing pathogenic mechanisms, and revealing new therapeutic targets against SARS‐CoV‐2.