Emerging technologies focused on the detection and quantification of circulating tumor DNA (ctDNA) in blood show extensive potential for managing patient treatment decisions, informing risk of ...recurrence, and predicting response to therapy. Currently available tissue-informed approaches are often limited by the need for additional sequencing of normal tissue or peripheral mononuclear cells to identify non-tumor-derived alterations while tissue-naïve approaches are often limited in sensitivity. Here we present the analytical validation for a novel ctDNA monitoring assay, FoundationOne®Tracker. The assay utilizes somatic alterations from comprehensive genomic profiling (CGP) of tumor tissue. A novel algorithm identifies monitorable alterations with a high probability of being somatic and computationally filters non-tumor-derived alterations such as germline or clonal hematopoiesis variants without the need for sequencing of additional samples. Monitorable alterations identified from tissue CGP are then quantified in blood using a multiplex polymerase chain reaction assay based on the validated SignateraTM assay. The analytical specificity of the plasma workflow is shown to be 99.6% at the sample level. Analytical sensitivity is shown to be >97.3% at ≥5 mean tumor molecules per mL of plasma (MTM/mL) when tested with the most conservative configuration using only two monitorable alterations. The assay also demonstrates high analytical accuracy when compared to liquid biopsy-based CGP as well as high qualitative (measured 100% PPA) and quantitative precision (<11.2% coefficient of variation).
Spatio-temporal models can be used to analyze data collected at various spatial locations throughout multiple time points. However, even with a finite number of spatial locations, there may be ...insufficient resources to collect data from every spatial location at every time point. We develop a spatio-temporal finite-population block kriging (ST-FPBK) method to predict a quantity of interest, such as a mean or total, across a finite number of spatial locations. This ST-FPBK predictor incorporates an appropriate variance reduction for sampling from a finite population. Through an application to moose surveys in the east-central region of Alaska, we show that the predictor has a substantially smaller standard error compared to a predictor from the purely spatial model that is currently used to analyze moose surveys in the region. We also show how the model can be used to forecast a prediction for abundance in a time point for which spatial locations have not yet been surveyed. A separate simulation study shows that the spatio-temporal predictor is unbiased and that prediction intervals from the ST-FPBK predictor attain appropriate coverage. For ecological monitoring surveys completed with some regularity through time, use of ST-FPBK could improve precision. We also give an R package that ecologists and resource managers could use to incorporate data from past surveys in predicting a quantity from a current survey. Supplementary materials accompanying this paper appear on-line.
Purpose To evaluate how the transition of United States Medical Licensing Examination (USMLE) Step 1 to a pass/fail scoring influenced medical student perceptions of the importance of research ...required to match into their preferred residency specialty. Methods A 14-item survey was distributed by e-mail to medical students at one medical school in the southeastern United States in November of 2021. Responses were compared between medical students taking USMLE Step 1 pass/fail in the future and medical students taking USMLE Step 1 for a three-digit score. Results A total of 168 medical students responded to the survey with 98 respondents who planned on taking USMLE Step 1 pass/fail (45 first-year medical students (MS1) and 53 MS2) and 70 respondents who took USMLE Step 1 for a numerical score (37 MS3 and 33 MS4). There were no differences in how each cohort scored the level of importance of research in matching into their preferred residency specialty (p=0.10); however, those taking USMLE Step 1 pass/fail believe an average of 4.6 research experiences are necessary to match into their preferred residency, compared to only 3.4 research experiences for those who took it for a numerical score (p=0.04). Conclusion No statistically significant difference in the perceived importance of research in matching into one's preferred residency specialty was found between cohorts. However, the pass/fail cohort believes they will need more research experiences to match their chosen specialty than the numerical score cohort. Results could indicate that students participate in more research and extracurricular activities to be more competitive for residency applications.
