Toxicity of airborne nanoparticles: Facts and challenges.

Air pollution is one of the most severe environmental healthhazards, and airborne nanoparticles (diameter <100 nm) are considered particularly hazardous to human health. They are produced by various sources such as internal combustion engines, wood and biomass burning, and fuel and natural gas combustion, and their origin, among other parameters, determines their intrinsic toxicity for reasons that are not yet fully understood. Many constituents of the nanoparticles are considered toxic or at least hazardous, including polycyclic aromatic hydrocarbons (PAHs) and heavy metal compounds, in addition to gaseous pollutants present in the aerosol fraction, such as NOx, SO2, and ozone. All these compounds can cause oxidative stress, mitochondrial damage, inflammation in the lungs and other tissues, and cellular organelles. Epidemiological investigations concluded that airborne pollution may affect the respiratory, cardiovascular, and nervous systems. Moreover, particulate matter has been linked to an increased risk of lung cancer, a carcinogenic effect not related to DNA damage, but to the cellular inflammatory response to the pollutants, in which the release of cytokines promotes the proliferation of pre-existing mutated cancer cells. The mechanisms behind toxicity can be investigated experimentally using cell cultures or animal models. Methods for gathering particulate matter have been explored, but standardized protocols are needed to ensure that the samples accurately represent chemical mixtures in the environment. Toxic constituents of nanoparticles can be studied in animal and cellular models, but designing realistic exposure settings is challenging. The air-liquid interface (ALI) system directly exposes cells, mimicking particle inhalation into the lungs. Continuous research and monitoring of nanoparticles and other airborne pollutants is essential for understanding their effects and developing active strategies to mitigate their risks to human and environmental health.

Pharmacokinetics of oral clonazepam in growing commercial pigs (Sus scrofa domestica).

Clonazepam causes sedation and psychomotor impairment in people. Due to similarities between people and swine in response to benzodiazepines, clonazepam may represent a viable option to produce mild-to-moderate tranquillization in pigs. The objective of this study was to determine the pharmacokinetic profile of a single oral dose (0.5 mg/kg) of clonazepam in eight healthy, growing commercial cross pigs. Serial plasma samples were collected at baseline and up to 96 h after administration. Plasma concentrations were quantified using reverse-phase high-performance liquid chromatography, and compartment models were fit to time-concentration data. A one-compartment first-order model best fits the data. Maximum plasma concentration was 99.5 ng/mL, and time to maximum concentration was 3.4 h. Elimination half-life was 7.3 h, mean residence time 7.4 h, and apparent volume of distribution 5.7 L/kg. Achieved plasma concentrations exceeded those associated with psychomotor impairment in people although pharmacodynamic effects have not been investigated in pigs. A simulated oral regimen consisting of 0.35 mg/kg administered every 8 h to pigs would achieve plasma concentrations above 32 ng/mL which are shown to produce psychomotor impairment in people. Further studies to test the clinical efficacy of these dosages in commercial and miniature pigs are warranted.

Drivers and impact of the early silent invasion of SARS-CoV-2 Alpha.

SARS-CoV-2 variants of concern (VOCs) circulated cryptically before being identified as a threat, delaying interventions. Here we studied the drivers of such silent spread and its epidemic impact to inform future response planning. We focused on Alpha spread out of the UK. We integrated spatio-temporal records of international mobility, local epidemic growth and genomic surveillance into a Bayesian framework to reconstruct the first three months after Alpha emergence. We found that silent circulation lasted from days to months and decreased with the logarithm of sequencing coverage. Social restrictions in some countries likely delayed the establishment of local transmission, mitigating the negative consequences of late detection. Revisiting the initial spread of Alpha supports local mitigation at the destination in case of emerging events.

SARS-CoV-2 infection prevalence and associated factors among primary healthcare workers in France after the third COVID-19 wave.

