Prescribed Time Points Research Articles

Online Corrections to Neural Policy Guidance for Pinpoint Powered Descent

This study presents incremental correction methods for refining neural network parameters or control functions entering into a continuous-time dynamic system to achieve improved solution accuracy in satisfying the interim point constraints placed on the performance output variables. The proposed approach is to linearize the dynamics around the baseline values of its arguments and then to solve for the corrective input required to transfer the perturbed trajectory to precisely known or desired values at specific time points, in other words, the interim points. Depending on the type of decision variables to adjust, parameter correction and control function correction methods are developed. These incremental correction methods can be used as a means to compensate for the prediction errors of pretrained neural networks in real-time applications where high accuracy of the prediction of dynamical systems at prescribed time points is imperative. In this regard, the online update approach can be useful for enhancing overall targeting accuracy of finite-horizon control subject to point constraints using a neural policy. A numerical example demonstrates the effectiveness of the proposed approach in an application to a powered descent problem on Mars.

Gene Expression Alterations in Peripheral Blood Following Sport-Related Concussion in a Prospective Cohort of Collegiate Athletes: A Concussion Assessment, Research and Education (CARE) Consortium Study

BackgroundMolecular-based approaches to understanding concussion pathophysiology provide complex biological information that can advance concussion research and identify potential diagnostic and/or prognostic biomarkers of injury.ObjectiveThe aim of this study was to identify gene expression changes in peripheral blood that are initiated following concussion and are relevant to concussion response and recovery.MethodsWe analyzed whole blood transcriptomes in a large cohort of concussed and control collegiate athletes who were participating in the multicenter prospective cohort Concussion Assessment, Research, and Education (CARE) Consortium study. Blood samples were collected from collegiate athletes at preseason (baseline), within 6 h of concussion injury, and at four additional prescribed time points spanning 24 h to 6 months post-injury. RNA sequencing was performed on samples from 230 concussed, 130 contact control, and 102 non-contact control athletes. Differential gene expression and deconvolution analysis were performed at each time point relative to baseline.ResultsCytokine and immune response signaling pathways were activated immediately after concussion, but at later time points these pathways appeared to be suppressed relative to the contact control group. We also found that the proportion of neutrophils increased and natural killer cells decreased in the blood following concussion.ConclusionsTranscriptome signatures in the blood reflect the known pathophysiology of concussion and may be useful for defining the immediate biological response and the time course for recovery. In addition, the identified immune response pathways and changes in immune cell type proportions following a concussion may inform future treatment strategies.

Investigating the survival of herpes simplex virus on toothbrushes and surrogate phallic devices.

Herpes simplex virus-1 (HSV-1) is a member of the alphaherpesvirus (alphaherpesvirinae) subfamily, allowing it to affect a wide range of hosts. Herpes simplex virus-1 affects 3.7 billion people, or 67% of the population, under the age of 50. With a vast number of people infected by the virus, everyday objects are often contaminated with this agent. In this study we determined how long HSV-1 can remain viable on contaminated fomites. Fomites were selected for their use near potentially contaminated orifices and variable frequency of sanitization. Toothbrushes and surrogate phallic devices (SPDs) were cut, sterilized, and contaminated. After contaminating the fomites, we collected samples over a 24h period, then used plaque assays to determine viral titers at prescribed time points. The quantity of replication-competent virus present appears to decrease significantly 2h post-contamination, then steadily declines over time, nearing zero at 24h. Our findings suggest that different surfaces influence HSV-1 survival. Proper cleaning must be performed for these types of fomites, especially if shared in an environment where someone with active genital or oral herpes lesions uses one of these fomites shortly after someone else.

PSMA-Targeted Therapeutics: A Tale About Law and Economics.

