👤 Charles Tapley Hoyt

Posttraumatic Stress Disorder (PTSD) is a common condition with few effective medication treatments. Glecaprevir/Pibrentasvir (GLE/PIB), a treatment for hepatitis C virus (HCV) infection, demonstrated possible evidence of effectiveness for PTSD in an epidemiological study. We sought to determine if GLE/PIB decreases the symptoms of PTSD and modulates inflammation. An uncontrolled open trial was conducted at the Veterans Affairs Medical Center in White River Junction Vermont. Participants were veterans with PTSD and no HCV infection. Ten participants received Glecaprevir 100 mg/Pibrentasvir 40 mg, three tablets daily for 8 weeks. Symptoms were measured at baseline, mid-treatment, post-treatment, as well as at three- and six-months post-treatment. The primary outcome was PTSD symptoms as measured by the Clinician Administered PTSD Scale for DSM 5 (CAPS-5). Exploratory analyses were conducted to assess serum inflammatory biomarkers at baseline and post-treatment. The mean baseline CAPS-5 score was 33.6 (SD = 3.3). Six-month post-treatment effects were large (CAPS-5: d = 1.6, p < 0.01). By the end of the study, eight patients met the criteria for response, including eight who met the criteria for loss of PTSD diagnosis and six who met the criteria for total remission of PTSD (CAPS-5 score of less than 12). Lower interleukin (IL)-27 levels prior to treatment were predictive of treatment response. Eight-week IL-9 levels changes with treatment were associated with symptom improvement. GLE/PIB may be an effective treatment for PTSD. Furthermore, treatment may modulate inflammatory responses in PTSD. Future studies are required to confirm these findings regarding GLE/PIB, PTSD, and inflammation. Show less

The early phase of drug development relies on the examination of the efficacy and safety of therapeutic agents in animal models. Due to their close genetic and physiological relation to humans, cynomolgus monkeys ( Show less

Neuroimaging markers provide quantitative insight into brain structure and function in neurodegenerative diseases, such as Alzheimer's disease, where we lack mechanistic insights to explain pathophysiology. These mechanisms are often mediated by genes and genetic variations and are often studied through the lens of genome-wide association studies. Linking these two disparate layers (i.e., imaging and genetic variation) through causal relationships between biological entities involved in the disease's etiology would pave the way to large-scale mechanistic reasoning and interpretation. We explore how genetic variants may lead to functional alterations of intermediate molecular traits, which can further impact neuroimaging hallmarks over a series of biological processes across multiple scales. We present an approach in which knowledge pertaining to single nucleotide polymorphisms and imaging readouts is extracted from the literature, encoded in Biological Expression Language, and used in a novel workflow to assist in the functional interpretation of SNPs in a clinical context. We demonstrate our approach in a case scenario which proposes KANSL1 as a candidate gene that accounts for the clinically reported correlation between the incidence of the genetic variants and hippocampal atrophy. We find that the workflow prioritizes multiple mechanisms reported in the literature through which KANSL1 may have an impact on hippocampal atrophy such as through the dysregulation of cell proliferation, synaptic plasticity, and metabolic processes. We have presented an approach that enables pinpointing relevant genetic variants as well as investigating their functional role in biological processes spanning across several, diverse biological scales. Show less