Data on the SARS-CoV-2 infection among primary health care workers (PHCWs) are scarce but essential to reflect on policy regarding prevention and control measures. We assessed the prevalence of PHCWs who have been infected by SARS-CoV-2 in comparison with modeling from the general population in metropolitan France, and associated factors. A cross-sectional study was conducted among general practitioners (GPs), pediatricians, dental and pharmacy workers in primary care between May and August 2021. Participants volunteered to provide a dried-blood spot for SARS-CoV-2 antibody assessment and completed a questionnaire. The primary outcome was defined as the detection of infection-induced antibodies (anti-nucleocapsid IgG, and for non-vaccinees: anti-Spike IgG and neutralizing antibodies) or previous self-reported infection (positive RT-qPCR or antigenic test, or positive ELISA test before vaccination). Estimates were adjusted using weights for representativeness and compared with prediction from the general population. Poisson regressions were used to quantify associated factors. The analysis included 1612 PHCWs. Weighted prevalences were: 31.7% (95% CI 27.5-36.0) for GPs, 28.7% (95% CI 24.4-33.0) for pediatricians, 25.2% (95% CI 20.6-31.0) for dentists, and 25.5% (95% CI 18.2-34.0) for pharmacists. Estimates were compatible with model predictions for the general population. PHCWs more likely to be infected were: GPs compared to pharmacist assistants (adjusted prevalence ratio [aPR] = 2.26; CI 95% 1.01-5.07), those living in Île-de-France (aPR = 1.53; CI 95% 1.14-2.05), South-East (aPR = 1.57; CI 95% 1.19-2.08), North-East (aPR = 1.81; CI 95% 1.38-2.37), and those having an unprotected contact with a COVID-19 case within the household (aPR = 1.48; CI 95% 1.22-1.80). Occupational factors were not associated with infection. In conclusion, the risk of SARS-CoV-2 exposure for PHCWs was more likely to have occurred in the community rather than at their workplace.

Evaluation of the analgesic efficacy of grapiprant compared with robenacoxib in cats undergoing elective ovariohysterectomy in a prospective, randomized, masked, non-inferiority clinical trial.

OBJECTIVES: The main objective of this study was to compare the postoperative analgesic effects of grapiprant with those of robenacoxib in cats undergoing ovariohysterectomy (OVH). METHODS: In total, 37 female cats (age range 4 months-10 years, weighing ⩾2.5 kg) were enrolled in a prospective, randomized, masked, non-inferiority (NI) clinical trial. Cats received oral robenacoxib (1 mg/kg) or grapiprant (2 mg/kg) 2 h before OVH. Analgesia was assessed via the Feline Grimace Scale (FGS), the Glasgow Composite Measure Pain Scale-Feline (CMPS-F), von Frey monofilaments (vFFs) and pressure algometry (ALG) 2 h before treatment administration, at extubation, and 2, 4, 6, 8, 18 and 24 hours after extubation. Hydromorphone (<8 h postoperatively) or buprenorphine (>18 h postoperatively) were administered to cats with scores of ⩾5/20 on CMPS-F and/or ⩾4/10 on FGS. NI margins for CMPS-F and vFFs were set at 3 and -0.2, respectively. A mixed-effect ANOVA was used for FGS scores (P <0.05). Data are reported as mean ± SEM. RESULTS: The data from 33 cats were analyzed. The upper limit of the 95% confidence interval (CI) (0.35) was less than the NI margin of 3 for CMPS-F, and the lower limit of the 95% CI (0.055) was greater than the NI margin of -0.2 for vFFs, indicating NI of grapiprant. The FGS scores were greater than baseline at extubation for both treatments (1.65 ± 0.63; P = 0.001); however, there was no difference between treatments. There was no difference between treatments, nor treatment by time interaction, for vFFs (P <0.001). The CMPS-F scores for both treatments were higher at extubation but returned to baseline after 4 h (P <0.001). For ALG, there was no difference in treatment or treatment by time interaction. The robenacoxib group had lower pressure readings at extubation and 6 h compared with baseline. CONCLUSIONS AND RELEVANCE: These results indicate that grapiprant was non-inferior to robenacoxib for mitigating postsurgical pain in cats after OVH performed via ventral celiotomy. The impact of grapiprant for analgesia in OVH via the flank is unknown.

