Exploring the Pharmacokinetics of Phenoxymethylpenicillin (Penicillin-V) in Adults: A Healthy Volunteer Study

This healthy volunteer study aimed to explore phenoxymethylpenicillin (penicillin-V) pharmacokinetics (PK) to support the planning of large dosing studies in adults. Volunteers were dosed with penicillin-V at steady state. Total and unbound penicillin-V serum concentrations were determined, and a base population PK model was fitted to the data.

Variation of eurycomanone content within and among populations of E. apiculata A.W. Benn.

Information on the eurycomanone content of E. apiculata A.W. Benn from natural populations in Indonesia is unknown. This study aimed to assess the variation of eurycomanone content within and among populations of E. apiculata, determine the correlation of eurycomanone content with environmental factors, and determine the collection sites of genetic material for the establishment of the breeding base population of E. apiculata. The analysis of eurycomanone content was carried out using High-Performance Liquid Chromatography. This study found that the highest eurycomanone content was observed in the Rumbio population (9.86 mg/g) and the lower value was observed in the Pokomo population (4.44 mg/g). The average variation of eurycomanone content within the population was 25.72%. The coefficient of eurycomanone differentiation among populations was 84.33%, indicating that the variation of eurycomanone content among populations of E. apiculata was higher than the variation of eurycomanone content within-population (15.67%). Pearson correlation of eurycomanone content with population environmental factors showed no significant correlation. Based on the eurycomanone content and clustering, the Rumbio population can be selected as a source of the genetic material of E. apiculata for eurycomanone production via the breeding program in the future.

QUASISPECIES FEATURE IN SARS-CoV-2

Since the identification of the SARS-CoV-2, genus Beta- Coronavirus, in January 2020, the virus quickly spread in less than 3 months to all continents with a susceptible human population of about a 7.9billion, and still in active circulation. In the process, it has accumulated mutations leading to genetic diversity. Regular emergence of variants of concern/significance in different ecology shows genetic heterogeneity in the base population of SARS-CoV-2 that is continuously expanding with the passage of the virus in the vast susceptible human population. Natural selection of mutant occurs frequently in a positive sense (+) single-stranded (ss) RNA virus upon replication in the host. The Pressure of sub-optimal levels of virus-neutralizing antibodies and also innate immunity influence the process of genetic/ antigenic selection. The fittest of the mutants, that could be more than one, propagate and emerge as variants. The existence of different lineages, clades, and strains, as well as genetic heterogeneity of plaque purified virus population, justifies SARS-CoV-2 as ‘Quasispecies’ that refers to swarms of mutant sequences generated during replication of the viral genome, and all mutant sequences may not lead to virion. Viruses having a quasispecies nature may end up with progressive antigenic changes leading to antigenic plurality that is driven by ecology, and this phenomenon challenges vaccination-based control programs.

Impact of an Education Intervention on COVID-19 Vaccine Hesitancy in a Military Base Population

ABSTRACT Background Coronavirus disease 2019 (COVID-19) vaccine hesitancy is a major impediment to achieving herd immunity and overcoming the current pandemic. Our aim was to decrease the prevalence of vaccine hesitancy through an education intervention. Method An education intervention, consisting of a PowerPoint presentation addressing the two mRNA COVID-19 vaccine concerns/myths and a question and answer panel comprising health care providers from various specialties, was implemented to address vaccine hesitancy among personnel associated with Wright-Patterson Air Force Base through a series of virtual and in-person seminars. Participants completed a post-seminar survey as a retrospective self-assessment to identify attitudes and views surrounding vaccine hesitancy and the impact of the education intervention. Chi-squared test was used to examine relationships between categorical variables, and multiple logistic regression was used to identify risk factors for vaccine hesitancy pre- and post-seminar. All analyses were done using SPSS Statistics Version 25.0 (IBM, Armonk, NY). Institutional Review Board approval was not obtained before this study as it began as a non-research initiative and received non-research determination post hoc. Results Five hundred participants completed the survey. Mean age was 44.7 years with 13.4 and 86.6% medical and non-medical personnel, respectively. Nearly all (98.8%) had not received their first shot of the vaccine series. 402 (80.9%) were receptive to vaccination, and 95 (19.1%) were hesitant post-seminar. Of the 139 participants who reported they were initially hesitant after our intervention, 50 (36%) indicated that they were now receptive to the vaccine, while 89 (64%) remained hesitant. Of those 50, 48 (96%) had moderate to great amount of trust in COVID-19 vaccine information presented by physicians/other providers. Six respondents who wanted the vaccine before the intervention no longer wanted the vaccine. A medical occupation (OR = 4.85, 95% CI = 2.63-8.96, P < .001), little or no trust in COVID-19 vaccine information from physicians/other providers (OR = 19.48, 95% CI = 7.31-51.90, P < 0.001), and being age 30 or younger (OR = 1.81, 95% CI = 1.02-3.2, P = 0.041) were independent predictors of vaccine hesitancy. Trust in providers was a significant factor in change of intent from vaccine hesitant to receptive post-intervention (OR 0.13, 95% CI = 0.03-0.59, P = .008). Age and occupation were not significant factors associated with change in intent. Conclusion Our education intervention was effective in reducing COVID-19 vaccine hesitancy in a military base population. Study limitations include applications toward other military and non-military populations, the possibility of nonresponse bias, and absence of prior validated interventions. Area for future studies includes improvement upon educational intervention, development of other effective methods, and application of intervention in other populations.