1482 Introduction: Thorium-227 (227Th) offers a longer half-life, 18.7 days, than other Targeted Alpha Therapy (TAT) agents currently being evaluated clinically such as actinium-225 (t1/2= 9.9 days) and astatine-211 (t1/2= 7.2 hours). This physical characteristic favors its use with biomolecules that have slower pharmacokinetics like monoclonal antibodies. Utilizing 227Th is also advantageous due to the 5 alpha emissions occurring during decay. Hydroxypyridinonate (HOPO) derivatives have been shown to be effective decorporation agents for actinides owing to their hard oxygen donor atoms and strong complexation. Therefore, utilizing these molecules as chelators for potential nuclear medicine agents should allow for radiometals to be effectively sequestered by the ligand. The biological chemistry of thorium is similar to calcium in that the unbound radiometal tends to localize in bone. Consequently, it is pivotal to establish a thorium complex that possesses high stability and thwarts bone uptake. Methods: 227Th received from Oak Ridge National Laboratory was purified from its daughters on a MP1 BioRad resin. The purified thorium was then complexed to the 3,4,3-(LI-1,2-HOPO) ligand by adding the radiometal to a 0.1 M acetate solution containing the ligand (0.08 mM) for 1 hour at 50 °C and was purified using Chelex resin column. The biological distribution of the 227Th-HOPO complex was compared to the “bare” 227Th (227Th-nitrate in 0.1 M HCl/ 5 M acetate solution) in male CD1 mice (n=3) injected with 1 μCi of either construct. At the prescribed time points (15 m, 1 h, 3 h, 6 h, 24 h, 3 d, 7 d, 14 d, 21 d, and 28 d) the organs of interest were harvested and counted using a gamma counter calibrated for 227Th. The biodistribution data was used to calculate the residence time in each organ and was then entered into the OLINDA software to produce the effective dose in rem/mCi. Terminal SPECT/CT imaging of 227Th-nitrate and 227Th-HOPO was obtained in representative mice at 20 min post injection of 15 µCi. Results: The biodistribution results for the 227Th-nitrate species shows clearance through the kidneys (%ID/g = 26.3 ±5.3, 1-day p.i.). Also, substantial localization in the bone as expected is observed. At 15 minutes p.i. the %ID/g in the bone is 7.1 ± 3.9 and gradually increases through the 7-day timepoint, %ID/g- 28.8 ± 12.8, ending the study 28 days p.i with an accumulation of 33.6 ± 17.5 %ID/g. Conversely the 227Th-HOPO species appears to clear through the hepatobiliary tract with accumulation in the gallbladder (54.2 ± 27.7 %ID/g, 1-hour p.i.) and the intestines (29.5 ± 2.2 %ID/g, 1-hour p.i.). Most significantly the bone localization is relatively low and remains constant, approximately 1.5 %ID/g, through all timepoints. The low bone uptake is also reflected in the dosimetry where the effective dose in the bone for 227Th-nitrate and 227Th-HOPO is 1680 rem/mCi and 192 rem/mCi respectively. The effective dose of the 227Th-HOPO species is at least 1 order of magnitude lower than the nitrate species in all organs. Conclusion: We have shown that the 227Th-HOPO complex is stable in vivo and facilitates rapid elimination from the body which results in lower dose to organs, specifically the bone. The stability of the 227Th-HOPO complex suggests that it has potential for use in TAT. Acknowledgments: This work has been funded by BNL LDRD 21-00 and Seed grant under B&R code YN0100000. We would also like to thank all those who assisted with the project.

Regional Deposition: Targeting.