Examining the role of firearm involvement in repeat intimate partner violence assaults.

BACKGROUND: Intimate partner violence (IPV) remains a pervasive and complex issue with significant social and public health implications. The nexus of firearms and intimate partner violence (IPV) is an especially dangerous one. However, little is known about how firearm involvement can influence the risk of repeat IPV assaults. METHODS: We use data from 346 male perpetrated IPV incidents reported to the Detroit Police Department between December 2016 and April 2017 to examine the role of firearm involvement in IPV recidivism during a 5 and half year follow up period. Employing a conditional gap-time frailty model that accommodates heterogeneity among individuals through a frailty term, we analyze time to multiple IPV assaults that occur over the follow up period. We identify various pathways through which firearms impact the likelihood of subsequent IPV incidents, including intimidation, threats, and use of firearms, while controlling for observable perpetrator characteristics to understand the explicit roles of firearms. RESULTS: Firearm involvement at the index assault was not associated with IPV recidivism. However, involvement of firearms in past IPV assaults significantly increased the risk of subsequent physical IPV. The discrepancy is likely arising from a high degree of censoring among individuals who were armed with a firearm during the index assault. CONCLUSION: Our research reveals a nuanced relationship between firearm involvement and IPV recidivism, shedding light on the multifaceted dynamics at play. By elucidating the intricate dynamics at the intersection of firearms and intimate partner violence, our study underscores the need for targeted policy interventions and preventative measures aimed at reducing IPV recidivism.

Progressive heterogeneity of enlarged and irregularly shaped apicoplasts in P. falciparum persister blood stages after drug treatment.

Morphological modifications and shifts in organelle relationships are hallmarks of dormancy in eukaryotic cells. Communications between altered mitochondria and nuclei are associated with metabolic quiescence of cancer cells that can survive chemotherapy. In plants, changes in the pathways between nuclei, mitochondria, and chloroplasts are associated with cold stress and bud dormancy. Plasmodium falciparum parasites, the deadliest agent of malaria in humans, contain a chloroplast-like organelle (apicoplast) derived from an ancient photosynthetic symbiont. Antimalarial treatments can fail because a small fraction of the blood stage parasites enter dormancy and recrudesce after drug exposure. Altered mitochondrial-nuclear interactions in these persisters have been described for P. falciparum, but interactions of the apicoplast remained to be characterized. In the present study, we examined the apicoplasts of dormant persisters obtained after exposure to dihydroartemisinin (a first-line antimalarial drug) followed by sorbitol treatment, or after exposure to sorbitol treatment alone. As previously observed, the mitochondrion of persisters was consistently enlarged and in close association with the nucleus. In contrast, the apicoplast varied from compact and oblate, like those of active ring stage parasites, to enlarged and irregularly shaped. Enlarged apicoplasts became more prevalent later in dormancy, but regular size apicoplasts subsequently predominated when actively replicating parasites recrudesced. All three organelles, nucleus, mitochondrion, and apicoplast, became closer during dormancy. Understanding their relationships in erythrocytic-stage persisters may lead to new strategies to prevent recrudescences and protect the future of malaria chemotherapy.

Mechanical Manipulation of Quantum Interference in Single-Molecule Junctions.

