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BackgroundA comprehensive understanding of the SARS-CoV-2 infection dynamics and the ensuing host immune responses is needed to explain the pathogenesis as it relates to viral transmission. Knowledge gaps exist surrounding SARS-CoV-2 in vivo kinetics, particularly in the earliest stages after exposure.MethodsAn ongoing, workplace clinical surveillance study was used to intensely sample a small cohort longitudinally. Nine study participants who developed COVID-19 between November, 2020 and March, 2021 were monitored at high temporal resolution for three months in terms of viral loads as well as associated inflammatory biomarker and antibody responses. CD8 + T cells targeting SARS-CoV-2 in blood samples from study participants were evaluated.ResultsHere we show that the resulting datasets, supported by Bayesian modeling, allowed the underlying kinetic processes to be described, yielding a number of unexpected findings. Early viral replication is rapid (median doubling time, 3.1 h), providing a narrow window between exposure and viral shedding, while the clearance phase is slow and heterogeneous. Host immune responses different widely across participants.ConclusionsResults from our small study give a rare insight into the life-cycle of COVID-19 infection and hold a number of important biological, clinical, and public health implications.

Public health practices and high vaccination rates currently represent the primary interventions for managing the spread of coronavirus disease 2019 (COVID-19). We initiated a clinical study based on frequent, longitudinal workplace disease surveillance to control severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission among employees and their household members. We hypothesized that the study would reduce the economic burden and loss of productivity of both individuals and small businesses resulting from standard isolation methods, while providing new insights into virus-host dynamics. Study participants (27 employees and 27 household members) consented to provide frequent nasal or oral swab samples that were analyzed by reverse transcription-quantitative PCR (RT-qPCR) for SARS-CoV-2 RNA. Two study participants were found to be infected by SARS-CoV-2 during the study. One subject, a household member, was SARS-CoV-2 RNA positive for at least 71 days and had quantifiable serum virus-specific antibody concentrations for over 1 year. One unrelated employee became positive for SARS-CoV-2 RNA over the course of the study but remained asymptomatic, with low associated viral RNA copy numbers, no detectable serum IgM and IgG concentrations, and IgA concentrations that decayed rapidly (half-life: 1.3 days). A COVID-19 infection model was used to predict that without surveillance intervention, up to 7 employees (95% confidence interval [CI] = 3 to 10) would have become infected, with at most 1 of them requiring hospitalization. Our scalable and transferable surveillance plan met its primary objectives and represents a powerful example of an innovative public health initiative dovetailed with scientific discovery. IMPORTANCE The rapid spread of SARS-CoV-2 and the associated COVID-19 has precipitated a global pandemic heavily challenging our social behavior, economy, and health care infrastructure. In the absence of widespread, worldwide access to safe and effective vaccines and therapeutics, public health measures represent a key intervention for curbing the devastating impacts from the pandemic. We are conducting an ongoing clinical study based on frequent, longitudinal workplace disease surveillance to control SARS-CoV-2 transmission among employees and their household members. Our study was successful in surveying the viral and immune response dynamics in two participants with unusual infections: one remained positive for SARS-CoV-2 for 71 days, while the other was asymptomatic, with low associated viral RNA copy numbers. A COVID-19 infection model was used to predict that without surveillance intervention, up to 7 employees would have become infected, with at most 1 of them requiring hospitalization, underscoring the importance of our program.

ObjectiveInvestigate a new polymer-based drug coating suitability for safe intracochlear delivery and ability to maintain long-term physiologically active levels of the corticosteroid fluticasone propionate.Study designIn vitro dissolution study to evaluate release profiles of polymer-coated drug particles and in vivo studies using a guinea pig model to measure perilymph drug concentrations at specific time points after implantation with polymer-coated drug particles and evaluate their effect on hearing function.MethodsPolymer-coated fluticasone propionate (FP) particles were surgically implanted in guinea pigs through the round window membrane into the cochlear scala tympani. In the pilot study, pre- and post-op hearing thresholds were conducted on days 7, 14, and 42. In a second study, post-op hearing thresholds were conducted on days 90, 120, and 180. Perilymph drug concentrations were measured on the same time points.ResultsIn 15 of 16 animals from day 7 through day 90, drug levels were within the targeted range, with no initial burst release detected. Drug was present in all animals on day 90 and was detected in some animals at 120 and 180 days. Hearing was tested and compared with non-implanted ears. Very good hearing preservation was observed in ears implanted with intracochlear particles when compared with contralateral ears.ConclusionsThe polymer-based extended release system is effective in providing long-term, stable drug delivery for at least 90 days with good hearing outcomes. The results of this study support the potential for achieving long-term drug delivery with a single intracochlear administration.