Patterns of regional aerosol deposition within the lungs are known to vary in a predictable manner with a number of factors, most notably aerodynamic particle size and inhalation pattern. Targeting deposition involves the intentional manipulation of one or more of these factors to promote aerosol deposition in certain locations within the respiratory tract. This section will begin by exploring existing evidence supporting the need to target regional deposition. Thereafter, various approaches to targeting will be introduced. In addition to control of aerodynamic particle size and inhalation pattern, a collection of approaches are available through which to passively target deposition to more central or peripheral lung regions. These include the delivery of short aerosol boluses at prescribed time points in inhalation, control of transient hygroscopic aerosol size changes during transport through the respiratory tract, and use of alternative carrier gas mixtures such as helium/oxygen mixtures. Comparatively, targeting aerosol deposition locally to very precise, spatially-defined lung regions is in its infancy. Early, exploratory techniques used for local targeting will be described. The continued evolution of deposition targeting towards ever more specific locations within the lungs is required to explore fundamental research questions in aerosol medicine: namely, how precise does targeting need to be before additional refinement fails to produce appreciably different therapeutic effects, and which nascent applications of aerosols in medicine might benefit from more selective regional targeting?

A self‐preserving, partially biodegradable eDNA filter

Abstract eDNA studies often rely on water filtration in the field and immediate sample preservation to prevent DNA degradation during sample transport. However, filter membrane transfer steps for preservation can increase risk of sample contamination and the reliance on typical single‐use filter housings produces significant plastic waste. We created a new eDNA filter housing (compatible with any suction pump) partially comprised of a biodegradable, hydrophilic material that functions to automatically preserve captured eDNA via desiccation—no filter membrane transfer steps, no chemical or cold storage required. We tested the self‐preservation capabilities of the desiccating filter housings by filtering replicate samples in an eDNA mesocosm study and compared with ethanol preservation. Self‐preserving filters were placed back into original packaging for storage, and samples for both preservation methods were kept at room temperature until extraction at prescribed time points (11 days, 18 days, 25 days, 32 days, 60 days, 88 days, 172 days) post‐filtration. Paired field samples were also collected from six pond locations targeting an additional species to demonstrate field performance. Quantitative PCR results from the mesocosm study indicated that both methods effectively preserved eDNA over a 6‐month storage period, with the self‐preserving filters yielding slightly more target DNA on average (SQ = 329 copies) than ethanol‐preserved samples (SQ = 288 copies) (F1,38 = 4.050, p = 0.051). Neither method showed signs of degradation after 172 days. Results from field sampling indicated a larger difference between preservation methods, with the self‐preserving filters containing approximately 2X the eDNA of ethanol‐preserved samples on average (paired t test, p = 0.020). These data suggest that self‐preserving eDNA filter housings are a viable alternative to standard ethanol preservation methods and may provide higher detection sensitivity in some circumstances. The new filter housings should also help in reducing the risk of sample contamination, minimize protocol steps and result in less plastic waste. Such innovations are important to assure eDNA data quality and to help in facilitating the inclusion of non‐expert sample collectors (e.g. citizen scientists) in research programs.

Providing lipid-based nutrient supplement during pregnancy does not reduce the risk of maternal P falciparum parasitaemia and reproductive tract infections: a randomised controlled trial

BackgroundMaternal infections are associated with maternal and foetal adverse outcomes. Nutrient supplementation during pregnancy may reduce the occurrence of infections by improving maternal immunity. We aimed to investigate the impact of small-quantity lipid-based nutrient supplement (SQ-LNS) on the occurrence of Plasmodium falciparum parasitaemia during pregnancy and trichomoniasis, vaginal candidiasis and urinary tract infection (UTI) after delivery.MethodsPregnant Malawian women enrolled in the iLiNS-DYAD trial receiving daily supplementation with SQ-LNS, multiple micronutrients (MMN) or iron & folic acid (IFA) from <20 gestation weeks (gw) were assessed for P. falciparum parasitaemia at 32 gw using rapid diagnostic testing (RDT), at 36 gw using polymerase chain reaction (PCR) and at delivery using both RDT and PCR; and at one week after delivery for trichomoniasis and vaginal candidiasis using wet mount microscopy and for UTI using urine dipstick analysis. The prevalence of each infection by intervention group was estimated at the prescribed time points and the global null hypothesis was tested using logistic regression. Adjusted analyses were performed using preselected covariates.ResultsThe prevalence of P. falciparum parasitaemia was 10.7% at 32 gw, 9% at 36 gw, and 8.3% by RDT and 20.2% by PCR at delivery. After delivery the prevalence of trichomoniasis was 10.5%, vaginal candidiasis was 0.5%, and UTI was 3.1%. There were no differences between intervention groups in the prevalence of any of the infections.ConclusionIn this population, SQ-LNS did not influence the occurrence of maternal P. falciparum parasitaemia, trichomoniasis, vaginal candidiasis or UTI.Trial registrationIdentifier: NCT01239693 (10 November 2010).