Mechanosensitive molecular junctions, where conductance is sensitive to an applied stress such as force or displacement, are a class of nanoelectromechanical systems unique for their ability to exploit quantum mechanical phenomena. Most studies so far relied on reconfiguration of the molecule-electrode interface to impart mechanosensitivity, but this approach is limited and, generally, poorly reproducible. Alternatively, devices that exploit conformational flexibility of molecular wires have been recently proposed. The mechanosensitive properties of molecular wires containing the 1,1'-dinaphthyl moiety are presented here. Rotation along the chemical bond between the two naphthyl units is possible, giving rise to two conformers (transoid and cisoid) that have distinctive transport properties. When assembled as single-molecule junctions, it is possible to mechanically trigger the transoid to cisoid transition, resulting in an exquisitely sensitive mechanical switch with high switching ratio (> 102). Theoretical modeling shows that charge reconfiguration upon transoid to cisoid transition is responsible for the observed behavior, with generation and subsequent lifting of quantum interference features. These findings expand the experimental toolbox of molecular electronics with a novel chemical structure with outstanding electromechanical properties, further demonstrating the importance of subtle changes in charge delocalization on the transport properties of single-molecule devices.

In-situ Oxidation and Coupling of Anilines towards Unsymmetric Azobenzenes Using Flow Chemistry.

Molecular switches, especially azobenzenes, are used in numerous applications, such as molecular solar thermal storage (MOST) systems and photopharmacology. The Baeyer-Mills reaction of anilines and nitrosobenzenes has been established as an efficient synthetic method for non-symmetric azobenzenes. However, nitrosobenzenes are not stable, depending on their substitution pattern and pose a health risk. An in-situ oxidation of anilines with Oxone® was optimized under continuous flow conditions avoiding isolation and contact. The in-situ generated nitrosobenzene derivatives were subjected to a telescoped Baeyer-Mills reaction in flow. That way azobenzenes with a broad substituent spectrum were made accessible.

The impact of spatial connectivity on NPIs effectiveness.

BACKGROUND: France implemented a combination of non-pharmaceutical interventions (NPIs) to manage the COVID-19 pandemic between September 2020 and June 2021. These included a lockdown in the fall 2020 - the second since the start of the pandemic - to counteract the second wave, followed by a long period of nighttime curfew, and by a third lockdown in the spring 2021 against the Alpha wave. Interventions have so far been evaluated in isolation, neglecting the spatial connectivity between regions through mobility that may impact NPI effectiveness. METHODS: Focusing on September 2020-June 2021, we developed a regionally-based epidemic metapopulation model informed by observed mobility fluxes from daily mobile phone data and fitted the model to regional hospital admissions. The model integrated data on vaccination and variants spread. Scenarios were designed to assess the impact of the Alpha variant, characterized by increased transmissibility and risk of hospitalization, of the vaccination campaign and alternative policy decisions. RESULTS: The spatial model better captured the heterogeneity observed in the regional dynamics, compared to models neglecting inter-regional mobility. The third lockdown was similarly effective to the second lockdown after discounting for immunity, Alpha, and seasonality (51% vs 52% median regional reduction in the reproductive number R0, respectively). The 6pm nighttime curfew with bars and restaurants closed, implemented in January 2021, substantially reduced COVID-19 transmission. It initially led to 49% median regional reduction of R0, decreasing to 43% reduction by March 2021. In absence of vaccination, implemented interventions would have been insufficient against the Alpha wave. Counterfactual scenarios proposing a sequence of lockdowns in a stop-and-go fashion would have reduced hospitalizations and restriction days for low enough thresholds triggering and lifting restrictions. CONCLUSIONS: Spatial connectivity induced by mobility impacted the effectiveness of interventions especially in regions with higher mobility rates. Early evening curfew with gastronomy sector closed allowed authorities to delay the third wave. Stop-and-go lockdowns could have substantially lowered both healthcare and societal burdens if implemented early enough, compared to the observed application of lockdown-curfew-lockdown, but likely at the expense of several labor sectors. These findings contribute to characterize the effectiveness of implemented strategies and improve pandemic preparedness.

A 3D In Vitro Cortical Tissue Model Based on Dense Collagen to Study the Effects of Gamma Radiation on Neuronal Function.

