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The aim of the present study was to investigate the suitability of insoluble Eudragit® water dispersions (NE, NM, RL, and RS) for direct high-shear granulation of very soluble levetiracetam in order to decrease its burst effect from HPMC K100M matrices. The process characteristics, ss-NMR analysis, in vitro dissolution behavior, drug release mechanism and kinetics, texture profile analysis of the gel layer, and PCA analysis were explored. An application of water dispersions directly on levetiracetam was feasible only in a multistep process. All prepared formulations exhibited a 12-hour sustained release profile characterized by a reduced burst effect in a concentration-dependent manner. No effect on swelling extent of HPMC K100M was observed in the presence of Eudragit®. Contrary, higher rigidity of formed gel layer was observed using combination of HPMC and Eudragit®. Not only the type and concentration of Eudragit®, but also the presence of the surfactant in water dispersions played a key role in the dissolution characteristics. The dissolution profile close to zero-order kinetic was achieved from the sample containing levetiracetam directly granulated by the water dispersion of Eudragit® NE (5% of solid polymer per tablet) with a relatively high amount of surfactant nonoxynol 100 (1.5%). The initial burst release of drug was reduced to 8.04% in 30 min (a 64.2% decrease) while the total amount of the released drug was retained (97.02%).

Intravaginal anti-HIV microbicides could provide women with a self-controlled means for HIV prevention, but results from clinical trials have been largely disappointing. We postulated that unrecognized effects of intravaginal gels on the upper female reproductive tract might contribute to the lower-than-expected efficacy of HIV microbicides. Our objective was to study the effects of intravaginal gels on the immune microenvironment of the cervix and uterus. In this randomized crossover study, 27 healthy female volunteers used a nightly application of intravaginal nonoxynol-9 (N9) gel as a \"failed\" microbicide or the universal placebo gel (UPG) as a \"safe\" gel (intervention cycles), or nothing (control cycle) from the end of menses to the mid-luteal phase. At a specific time-point following ovulation, all participants underwent sample collection for measurements of T-cell phenotypes, gene expression, and cytokine/chemokine protein concentrations from 3 anatomic sites above the vagina: the cervical transformation zone, the endocervix and the endometrium. We used hierarchical statistical models to estimate mean (95% CI) intervention effects, for N9 and UPG relative to control. Exposure to N9 gel and UPG generated a common \"harm signal\" that included transcriptional up-regulation of inflammatory genes chemokine (C-C motif) ligand 20 (macrophage inflammatory factor-3alpha) and interleukin 8 in the cervix, decreased protein concentrations of secretory leukocyte protease inhibitor, and transcriptional up-regulation of inflammatory mediators glycodelin-A and osteopontin in the endometrium. These results need to be replicated with a larger sample, but underscore the need to consider the effects of microbicide agents and gel excipients on the upper female reproductive tract in studies of vaginal microbicides.

Abstract Craniofacial modification by orthodontic techniques is increasingly incorporated into the multidisciplinary management of sleep-disordered breathing in children and adolescents. With increasing application of orthodontics to this clinical population it is important for healthcare providers, families, and patients to understand the wide range of available treatments. Orthodontists can guide craniofacial growth depending on age; therefore, it is important to work with other providers for a team-based approach to sleep-disordered breathing. From infancy to adulthood the dentition and craniofacial complex change with growth patterns that can be intercepted and targeted at critical time points. This article proposes a clinical guideline for application of multidisciplinary care with emphasis on dentofacial interventions that target variable growth patterns. We also highlight how these guidelines serve as a roadmap for the key questions that will influence future research directions. Ultimately the appropriate application of these orthodontic techniques will not only provide an important therapeutic option for children and adolescents with symptomatic sleep-disordered breathing but may help also mitigate or prevent its onset. Graphical abstract Graphical Abstract