Near-infrared light-triggered release of small molecules for controlled differentiation and long-term tracking of stem cells in vivo using upconversion nanoparticles

Human mesenchymal stem cells (hMSCs) hold considerable potential for regenerative medicine, but their application is limited by the lack of an efficient method to control differentiation and track the migration of implanted cells invivo. In this study, we developed a multifunctional nanocarrier based on upconversion nanoparticles (UCNPs) for controlling differentiation and long-term tracking of hMSCs. The UCNPs are conjugated with the peptide (Cys-Arg-Gly-Asp, CRGD) and the differentiation-inducing kartogenin (KGN) via a photocaged linker on the surface, and the obtained UCNP nanocarrier can be efficiently uptaken by hMSCs. Under the exposure of near-infrared (NIR) light, the upconverted UV emission from the UCNP nanocarrier leads to the photocleavage of the photocaged linker and intracellular release of KGN. The NIR-triggered release of KGN mediated by the UCNP nanocarrier efficiently induces chondrogenic differentiation of hMSCs invitro with reduced KGN dosage compared to the conventional protocol of directly supplementing KGN in the media. Furthermore, NIR irradiation through the skin of living animals induces the chondrogenic differentiation of the subcutaneously implanted hMSCs treated with the KGN-laden UCNP nanocarrier, thereby enhancing neocartilage formation invivo. Finally, the luminescent UCNP nanocarrier enables the long-term tracking of the labeled hMSCs invivo. We believe that our UCNP nanocarrier is a promising tool for the remote control of triggered delivery of inductive agents to stem cells at the prescribed time points and the elucidation of the function and the fate of the transplanted stem cells invivo.

A Prospective, Case-Controlled Study Evaluating the Use of Enamel Matrix Derivative on Human Buccal Recession Defects: A Human Histologic Examination.

Connective tissue grafts (CTGs) and coronally advanced flaps (CAFs) do not regenerate periodontal attachment apparatus when used to treat gingival recessions (GRs). Instead of generating new bone, cementum, and inserting periodontal ligament fibers, CTG+CAF repairs through a long epithelial junction and connective tissue attachment. Enamel matrix derivatives (EMDs) have demonstrated proof-of-principle that periodontal regeneration can be achieved, although data are limited. Three patients, each requiring extraction of four premolars before orthodontic treatment, were enrolled in a randomized, open-label study. Two months after induction of Miller Class I and II GR, each patient received EMD+CAF for three teeth and CTG+CAF for one tooth for root coverage. Nine months after root coverage, all four premolars from each of the three patients were surgically extracted en bloc for histologic and microcomputed tomography (micro-CT) analysis, looking for evidence of periodontal regeneration. Standard clinical measurements, radiographs, and intraoral photographs were taken over prescribed time points. Seven of the nine teeth treated with EMD+CAF demonstrated varying degrees of periodontal regeneration, detailed through histology with new bone, cementum, and inserting fibers. Micro-CT corroborated these findings. None of the three teeth treated with CTG+CAF showed periodontal regeneration. Clinical measurements were comparable for both treatments. One instance of root resorption and ankylosis was noted with EMD+CAF. EMD+CAF continues to show histologic evidence of periodontal regeneration via human histology, this being the largest study (nine teeth) examining its effect when treating GR. The mechanism of action, ideal patient profile, and criteria leading to predictable regeneration are in need of further exploration.