Studies on gamma radiation-induced injury have long been focused on hematopoietic, gastrointestinal, and cardiovascular systems, yet little is known about the effects of gamma radiation on the function of human cortical tissue. The challenge in studying radiation-induced cortical injury is, in part, due to a lack of human tissue models and physiologically relevant readouts. Here, a physiologically relevant 3D collagen-based cortical tissue model (CTM) is developed for studying the functional response of human iPSC-derived neurons and astrocytes to a sub-lethal radiation exposure (5 Gy). Cytotoxicity, DNA damage, morphology, and extracellular electrophysiology are quantified. It is reported that 5 Gy exposure significantly increases cytotoxicity, DNA damage, and astrocyte reactivity while significantly decreasing neurite length and neuronal network activity. Additionally, it is found that clinically deployed radioprotectant amifostine ameliorates the DNA damage, cytotoxicity, and astrocyte reactivity. The CTM provides a critical experimental platform to understand cell-level mechanisms by which gamma radiation (GR) affects human cortical tissue and to screen prospective radioprotectant compounds.

Intensified screening for SARS-CoV-2 in 18 emergency departments in the Paris metropolitan area, France (DEPIST-COVID): A cluster-randomized, two-period, crossover trial.

BACKGROUND: Asymptomatic and paucisymptomatic infections account for a substantial portion of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) transmissions. The value of intensified screening strategies, especially in emergency departments (EDs), in reaching asymptomatic and paucisymptomatic patients and helping to improve detection and reduce transmission has not been documented. The objective of this study was to evaluate in EDs whether an intensified SARS-CoV-2 screening strategy combining nurse-driven screening for asymptomatic/paucisymptomatic patients with routine practice (intervention) could contribute to higher detection of SARS-CoV-2 infections compared to routine practice alone, including screening for symptomatic or hospitalized patients (control). METHODS AND FINDINGS: We conducted a cluster-randomized, two-period, crossover trial from February 2021 to May 2021 in 18 EDs in the Paris metropolitan area, France. All adults visiting the EDs were eligible. At the start of the first period, 18 EDs were randomized to the intervention or control strategy by balanced block randomization with stratification, with the alternative condition being applied in the second period. During the control period, routine screening for SARS-CoV-2 included screening for symptomatic or hospitalized patients. During the intervention period, in addition to routine screening practice, a questionnaire about risk exposure and symptoms and a SARS-CoV-2 screening test were offered by nurses to all remaining asymptomatic/paucisymptomatic patients. The primary outcome was the proportion of newly diagnosed SARS-CoV-2-positive patients among all adults visiting the 18 EDs. Primary analysis was by intention-to-treat. The primary outcome was analyzed using a generalized linear mixed model (Poisson distribution) with the center and center by period as random effects and the strategy (intervention versus control) and period (modeled as a weekly categorical variable) as fixed effects with additional adjustment for community incidence. During the intervention and control periods, 69,248 patients and 69,104 patients, respectively, were included for a total of 138,352 patients. Patients had a median age of 45.0 years [31.0, 63.0], and women represented 45.7% of the patients. During the intervention period, 6,332 asymptomatic/paucisymptomatic patients completed the questionnaire; 4,283 were screened for SARS-CoV-2 by nurses, leading to 224 new SARS-CoV-2 diagnoses. A total of 1,859 patients versus 2,084 patients were newly diagnosed during the intervention and control periods, respectively (adjusted analysis: 26.7/1,000 versus 26.2/1,000, adjusted relative risk: 1.02 (95% confidence interval (CI) [0.94, 1.11]; p = 0.634)). The main limitation of this study is that it was conducted in a rapidly evolving epidemiological context. CONCLUSIONS: The results of this study showed that intensified screening for SARS-CoV-2 in EDs was unlikely to identify a higher proportion of newly diagnosed patients. TRIAL REGISTRATION: Trial registration number: ClinicalTrials.gov NCT04756609.

Microwave-assisted extraction in closed vessel in food analysis.