Around 40% of preterm births are attributed to ascending intrauterine infection, and Ureaplasma parvum (UP) is commonly isolated in these cases. Here we present a mouse model of ascending UP infection that resembles human disease, using vaginal inoculation combined with mild cervical injury induced by a common spermicide (Nonoxynol-9, as a surrogate for any mechanism of cervical epithelial damage). We measure bacterial load in a non-invasive manner using a luciferase-expressing UP strain, and post-mortem by qPCR and bacterial titration. Cervical exposure to Nonoxynol-9, 24 h pre-inoculation, facilitates intrauterine UP infection, upregulates pro-inflammatory cytokines, and increases preterm birth rates from 13 to 28%. Our results highlight the crucial role of the cervical epithelium as a barrier against ascending infection. In addition, we expect the mouse model will facilitate further research on the potential links between UP infection and preterm birth. Ureaplasma parvum is often isolated from intrauterine infections, which are associated with 40% of preterm births. Here, Pavlidis et al. present a mouse model of ascending U. parvum infection that resembles human disease, and show that mild cervical damage promotes intrauterine infection, inflammation and preterm birth.

Nonoxynol-9 (rINN, nonoxinol-9) is an over-the-counter spermicide that has in-vitro anti-HIV-1 activity. Results of studies of its effectiveness in prevention of HIV-1 infection in women have been inconclusive. We aimed to assess effectiveness of this vaginal gel. We did a randomised, placebo-controlled, triple-blinded, phase 2/3 trial with COL-1492, a nonoxynol-9 vaginal gel, in 892 female sex workers in four countries: Benin, Côte d'lvoire, South Africa, and Thailand. 449 women were randomly allocated nonoxynol-9 and 443 placebo. Primary endpoint was incident HIV-1 infection. Secondary endpoints included Neisseria gonorrhoeas and Chlamydia trachomatis infections. Analysis was by intention to treat. 765 women were included in the primary analysis. HIV-1 frequency in nonoxynol-9 users was 59 (16%) of 376 compared with 104 (27%) of 389 in placebo users (402·5 vs 435·0 woman-years; hazard ratio adjusted for centre 1·5; 95% Cl 1·0–2·2; p=0·047). 239 (32%) women reported use of a mean of more than 3·5 applicators per working day, and in these women, risk of HIV-1 infection in nonoxynol-9 users was almost twice that in placebo users (hazard ratio 1·8; 95% Cl 1·0–3·2). 516 (68%) women used the gel less frequently than 3·5 times a day, and in these, risk did not differ between the two treatments. No significant effect of nonoxynol-9 on N gonorrhoeas (1·2; 0·9–1·6) or C trachomatis (1·2; 0·8–1·6) infections was reported. This study did not show a protective effect of COL-1492 on HIV-1 transmission in high-risk women. Multiple use of nonoxynol-9 could cause toxic effects enhancing HIV-1 infection. This drug can no longer be deemed a potential HIV-1-prevention method. Assessment of other microbicides should continue.

Background Based on the results of existing observational studies, it can be found that the association between serum vitamin D levels and the risk of Sjogren’s syndrome (SS) in humans is still controversial. Based on this situation, this study aimed to assess the causal relationship between serum vitamin D levels and SS by using the Mendelian randomization (MR) approach. Methods In this study, genome-wide association studies (GWAS) summary statistics on serum vitamin D levels [sample size = 417,580 (UK Biobank)] and SS [sample size = 416,757 (cases = 2495, controls = 414,262) (FinnGen)] were used. The bi-directional MR analysis was then used to assess possible causal relationships. The major analysis method of MR was performed using inverse-variance weighted (IVW), supplemented by MR-Egger and the weighted median approaches. In addition, sensitivity analyses were used to ensure the stability of the results, including Cochran’s Q test, MR-PRESSO, MR-Egger intercept test, and the leave-one-out test. Results The MR suggested that no significant causal effects of serum 25(OH)D levels on SS risks were observed [odds ratio (OR) = 0.9824; 95% confidence interval (CI) = 0.7130 to 1.3538; P  = 0.9137]. Similarly, no evidence supported the causal effects of SS on serum vitamin D levels ( β : 0.0076, 95% CI: − 0.0031 to 0.0183; P  = 0.1640). Conclusion This study found no obvious evidence that serum vitamin D level is causally associated with SS risks or vice versa. We call for larger sample size studies to further unravel the potential causal relationship and the exact mechanism.