Evidence for Anaerobic Dechlorination of Dechlorane Plus in Sewage Sludge.

The environmental occurrence of dechlorination moieties from the high production volume flame retardant, Dechlorane Plus (DP), has largely been documented; however, the sources have yet to be well understood. In addition, few laboratory-based studies exist which identify the cause for the occurrence of these chemicals in the environment or humans. Anaerobic dechlorination of the two DP isomers was investigated using a laboratory-simulated wastewater treatment plant (WWTP) environment where anaerobic digestion is used as part of the treatment regime. Known amounts of each isomer were added separately to sewage sludge which provided the electron-donating substrate and at prescribed time points in the incubation, a portion of the media was removed and analyzed for DP and any dechlorination metabolites. After 7 days, monohydrodechlorinated products were observed for both the syn- and anti-DP which were continued throughout the duration of our study (49 days) in an increasing manner giving a calculated formation rate of 0.48 ± 0.09 and 0.79 ± 0.12 pmols/day for syn- and anti-DP, respectively. Furthermore, we observed a second monohydrodechlorinated product only in the anti-DP isomer incubation medium. This strongly suggests that anti-DP is more susceptible to anaerobic degradation than the syn isomer. We also provide compelling evidence to the location of chlorine loss in the dechlorination DP analogues. Finally, the dechlorination DP moieties formed in our study matched the retention times and identification of those observed in surficial sediment located downstream of the WWTP.

Comparison of Single-Point and Continuous Sampling Methods for Estimating Residential Indoor Temperature and Humidity

Residential temperature and humidity are associated with multiple health effects. Studies commonly use single-point measures to estimate indoor temperature and humidity exposures, but there is little evidence to support this sampling strategy. This study evaluated the relationship between single-point and continuous monitoring of air temperature, apparent temperature, relative humidity, and absolute humidity over four exposure intervals (5-min, 30-min, 24-hr, and 12-days) in 9 northern Utah homes, from March-June 2012. Three homes were sampled twice, for a total of 12 observation periods. Continuous data-logged sampling was conducted in homes for 2–3 wks, and simultaneous single-point measures (n = 114) were collected using handheld thermo-hygrometers. Time-centered single-point measures were moderately correlated with short-term (30-min) data logger mean air temperature (r = 0.76, β = 0.74), apparent temperature (r = 0.79, β = 0.79), relative humidity (r = 0.70, β = 0.63), and absolute humidity (r = 0.80, β = 0.80). Data logger 12-day means were also moderately correlated with single-point air temperature (r = 0.64, β = 0.43) and apparent temperature (r = 0.64, β = 0.44), but were weakly correlated with single-point relative humidity (r = 0.53, β = 0.35) and absolute humidity (r = 0.52, β = 0.39). Of the single-point RH measures, 59 (51.8%) deviated more than ±5%, 21 (18.4%) deviated more than ±10%, and 6 (5.3%) deviated more than ±15% from data logger 12-day means. Where continuous indoor monitoring is not feasible, single-point sampling strategies should include multiple measures collected at prescribed time points based on local conditions.

Histotripsy Fractionation of Prostate Tissue: Local Effects and Systemic Response in a Canine Model

Histotripsy is an extracorporeal ultrasound technology that uses cavitational mechanisms to produce nonthermal tissue destruction. Previously we reported the feasibility of histotripsy for prostate tissue fractionation and immediate debulking. In this study we characterized the local effects and systemic response after histotripsy treatment of prostate tissue in an in vivo canine model. Histotripsy was applied transabdominally to the prostate in 18 intact male canine subjects under general anesthesia. Acoustic bursts (4 μseconds) were delivered at a 300 Hz pulse repetition rate from a highly focused 750 kHz piezoelectric ultrasound transducer with a 15 cm aperture and 3 × 3 × 8 mm focal volume. Specimens of the prostate and surrounding structures were obtained at prescribed time points (0, 7, 28 or 56 days) after histotripsy. Blood and urine parameters were assessed periodically while clinical evaluation incorporating a validated veterinary pain scale was performed daily. Conventional transrectal ultrasound facilitated targeting of the focal volume and provided real-time assessment of cavitation activity. Fractionation of the targeted volume and clearance of the resultant debris with urination produced a treatment cavity in each prostate. No acoustic collateral damage was seen and urothelialization of the treatment cavity developed within 28 days of treatment. Only transient laboratory value abnormalities and minimal hematuria were noted after treatment. Pain scores revealed only mild posttreatment discomfort. Histotripsy produced consistent tissue fractionation and prostate debulking without collateral acoustic injury or clinical side effects and it was well tolerated in the canine model.