Microwave-assisted extraction (MAE) is an important technique in analytical chemistry. It offers several advantages over traditional extraction methods, such as improved extraction efficiency, shorter extraction times, reduced solvent consumption, and enhanced analyte recovery. Using microwaves, heat is directly applied to the sample, leading to rapid and efficient extraction of target compounds by enhancing the solubility and diffusion of the target compounds, thus requiring lower solvent volume. Therefore, MAE can be considered a more environmentally friendly and cost-effective option facilitating the transition toward greener and more sustainable analytical chemistry workflows. This contribution systematically reviews the application of MAE to a selection of target compounds/compounds classes of relevance for food quality and safety assessment. As inclusion criteria, MAE active temperature control and molecularly-resolved characterization of the extracts were considered. Contents include a brief introduction of the principles of operation, available systems characteristics, and key parameters influencing extraction efficiency and selectivity. The application section covers functional food components (e.g., phenols, diterpenes, and carotenoids), lipids, contaminants (e.g., polycyclic aromatic hydrocarbons and mineral oil hydrocarbons), pesticides, veterinary drug residues, and a selection of process contaminants and xenobiotics of relevance for food safety.

Identification of new drugs to counteract anti-spike IgG-induced hyperinflammation in severe COVID-19.

Previously, we and others have shown that SARS-CoV-2 spike-specific IgG antibodies play a major role in disease severity in COVID-19 by triggering macrophage hyperactivation, disrupting endothelial barrier integrity, and inducing thrombus formation. This hyperinflammation is dependent on high levels of anti-spike IgG with aberrant Fc tail glycosylation, leading to Fcγ receptor hyperactivation. For development of immune-regulatory therapeutics, drug specificity is crucial to counteract excessive inflammation whereas simultaneously minimizing the inhibition of antiviral immunity. We here developed an in vitro activation assay to screen for small molecule drugs that specifically counteract antibody-induced pathology. We identified that anti-spike-induced inflammation is specifically blocked by small molecule inhibitors against SYK and PI3K. We identified SYK inhibitor entospletinib as the most promising candidate drug, which also counteracted anti-spike-induced endothelial dysfunction and thrombus formation. Moreover, entospletinib blocked inflammation by different SARS-CoV-2 variants of concern. Combined, these data identify entospletinib as a promising treatment for severe COVID-19.

Validation of a human paper-based blood typing method for use in pet pigs.

BACKGROUND: Evidence-based medical practices for pet pigs are needed. EldonCard is a human blood-typing card shown to be rapid and reliable in identifying blood phenotypes of pet pigs. The objective of this study was to validate EldonCard by determining its reliability, reproducibility, and robustness for its routine use in the clinical setting. KEY FINDINGS: Twenty-four venous blood samples from pet pigs were collected for a prospective in vitro study. Blood genotypes ("EAAA0 " and "EAA00 ") were identified in 15 samples via polymerase chain reaction (PCR). All samples were phenotyped ("A," "Aweak ," and "0" or "-") via EldonCard. Kappa (κ) statistics measured the level of agreement between 2 raters, and between EldonCard and PCR. McNemar's test determined if an association between the blood types and EldonCard or PCR exists, with significance at P < 0.05. Agreement between raters and methods was perfect (60/60 [100%], κ:1, P < 0.001; 15/15 [100%], κ:1, P < 0.001). There was no difference in the proportions of blood groups based on method. SIGNIFICANCE: In conjunction with previous data, EldonCard is a rapid, accurate, reliable, precise, and robust in-clinic blood-typing method for the A0 system of pet pigs. EldonCard is now a validated blood-typing tool for the A0 system of pet pigs and maybe used for pretransfusion screenings and identification of donors and recipients.

The effect of age on the induction dose of propofol for general anesthesia in dogs.