The importance of the path loss in millimeter wave channel propagation cannot be taken for granted in terms of deployment, design, performance assessment, and planning. The path loss helps to determine the network’s geographic coverage. Although many path loss models, including statistical and empirical models based on measurement and linear regression, have been proposed by various researchers, high fidelity is required to determine the performance of the wireless network’s channel. This research validates the improved version of the well-known close in (CI) and floating intercept (FI) path loss models at frequency bands of 28 and 38 GHz. The measurement surroundings comprised of an enclosed passageway with vertical-horizontal (V-H) and vertical-vertical (V-V) antenna polarizations. One of the key findings of this study is that the enhanced versions of these models typically perform better in terms of consistency than the standard models thereby justifying their high accuracy level. The improved versions of the CI and the FI models demonstrate a significant improvement for various antenna polarizations. The mean prediction error (MPE) and standard deviation error (SDE) also show how precisely and accurately the improved models predict the path loss. Additionally, the improved models provide the reasonable responsiveness and uniformity of the parameters with the change in the antenna polarization and lower the shadow fading’s standard deviation in LOS as well as NLOS situations. The results confirm that the modified versions of CI and FI models predict path loss better in an enclosed environment for 5G networks.

[Display omitted] •Identification of a nonoxynol mixture in vaginal fluid and condoms’ residues.•Detection of a nonoxynol mixture in vaginal samples collected 8h after intercourse was achieved.•Different sample preparation and instrument setting methods were explored. In this study we demonstrate the use of Direct Analysis in Real Time Mass Spectrometry (DART) as a powerful tool for detection of nonoxynol in vaginal fluid post contact with a condom, enabling rapid tracing and added evidences in sexual assault crimes. Vaginal fluid was sampled using cotton swabs and glass rods and measured directly with DART. Sample preparation using water, hexane, methanol, and dichloromethane extraction, was explored for comparison and optimization of signals. Nonoxynol was detected up to eight hours after sampling. Optimal sampling conditions and mass spectrometry parameters are reported and discussed.

The smart home is a crucial embodiment of the internet of things (IoT), which can facilitate users to access smart home services anytime and anywhere. Due to the limited resources of cloud computing, it cannot meet users’ real-time needs. Therefore, edge computing emerges as the times require, providing users with better real-time access and storage. The application of edge computing in the smart home environment can enable users to enjoy smart home services. However, users and smart devices communicate through public channels, and malicious attackers may intercept information transmitted through public channels, resulting in user privacy disclosure. Therefore, it is a critical issue to protect the secure communication between users and smart devices in the smart home environment. Furthermore, authentication protocols in smart home environments also have some security challenges. In this paper, we propose an anonymous authentication protocol that applies edge computing to the smart home environment to protect communication security between entities. To protect the security of smart devices, we embed physical unclonable functions (PUF) into each smart device. Real-or-random model, informal security analysis, and ProVerif are adopted to verify the security of our protocol. Finally, we compare our protocol with existing protocols regarding security and performance. The comparison results demonstrate that our protocol has higher security and slightly better performance.

People can use the constant target-heading (CTH) strategy or the constant bearing (CB) strategy to guide their locomotor interception. But it is still unclear whether people can learn new interception behavior. Here, we investigated how people learn to adjust their steering to intercept targets faster. Participants steered a car to intercept a moving target in a virtual environment similar to a natural open field. Their baseline interceptions were better accounted for by the CTH strategy. After five learning sessions across multiple days, in which participants received feedback about their interception durations, they adopted a two-stage control: a quick initial burst of turning accompanied by an increase of the target-heading angle during early interception was followed by significantly less turning with small changes in target-heading angle during late interception. The target’s bearing angle did not only show this two-stage pattern but also changed comparatively little during late interception, leaving it unclear which strategy participants had adopted. In a following test session, the two-stage pattern of participants’ turning adjustment and the target-heading angle transferred to new target conditions and a new environment without visual information about an allocentric reference frame, which should preclude participants from using the CB strategy. Indeed, the pattern of the target’s bearing angle did not transfer to all the new conditions. These results suggest that participants learned a two-stage control for faster interception: they learned to quickly increase the target-heading angle during early interception and subsequently follow the CTH strategy during late interception.