A novel direct aerodynamically assisted threading methodology for generating biologically viable microthreads encapsulating living primary cells

AbstractIn a recent discovery, coaxial electrospinning was explored to encapsulate living organisms within a continuous bio‐polymeric microthread from which active biological scaffolds were fabricated (Townsend‐Nicholson and Jayasinghe, Biomacromolecules 2006, 7, 3364). The cells were demonstrated to have gone through all expected cellular activity without their viability being compromised. These biologically active threads and scaffolds have direct and tremendous applicability from regenerative to therapeutic medicine. Currently these post‐processed cells as composite threads and scaffolds are being investigated in‐depth at a cellular level to establish if the processing methodology has any affect on the cellular make‐up. We now demonstrate a competing non‐electric field driven approach for fabricating composite threads and scaffolds influenced only by a differential pressure. We refer to this novel composite thread to scaffold fabrication methodology as coaxial aerodynamically assisted bio‐threading (CAABT). Our investigations firstly, demonstrate that this technique can process handle living organisms without biologically perturbing them in anyway. Secondly the process is elucidated as possessing the ability to form composite active threads from which biologically viable scaffolds are formed. Finally our study employs florescent activated cell sorting (FACScan), a method by which the cellular dynamics and viability are quantified on control and threaded cellular samples at two prescribed time points. In parallel with FACScan, optical comparison of cellular morphology at three time points within a period of three weeks is carried out to photographically observe any changes in the post‐processed cellular phenotype. Our developmental investigations into this novel aerodynamically assisted threading methodology has unearthed a unique biomicrofabrication approach, which joins cell electrospinning in the cell threading to scaffold fabrication endeavor. © 2007 Wiley Periodicals, Inc. J Appl Polym Sci, 2008

A Novel Implantable Collagen Gel Assay for Fibroblast Traction and Proliferation during Wound Healing

Background. A novel implantable assay for studying cellular behavior in the wound environment was developed. The assay is unique in that it combines the more quantitative nature of in vitro assays with the greater physiological relevance of in vivo wound healing models.Materials and methods. Cells were seeded in a physiologically relevant biological matrix, a collagen gel, contained within a semipermeable tube, and then exposed to soluble factors of the wound environment at different stages of the wound healing response. Gels were harvested at prescribed time points, and cell proliferation rates and gel compaction were measured. These data were combined with our theory for cell–matrix mechanical interactions to estimate the cell traction exerted by the cells leading to gel compaction. Cell morphology and α-smooth muscle actin expression were also characterized.Results. The proliferation of and traction exerted by fibroblasts exposed to the soluble wound environment were different from those in similar collagen gels maintained in culture in complete medium. Proliferation and traction also varied over the course of the wound healing response. Traction was higher and proliferation lower in day 1–5 wounds compared to day 7–11 wounds. Recovered cells no longer stained for α-smooth muscle actin, in contrast to cells maintained in culture.Conclusions. Changes in the soluble wound environment that occur as the wound healing response proceeds alter fibroblast traction and migration. We have developed a new assay that employs a physiologically relevant biological matrix and allows the effects of the dynamic soluble wound environment on cellular traction, proliferation, and other phenomena such as protein expression to be quantified.