OBJECTIVE: In people, the dose of propofol (DOP) required for procedural sedation and anesthesia decreases significantly with age. The objective of this study was to determine if the DOP required to perform endotracheal intubation decreases with age in dogs. STUDY DESIGN: Retrospective case series. ANIMALS: 1397 dogs. METHODS: Data from dogs anesthetized at referral center (2017-2020) were analyzed with three multivariate linear regression models with backward elimination using a combination of either absolute age, physiologic age, or life expectancy (ratio between age at the time of anesthetic event and expected age of death for each breed obtained from previous literature) as well as other factors as independent variables, and DOP as the dependent variable. The DOP for each quartile of life expectancy (<25%, 25-50%, 50-75%, 75-100%, >100%) was compared using one-way ANOVA. Significance was set at alpha = 0.025. RESULTS: Mean age was 7.2 ± 4.1 years, life expectancy 59.8 ± 33%, weight 19 ± 14 kg, and DOP 3.76 ± 1.8 mg kg-1. Among age models, only life expectancy was a predictor of DOP (-0.37 mg kg-1; P = 0.013) but of minimal clinical importance. The DOP by life age expectancy quartile was 3.9 ± 2.3, 3.8 ± 1.8, 3.6 ± 1.8, 3.7 ± 1.7, and 3.4 ± 1.6 mg kg-1, respectively (P = 0.20). Yorkshire Terrier, Chihuahua, Maltese, mixed breed dogs under 10 kg, and Shih Tzu required higher DOP. Status of neutered male, ASA E, and Boxer, Labrador and Golden Retriever breeds decreased DOP, along with certain premedication drugs. CONCLUSIONS AND CLINICAL RELEVANCE: In contrast to what is observed in people, an age cut-off predictive of DOP does not exist. Percentage of elapsed life expectancy along with other factors such as breed, premedication drug, emergency procedure, and reproductive status significantly alter DOP. In older dogs, the dose of propofol can be adjusted based on their elapsed life expectancy.

Pharmacokinetics of a single oral dose of grapiprant in juvenile pigs (Sus scrofa domestica).

Both pet and research pigs can suffer from some degree of pain from surgery, injuries, or osteoarthritis (OA). Despite this, there is a paucity of data on safe and effective analgesia agents in pigs. Grapiprant is an EP4 antagonist that blocks the action of the pro-inflammatory prostanoid, PGE2 . It has shown efficacy in attenuating pain associated with ovariohysterectomy and OA in dogs. However, there are no data regarding grapiprant in pigs. Therefore, the pharmacokinetic profile of orally administered grapiprant to juvenile pigs (Sus scrofa domestica) was evaluated in this study. Seven juvenile pigs received 12 mg/kg grapiprant orally. Blood was collected from an indwelling jugular catheter using the push-pull method at set timepoints up to 48 hours. Sample analysis was performed with high-performance liquid chromatography. Mean grapiprant plasma concentration was 164.3 ± 104.7 ng/mL which occurred at 0.8 ± 0.3 h. This study demonstrated that grapiprant concentrations consistent with analgesia in dogs were reached at this dosage in pigs. Further studies are needed to evaluate the efficacy of grapiprant in pigs.

Underscoring the effect of swab type, workflow, and positive sample order on swab pooling for COVID-19 surveillance testing.

Sample pooling is a promising strategy to facilitate COVID-19 surveillance testing for a larger population in comparison to individual single testing due to resource and time constraints. Increased surveillance testing capacity will reduce the likelihood of outbreaks as the general population is returning to work, school, and other gatherings. We have analyzed the impact of three variables on the effectiveness of pooling test samples: swab type, workflow, and positive sample order. We investigated the performance of several commercially available swabs (Steripack polyester flocked, Puritan nylon flocked, Puritan foam) in comparison to a new injected molded design (Yukon). The bench-top performance of collection swab was conducted with a previously developed anterior nasal cavity tissue model, based on a silk-glycerol sponge to mimic soft tissue mechanics and saturated with a physiologically relevant synthetic nasal fluid spiked with heat-inactivated SARS-CoV-2. Overall, we demonstrated statistically significant differences in performance across the different swab types. A characterization of individual swab uptake (gravimetric analysis) and FITC microparticle release suggests that differences in absorbance and retention drive the observed differences in Ct of the pooled samples. We also proposed two distinct pooling workflows to encompass different community collection modes and analyzed the difference in resulting positive pools as an effect of workflow, swab type, and positive sample order. Overall, swab types with lower volume retention resulted in reduced false negative occurrence, also observed for collection workflows with limited incubation times. Concurrently, positive sample order did have a significant impact on pooling test outcome, particularly in the case of swab type with great volume retention. We demonstrated that the variables investigated here affect the results of pooled COVID-19 testing, and therefore should be considered while designing pooled surveillance testing.