Vaginally administered antiviral agents may reduce the risk of HIV and HSV acquisition. Delivery of these drugs using intravaginal rings (IVRs) holds the potential benefits of improving adherence and decreasing systemic exposure, while maintaining steady-state drug levels in the vaginal tract. Elucidating how IVRs interact with the vaginal microbiome constitutes a critical step in evaluating the safety of these devices, as shifts the vaginal microbiome have been linked with several disease states. To date, clinical IVR trials have relied on culture-dependent methods that omit the high diversity of unculturable microbial population. Longitudinal, culture-independent characterization of the microbiota in vaginal samples from 6 women with recurrent genital HSV who used an acyclovir IVR was carried out and compared to the communities developing in biofilms on the IVR surface. The analysis utilized Illumina MiSeq sequence datasets generated from bar-coded amplicons of 16S rRNA gene fragments. Specific taxa in the vaginal communities of the study participants were found to be associated with the duration of recurrent genital HSV status and the number of HSV outbreaks. Taxonomic comparison of the vaginal and IVR biofilm communities did not reveal any significant differences, suggesting that the IVRs were not systematically enriched with members of the vaginal microbiome. Device usage did not alter the participants' vaginal microbial communities, within the confines of the current study design. Rigorous, molecular analysis of the effects of intravaginal devices on the corresponding microbial communities shows promise for integration with traditional approaches in the clinical evaluation of candidate products.

The injectable progestin depot-medroxyprogesterone acetate (DMPA) is a popular contraceptive choice in sub-Saharan Africa although mouse models indicate it weakens genital epithelial integrity and barrier function and increases susceptibility to genital infection. The intravaginal ring NuvaRing® is another contraceptive option that like DMPA suppresses hypothalamic pituitary ovarian (HPO) axis function with local release of progestin (etonogestrel) and estrogen (ethinyl estradiol). As we previously reported that treating mice with DMPA and estrogen averts the loss of genital epithelial integrity and barrier function induced by DMPA alone, in the current investigation we compared genital levels of the cell-cell adhesion molecule desmoglein-1 (DSG1) and genital epithelial permeability in rhesus macaques (RM) treated with DMPA or a NuvaRing®re-sized for RM (N-IVR). While these studies demonstrated comparable inhibition of the HPO axis with DMPA or N-IVR, DMPA induced significantly lower genital DSG1 levels and greater tissue permeability to intravaginally administered low molecular mass molecules. By identifying greater compromise of genital epithelial integrity and barrier function in RM administered DMPA vs. N-IVR, our results add to the growing body of evidence that indicate DMPA weakens a fundamental mechanism of anti-pathogen host defense in the female genital tract. [ABSTRACT FROM AUTHOR]

The preliminary efforts to engage students in the physical sciences through research projects in environmental chemistry are described. The successful involvement of two demographics, community college (CC) students and female students in cutting-edge chemistry research suggests that recruiting methods were effective and the feedback from participants suggests that the chemistry projects selected by the students positively affected their career planning.