Cyclical response of maize populations versus base population and standard genotypes across environments

Recurrent selection is a cyclical breeding procedure in which selection is made generation after generation, with a reunion of selected plants to produce a new population for the next cycle of selection. Maize (Zea mays L.) base population 'PSEV3' was developed by using selfed progeny recurrent selection in spring and summer crop seasons during 2014 to 2016. During Summer 2017, two improved maize populations [PSEV3-(S1)-C1 and PSEV3-(S2)-C2], original genotype (PSEV3-C0) and three check varieties (two OPV - open-pollinated varieties - Azam and Jalal, and HV - hybrid variety - Kiramat) were assessed for silking and yield traits across four environments including two planting dates and two sites i.e., Cereal Crops Research Institute (CCRI), Pirsabak - Nowshera, and University of Agriculture (UAP), Peshawar, Pakistan. Genotypes and planting dates enunciated significant (p≤0.01) differences for majority of the traits. Maize improved populations (C1 and C2) enunciated comparable values with early flowering and least cob height compared to base population and check genotypes. On average, PSEV3-(S2)-C2 was foremost and exhibited maximum mean values for yield traits with enhanced grain yield with optimum planting at CCRI, followed by PSEV3-(S1)-C1. Base population - C0 and check genotypes were observed with delayed silking and least grain yield across the environments. Selfed progeny recurrent selection was established as an efficient breeding method in improving maize base populations.

Selection for environmental variance of litter size in rabbits involves genes in pathways controlling animal resilience

Background Environmental variance (VE) is partially under genetic control, which means that the VE of individuals that share the same environment can differ because they have different genotypes. Previously, a divergent selection experiment for VE of litter size (LS) during 13 generations in rabbit yielded a successful response and revealed differences in resilience between the divergent lines. The aim of the current study was to identify signatures of selection in these divergent lines to better understand the molecular mechanisms and pathways that control VE of LS and animal resilience. Three methods (FST, ROH and varLD) were used to identify signatures of selection in a set of 473 genotypes from these rabbit lines (377) and a base population (96). A whole-genome sequencing (WGS) analysis was performed on 54 animals to detect genes with functional mutations. Results By combining signatures of selection and WGS data, we detected 373 genes with functional mutations in their transcription units, among which 111 had functions related to the immune system, stress response, reproduction and embryo development, and/or carbohydrate and lipid metabolism. The genes TTC23L, FBXL20, GHDC, ENSOCUG00000031631, SLC18A1, CD300LG, MC2R, and ENSOCUG00000006264 were particularly relevant, since each one carried a functional mutation that was fixed in one of the rabbit lines and absent in the other line. In the 3ʹUTR region of the MC2R and ENSOCUG00000006264 genes, we detected a novel insertion/deletion (INDEL) variant. Conclusions Our findings provide further evidence in favour of VE as a measure of animal resilience. Signatures of selection were identified for VE of LS in genes that have a functional mutation in their transcription units and are mostly implicated in the immune response and stress response pathways. However, the real implications of these genes for VE and animal resilience will need to be assessed through functional analyses.

Mitigating SARS-CoV-2 in the Deployed Environment

ABSTRACT Introduction Unlike other communal living environments (universities, boarding schools, and camps) that have been suspended during the COVID-19 pandemic, the deployed military force must continue its mission. Early challenges in the 2020 deployed environment included limited availability of living and quarantine space and limited testing capacity. This is a brief report of stringent quarantine strategies employed to newly arriving cohorts at a NATO and U.S. military base to prevent release of SARS-CoV-2 into a larger base population. Methods With awareness of the worldwide pandemic, beginning in late February 2020, all personnel arriving to the Hamid Karzai International Airport NATO base were quarantined for 14 days to prevent interaction with the wider base population. Testing capacity was limited. Names, locations, and dates of those within quarantine were tracked to improve contact tracing. Between February and April 2020, the first cases of SARS-CoV-2 were diagnosed on a military base in Afghanistan within quarantine. Results Within quarantine, 11 males became PCR positive for SARS-CoV-2 during April 2020. Five of the 11 were PCR tested for symptoms of fever, cough, or loss of taste. A sixth individual, who had been asymptomatic upon leaving the base after completion of quarantine, later developed symptoms and tested positive. Another five asymptomatic individuals were found with antibody testing just before planned release from 14 days of quarantine post-exposure and confirmed with PCR testing. All PCR-positive individuals were diagnosed before being released into the general population of the base because of strict screening, quarantine, and exit criteria. Conclusion Quarantine creates significant strain on resources in a deployed environment. Group quarantine facilities where social distancing is limited allow for the possibility for intra-quarantine transmission of SARS-CoV-2. Ideally, PCR testing is done upon entry into quarantine and upon exit. With the possibility of false-negative PCR or limited PCR testing, we recommend daily symptom screening, pulse oximetry, temperature checks, and small quarantine groups that must “graduate” together—all meeting exit criteria. Any introduction of new individual, even with negative testing, to a group increases risk of SARS-CoV-2 transmission. Upon exit of quarantine, testing should be performed, regardless of entry testing. If PCR is limited, serology testing should be done, followed by PCR, if positive. Serology testing can be combined with clinical judgment to conserve PCR testing for quarantine release of asymptomatic individuals.