The SARS-CoV-2 virus has infected more than 261 million people and has led to more than 5 million deaths in the past year and a half
( https://www.who.org/ ). Individuals with SARS-CoV-2 infection ...typically develop mild-to-severe flu-like symptoms, whereas infection of a subset of individuals leads to severe-to-fatal clinical outcomes
. Although vaccines have been rapidly developed to combat SARS-CoV-2, there has been a dearth of antiviral therapeutics. There is an urgent need for therapeutics, which has been amplified by the emerging threats of variants that may evade vaccines. Large-scale efforts are underway to identify antiviral drugs. Here we screened approximately 18,000 drugs for antiviral activity using live virus infection in human respiratory cells and validated 122 drugs with antiviral activity and selectivity against SARS-CoV-2. Among these candidates are 16 nucleoside analogues, the largest category of clinically used antivirals. This included the antivirals remdesivir and molnupiravir, which have been approved for use in COVID-19. RNA viruses rely on a high supply of nucleoside triphosphates from the host to efficiently replicate, and we identified a panel of host nucleoside biosynthesis inhibitors as antiviral. Moreover, we found that combining pyrimidine biosynthesis inhibitors with antiviral nucleoside analogues synergistically inhibits SARS-CoV-2 infection in vitro and in vivo against emerging strains of SARS-CoV-2, suggesting a clinical path forward.
Pyronaridine tetraphosphate is on the WHO Essential Medicine List for its importance as a widely available and safe treatment for malaria. We find that pyronaridine is a highly effective antiviral ...therapeutic across mouse models using multiple variants of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), and the highly pathogenic viruses SARS-CoV-1 and Middle East respiratory syndrome coronavirus responsible for previous coronavirus outbreaks. Additionally, we find that pyronaridine additively combines with current COVID-19 treatments such as nirmatrelvir (protease inhibitor in Paxlovid) and molnupiravir to further inhibit SARS-CoV-2 infections. There are many antiviral compounds that demonstrate efficacy in cellular models, but few that show this level of impact in multiple mouse models and represent a promising therapeutic for the current coronavirus pandemic as well as future outbreaks as well.
Attention Deficit Hyperactivity Disorder (ADHD) can be comorbid with depression, often leading to the prescription of both methylphenidate (MP) and selective serotonin reuptake inhibitor (SSRI) ...antidepressants, such as fluoxetine (FLX). Moreover, these drugs are often misused as cognitive enhancers. This study examined the effects of chronic oral co-administration of MP and FLX on depressive- and anxiety-like behaviors.
Adolescent rats received daily either water (control), MP, FLX, or the combination of MP plus FLX in their drinking water over the course of 4 weeks.
Data analysis shows a decrease in food consumption and body weight for rats exposed to FLX or the combination of MP and FLX. Sucrose consumption was significantly greater in FLX or MP+FLX groups compared to controls. FLX-treated rats showed no effect in the elevated plus maze (EPM; open arm time) and forced swim test (FST; latency to immobility). However, rats treated with the combination (MP+FLX) showed significant anxiolytic-like and anti-depressive-like behaviors (as measured by EPM and FST), as well as significant increases in overall activity (distance traveled in open field test). Finally, the combined MP+FLX treatment induced a decrease in anxiety and depressive- like behaviors significantly greater than the response from either of these drugs alone.
These behavioral results characterize the long-term effects of these drugs (orally administered) that are widely co-administered and co-misused and provide important insight into the potential neurobiological and neurochemical effects. Future research will determine the potential risks of the long-term use of MP and FLX together.
SARS-CoV-2 variants have emerged with elevated transmission and a higher risk of infection for vaccinated individuals. We demonstrate that a recombinant prefusion-stabilized spike (rS) protein ...vaccine based on Beta/B.1.351 (rS-Beta) produces a robust anamnestic response in baboons against SARS-CoV-2 variants when given as a booster one year after immunization with NVX-CoV2373. Additionally, rS-Beta is highly immunogenic in mice and produces neutralizing antibodies against WA1/2020, Beta/B.1.351, and Omicron/BA.1. Mice vaccinated with two doses of Novavax prototype NVX-CoV2373 (rS-WU1) or rS-Beta alone, in combination, or heterologous prime-boost, are protected from challenge. Virus titer is undetectable in lungs in all vaccinated mice, and Th1-skewed cellular responses are observed. We tested sera from a panel of variant spike protein vaccines and find broad neutralization and inhibition of spike:ACE2 binding from the rS-Beta and rS-Delta vaccines against a variety of variants including Omicron. This study demonstrates that rS-Beta vaccine alone or in combination with rS-WU1 induces antibody-and cell-mediated responses that are protective against challenge with SARS-CoV-2 variants and offers broader neutralizing capacity than a rS-WU1 prime/boost regimen alone. Together, these nonhuman primate and murine data suggest a Beta variant booster dose could elicit a broad immune response to fight new and future SARS-CoV-2 variants.