Background Intravaginal rings (IVRs) for HIV pre-exposure prophylaxis (PrEP) theoretically overcome some adherence concerns associated with frequent dosing that can occur with oral or vaginal film/gel regimens. An innovative pod-IVR, composed of an elastomer scaffold that can hold up to 10 polymer-coated drug cores (or 'pods'), is distinct from other IVR designs as drug release from each pod can be controlled independently. A pod-IVR has been developed for the delivery of tenofovir (TFV) disoproxil fumarate (TDF) in combination with emtricitabine (FTC), as daily oral TDF-FTC is the only Food and Drug Administration (FDA)-approved regimen for HIV PrEP. A triple combination IVR building on this platform and delivering TDF-FTC along with the antiretroviral (ARV) agent maraviroc (MVC) also is under development. Methodology and findings This pilot Phase I trial conducted between June 23, 2015, and July 15, 2016, evaluated the safety, pharmacokinetics (PKs), and acceptability of pod-IVRs delivering 3 different ARV regimens: 1) TDF only, 2) TDF-FTC, and 3) TDF-FTC-MVC over 7 d. The crossover, open-label portion of the trial (N = 6) consisted of 7 d of continuous TDF pod-IVR use, a wash-out phase, and 7 d of continuous TDF-FTC pod-IVR use. After a 3-mo pause to evaluate safety and PK of the TDF and TDF-FTC pod-IVRs, TDF-FTC-MVC pod-IVRs (N = 6) were evaluated over 7 d of continuous use. Safety was assessed by adverse events (AEs), colposcopy, and culture-independent analysis of the vaginal microbiome (VMB). Drug and drug metabolite concentrations in plasma, cervicovaginal fluids (CVFs), cervicovaginal lavages (CVLs), and vaginal tissue (VT) biopsies were determined via liquid chromatographic-tandem mass spectrometry (LC-MS/MS). Perceptibility and acceptability were assessed by surveys and interviews. Median participant age was as follows: TDF/TDF-FTC group, 26 y (range 24-35 y), 2 White, 2 Hispanic, and 2 African American; TDF-FTC-MVC group, 24.5 y (range 21-41 y), 3 White, 1 Hispanic, and 2 African American. Reported acceptability was high for all 3 products, and pod-IVR use was confirmed by residual drug levels in used IVRs. There were no serious adverse events (SAEs) during the study. There were 26 AEs reported during TDF/TDF-FTC IVR use (itching, discharge, discomfort), with no differences between TDF alone or in combination with FTC observed. In the TDF-FTC-MVC IVR group, there were 12 AEs (itching, discharge, discomfort) during IVR use regardless of attribution to study product. No epithelial disruption/thinning was seen by colposcopy, and no systematic VMB shifts were observed. Median (IQR) tenofovir diphosphate (TFV-DP) tissue concentrations of 303 (277-938) fmol/10.sup.6 cells (TDF), 289 (110-603) fmol/10.sup.6 cells (TDF-FTC), and 302 (177.1-823.8) fmol/10.sup.6 cells (TDF-FTC-MVC) were sustained for 7 d, exceeding theoretical target concentrations for vaginal HIV prevention. The study's main limitations include the small sample size, short duration (7 d versus 28 d), and the lack of FTC triphosphate measurements in VT biopsies. Conclusions An innovative pod-IVR delivery device with 3 different formulations delivering different regimens of ARV drugs vaginally appeared to be safe and acceptable and provided drug concentrations in CVFs and tissues exceeding concentrations achieved by highly protective oral dosing, suggesting that efficacy for vaginal HIV PrEP is achievable. These results show that an alternate, more adherence-independent, longer-acting prevention device based on the only FDA-approved PrEP combination regimen can be advanced to safety and efficacy testing. Trial registration ClinicalTrials.gov NCT02431273, Author(s): Kathleen L. Vincent 1,*, John A. Moss 2, Mark A. Marzinke 3,4, Craig W. Hendrix 3, Peter A. Anton 2,5, Richard B. Pyles 6,7, Kate M. Guthrie 8,9, Lauren [...]

Researchers from Air Instruments & Measurements Inc. and the Oak Crest Institute of Science used a remote sensor utilizing ultraviolet and infrared spectrometers to measure over 20 pollutants in the exhaust of 19 in-use vehicles fueled by reformulated gasoline diesel, compressed natural gas, and methanol with 15% gasoline. Results reveal that gasoline and methanol engines contain high levels of NH3.

Abstract Background Microbial biofilms represent an incompletely understood, but fundamental mode of bacterial growth. These sessile communities typically consist of stratified, morphologically-distinct layers of extracellular material, where numerous metabolic processes occur simultaneously in close proximity. Limited reports on environmental isolates have revealed highly ordered, three-dimensional organization of the extracellular matrix, which may hold important implications for biofilm physiology in vivo. Results A Pseudomonas spp. isolated from a natural soil environment produced flocculent, nonmucoidal biofilms in vitro with unique structural features. These mature biofilms were made up of numerous viable bacteria, even after extended culture, and contained up to 50% of proteins and accumulated 3% (by dry weight) calcium, suggesting an important role for the divalent metal in biofilm formation. Ultrastructurally, the mature biofilms contained structural motifs consisting of dense, fibrillary clusters, nanofibers, and ordered, honeycomb-like chambers enveloped in thin sheets. Conclusion Mature biofilms contained living bacteria and were structurally, chemically, and physiologically heterogeneous. The principal architectural elements observed by electron microscopy may represent useful morphological clues for identifying bacterial biofilms in vivo. The complexity and reproducibility of the structural motifs observed in bacterial biofilms appear to be the result of organized assembly, suggesting that this environmental isolate may possess ecological advantages in its natural habitat.