Association of immune checkpoint inhibitors (ICI) and venous thromboembolism (VTE): A single healthcare system experience.

e14567 Background: Cancer and some anti-cancer therapies increase risk of VTE. ICIs cause immune activation and inflammation which are known to potentiate VTE formation. The risk of VTE associated with ICI is unclear, with conflicting evidence of association. Our study assessed the risk of VTE in patients treated with ICI compared to those receiving other cancer treatments. Methods: EPIC Slicer Dicer was used to collect data from three university-affiliated hospitals in New Orleans, LA. All patients >17 years of age, with an oncology treatment plan (TP) between January 1 2012 – January 31 2021 were considered the base population (n=6,894) for the study. The base population was divided into two cohorts - those that received ICI (n=794) versus those who did not (n=6,100). ICIs included pembrolizumab, nivolumab, avelumab, atezolizumab, durvalumab, cemiplimab, ipilimumab. An encounter diagnosis of deep venous thrombosis (DVT) or pulmonary embolism (PE) which was preceded by a TP in the last 1 year was used to identify patients with VTE after initiation of a TP. Categorical covariates compared across VTE groups using Chi-squared tests of independence. Two sample t-tests were used to compare continuous covariates based on VTE status. Logistic regression used to predict VTE as a function of ICIs and other potential confounders including age, BMI, gender, race and cancer subtypes. Results: Patients who experienced VTE were significantly more likely to have received ICI (1.43 times odds of VTE (95% CI = 1.12-1.83; p <0.005), be black or African American (p < 0.05 compared with White and Asian races), and have GI cancer (1.82 times odds, 95% CI= 1.41 – 2.36, p< 0.001), GU cancer (1.7 times odds, 95% CI = 1.3 – 2.23; p<0.001). Patients with VTE were significantly less likely to have breast cancer or other cancer types. Males had a decreased odd of VTE (0.73 odds, 95% CI= 0.62 – 0.85, p< 0.001). Conclusions: Based on the above results, there appears to be an increased likelihood of VTE in patients that receive ICI when compared to other types of cancer treatment. This study is a preliminary analysis and has limitations. At this time, it is unclear if prophylactic anticoagulation can reduce risk of VTE after ICI initiation. Further investigation is warranted in the form of individual chart review, or a prospective study.

The value of genomic relationship matrices to estimate levels of inbreeding

Background Genomic relationship matrices are used to obtain genomic inbreeding coefficients. However, there are several methodologies to compute these matrices and there is still an unresolved debate on which one provides the best estimate of inbreeding. In this study, we investigated measures of inbreeding obtained from five genomic matrices, including the Nejati-Javaremi allelic relationship matrix (FNEJ), the Li and Horvitz matrix based on excess of homozygosity (FL&H), and the VanRaden (methods 1, FVR1, and 2, FVR2) and Yang (FYAN) genomic relationship matrices. We derived expectations for each inbreeding coefficient, assuming a single locus model, and used these expectations to explain the patterns of the coefficients that were computed from thousands of single nucleotide polymorphism genotypes in a population of Iberian pigs. Results Except for FNEJ, the evaluated measures of inbreeding do not match with the original definitions of inbreeding coefficient of Wright (correlation) or Malécot (probability). When inbreeding coefficients are interpreted as indicators of variability (heterozygosity) that was gained or lost relative to a base population, both FNEJ and FL&H led to sensible results but this was not the case for FVR1, FVR2 and FYAN. When variability has increased relative to the base, FVR1, FVR2 and FYAN can indicate that it decreased. In fact, based on FYAN, variability is not expected to increase. When variability has decreased, FVR1 and FVR2 can indicate that it has increased. Finally, these three coefficients can indicate that more variability than that present in the base population can be lost, which is also unreasonable. The patterns for these coefficients observed in the pig population were very different, following the derived expectations. As a consequence, the rate of inbreeding depression estimated based on these inbreeding coefficients differed not only in magnitude but also in sign. Conclusions Genomic inbreeding coefficients obtained from the diagonal elements of genomic matrices can lead to inconsistent results in terms of gain and loss of genetic variability and inbreeding depression estimates, and thus to misleading interpretations. Although these matrices have proven to be very efficient in increasing the accuracy of genomic predictions, they do not always provide a useful measure of inbreeding.