Pharmacokinetics of intramuscular maropitant in pigs (Sus scrofa domesticus).

Pigs are at risk of vomiting from medical conditions as well as the emetic side effects of drugs administered for peri-operative manipulations, but there is a lack of pharmacokinetic data for potential anti-emetic therapies, such as maropitant, in this species. The main objective of this study was to estimate plasma pharmacokinetic parameters for maropitant in pigs after a single intramuscular (IM) administration dosed at 1.0 mg/kg. A secondary objective was to estimate pilot pharmacokinetic parameters in pigs after oral (PO) administration at 2.0 mg/kg. Maropitant was administered to six commercial pigs at a dose of 1.0 mg/kg IM. Plasma samples were collected over 72 h. After a 7-day washout period, two pigs were administered maropitant at a dose of 2.0 mg/kg PO. Maropitant concentrations were measured via liquid chromatography/mass spectrometry (LC-MS/MS). A non-compartmental analysis was used to derive pharmacokinetics parameters. No adverse events were noted in any of the study pigs after administration. Following single IM administration, maximum plasma concentration was estimated at 412.7 ± 132.0 ng/mL and time to maximum concentration ranged from 0.083 to 1.0 h. Elimination half-life was estimated at 6.7 ± 1.28 h, and mean residence time was 6.1 ± 1.2 h. Volume of distribution after IM administration was 15.9 L/kg. Area under the curve was 1336 ± 132.0 h*ng/mL. The relative bioavailability of PO administration was noted to be 15.5% and 27.2% in the two pilot pigs. The maximum systemic concentration observed in the study pigs after IM administration was higher than what was observed after subcutaneous administration in dogs, cats, or rabbits. The achieved maximum concentration exceeded the concentrations for anti-emetic purposes in dogs and cats; however, a specific anti-emetic concentration is currently not known for pigs. Further research is needed into the pharmacodynamics of maropitant in pigs to determine specific therapeutic strategies for this drug.

Three-Dimensional Humanized Model of the Periodontal Gingival Pocket to Study Oral Microbiome.

The oral cavity contains distinct microenvironments that serve as oral barriers, such as the non-shedding surface of the teeth (e.g., enamel), the epithelial mucosa and gingival tissue (attached gingiva) where microbial communities coexist. The interactions and balances between these communities are responsible for oral tissue homeostasis or dysbiosis, that ultimately dictate health or disease. Disruption of this equilibrium can lead to chronic inflammation and permanent tissue damage in the case of chronic periodontitis. There are currently no experimental tissue models able to mimic the structural, physical, and metabolic conditions present in the human oral gingival tissue to support the long-term investigation of host-pathogens imbalances. Herein, the authors report an in vitro 3D anatomical gingival tissue model, fabricated from silk biopolymer by casting a replica mold of an adult human mandibular gingiva to recreate a tooth-gum unit. The model is based on human primary cultures that recapitulate physiological tissue organization, as well as a native oxygen gradient within the gingival pocket to support human subgingival plaque microbiome with a physiologically relevant level of microbial diversity up to 24 h. The modulation of inflammatory markers in the presence of oral microbiome indicates the humanized functional response of this model and establishes a new set of tools to investigate host-pathogen imbalances in gingivitis and periodontal diseases.