Global deployment of vaccines that can provide protection across several age groups is still urgently needed to end the COVID-19 pandemic, especially in low- and middle-income countries. Although ...vaccines against SARS-CoV-2 based on mRNA and adenoviral vector technologies have been rapidly developed, additional practical and scalable SARS-CoV-2 vaccines are required to meet global demand. Protein subunit vaccines formulated with appropriate adjuvants represent an approach to address this urgent need. The receptor binding domain (RBD) is a key target of SARS-CoV-2 neutralizing antibodies but is poorly immunogenic. We therefore compared pattern recognition receptor (PRR) agonists alone or formulated with aluminum hydroxide (AH) and benchmarked them against AS01B and AS03-like emulsion-based adjuvants for their potential to enhance RBD immunogenicity in young and aged mice. We found that an AH and CpG adjuvant formulation (AH:CpG) produced an 80-fold increase in anti-RBD neutralizing antibody titers in both age groups relative to AH alone and protected aged mice from the SARS-CoV-2 challenge. The AH:CpG-adjuvanted RBD vaccine elicited neutralizing antibodies against both wild-type SARS-CoV-2 and the B.1.351 (beta) variant at serum concentrations comparable to those induced by the licensed Pfizer-BioNTech BNT162b2 mRNA vaccine. AH:CpG induced similar cytokine and chemokine gene enrichment patterns in the draining lymph nodes of both young adult and aged mice and enhanced cytokine and chemokine production in human mononuclear cells of younger and older adults. These data support further development of AH:CpG-adjuvanted RBD as an affordable vaccine that may be effective across multiple age groups.
Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has caused a wide spectrum of diseases in the human population, from asymptomatic infections to death. It is important to study the host ...differences that may alter the pathogenesis of this virus. One clinical finding in coronavirus disease 2019 (COVID-19) patients is that people with obesity or diabetes are at increased risk of severe illness from SARS-CoV-2 infection. We used a high-fat diet model in mice to study the effects of obesity and type 2 diabetes on SARS-CoV-2 infection as well as how these comorbidities alter the response to vaccination. We find that diabetic/obese mice have increased disease after SARS-CoV-2 infection and they have slower clearance of the virus. We find that the lungs of these mice have increased neutrophils and that removing these neutrophils protects diabetic/obese mice from disease. This demonstrates why these diseases have increased risk of severe disease and suggests specific interventions upon infection.
In this study, we asked participants to “describe their sexual orientation” in an open-ended measure of self-generated sexual orientation. The question was included as part of the New Zealand ...Attitudes and Values Study (
N
= 18,261) 2013/2014 wave, a national probability survey conducted shortly after the first legal same-sex marriages in New Zealand. We present a two-level classification scheme to address questions about the prevalence of, and demographic differences between, sexual orientations. At the most detailed level of the coding scheme, 49 unique categories were generated by participant responses. Of those who responded with the following, significantly more were women: bisexual (2.1 % of women, compared to 1.5 % of men), bicurious (0.7 % of women, 0.4 % of men), and asexual (0.4 % of women and less than 0.1 % of men). However, significantly fewer women than men reported being lesbian or gay (1.8 % of women, compared to 3.5 % of men). Those openly identifying as bicurious, bisexual, or lesbian/gay were significantly younger than those with a heterosexual orientation. This study shows diversity in the terms used in self-generated sexual orientations, and provides up-to-date gender, age, and prevalence estimates for the New Zealand population. Finally, results reveal that a substantial minority of participants may not have understood the question about sexual orientation.
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