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Şehmus Pala,1 Remzi Atilgan,1 Tuncay Kuloğlu,2 Murat Kara,3 Melike Başpinar,1 Behzat Can,1 Gökhan Artaş4 1Department of Obstetrics and Gynecology, 2Department of Histology and Embriology, Firat University School of Medicine, Elazig, 3Department of Medical Biology and Genetics, Muğla Sıtkı Koçman University School of Medicine, Muğla, 4Department of Pathology, Firat University School of Medicine, Elazig, Turkey Aim: The aim of this study was to examine the protective effects of vitamin C (VC) and vitamin E (VE) against hysterosalpingography (HSG)-induced epithelial degeneration and proliferation in rat endometrium. Materials and methods: A total of 28 female Wistar albino rats were randomized into four groups: G1 (n=7; abdomen was opened and closed), G2 (n=7; 0.1 mL Lipiodol [ethiodized oil] was administered to each uterine horn in conjunction with X-ray irradiation), G3 (n=7; 50 mg/kg of intraperitoneal (ip) VC was administered, followed by the administration of 0.1 mL of ethiodized oil into the uterine horns after 15 minutes), and G4 (n=7; 50 mg/kg of ip VE was administered, followed by the administration of 0.1 mL of ethiodized oil into the uterine horns after 15 minutes). After abdominal closure, rats in G2, G3 and G4 groups were exposed to whole-body X-irradiation three times with 2-minute intervals at a total dose of 15–20 mrad. Three hours after exposure, abdominal cavities of all the rats were reopened and uterine horns were removed. The right uterine horns were embedded into paraffin blocks after fixing in 10% formaldehyde for histopathological and immunohistochemical examination. Uterine horns on the other side were rapidly excised and stored at -80°C for the examination of expression of microRNAs (miRNAs) and oxidant, antioxidant, apoptotic and antiapoptotic gene expression using real-time polymerase chain reaction (RT-PCR) method. Results: No differences were observed in terms of expression of miRNAs and oxidant, antioxidant, apoptotic and anti-apoptotic gene expression between the study groups. Congestion, epithelial degeneration and malondialdehyde immunoreactivity were significantly lower in G3 and G4 groups than in G2 group; no differences were observed between G1, G3 and G4 groups. Ki-67 immunoreactivity score was significantly higher in G2 group when compared with G1, G3 and G4 groups. Caspase-3 immunoreactivity was not statistically different between the groups. Conclusion: VC and VE may confer cellular protection against radiation injury induced by HSG in endometrial epithelium. Keywords: vitamin C, vitamin E, radiation, endometrium, rat, miRNA

This article uses one year’s worth of daily travel distance data for 252 Seattle households’ vehicles to ascertain that one day’s distance (plus day of week and month of year information) accounts for 10.7% of the variability in that vehicle’s annual (total) distance traveled, while two and seven consecutive days’ distance values predict 16.7% and 33.6%, respectively. In analyzing Gini coefficients (which average 0.546 + / − 0.117 across these instrumented vehicles), one finds that full-time employed females have the most stable day-to-day driving patterns, allowing for shorter-duration surveys of such households.

ABSTRACT The ability of Cryptococcus neoformans to cause disease in humans varies significantly among strains with highly related genotypes. In general, environmental isolates of pathogenic species such as Cryptococcus neoformans var. grubii have reduced virulence relative to clinical isolates, despite having no differences in the expression of the canonical virulence traits (high-temperature growth, melanization, and capsule formation). In this observation, we report that environmental isolates of C. neoformans tolerate host CO2 concentrations poorly compared to clinical isolates and that CO2 tolerance correlates well with the ability of the isolates to cause disease in mammals. Initial experiments also suggest that CO2 tolerance is particularly important for dissemination of C. neoformans from the lung to the brain. Furthermore, CO2 concentrations affect the susceptibility of both clinical and environmental C. neoformans isolates to the azole class of antifungal drugs, suggesting that antifungal testing in the presence of CO2 may improve the correlation between in vitro azole activity and patient outcome. IMPORTANCE A number of studies comparing either patient outcomes or model system virulence across large collections of Cryptococcus isolates have found significant heterogeneity in virulence even among strains with highly related genotypes. Because this heterogeneity cannot be explained by variations in the three well-characterized virulence traits (growth at host body temperature, melanization, and polysaccharide capsule formation), it has been widely proposed that additional C. neoformans virulence traits must exist. The natural niche of C. neoformans is in the environment, where the carbon dioxide concentration is very low (∼0.04%); in contrast, mammalian host tissue carbon dioxide concentrations are 125-fold higher (5%). We have found that the ability to grow in the presence of 5% carbon dioxide distinguishes low-virulence strains from high-virulence strains, even those with a similar genotype. Our findings suggest that carbon dioxide tolerance is a previously unrecognized virulence trait for C. neoformans.

Q fever is a zoonotic bacterial infection caused by Coxiella burnetii. Chronic Q fever comprises less than five percent of all Q fever cases and, of those, endocarditis is the most common presentation (up to 78% of cases), followed by vascular involvement. Risk factors for chronic Q fever with vascular involvement include previous vascular surgery, preexisting valvular defects, aneurysms, and vascular prostheses. The most common symptoms of chronic Q fever with vascular involvement are nonspecific, including weight loss, fatigue, and abdominal pain. Criteria for diagnosis of chronic Q fever include clinical evidence of infection and laboratory criteria (antibody detection, detection of Coxiella burnetii DNA, or growth in culture). Treatment of chronic Q fever with vascular involvement includes a prolonged course of doxycycline and hydroxychloroquine (≥18 months) as well as early surgical intervention, which has been shown to improve survival. Mortality is high in untreated chronic Q fever. We report a case of chronic Q fever with vascular involvement in a 77-year-old man with prior infrarenal aortic aneurysm repair, who lived near a livestock farm in the southeastern United States.

Background Isotemporal substitution examines the effect on health outcomes of replacing sedentary time with light‐intensity physical activity or moderate‐to‐vigorous intensity physical activity; however, existing studies are limited by cross‐sectional study designs. Methods and Results Participants were 1922 adults from the CARDIA (Coronary Artery Risk Development in Young Adults) study. Linear regression examined the associations of sedentary, light‐intensity physical activity, and moderate‐to‐vigorous intensity physical activity at year 20 (2005–2006) with waist circumference, blood pressure, glucose, insulin, triglycerides, high‐density lipoprotein cholesterol, and a composite risk score at year 30 (2015–2016). Models then examined change in activity with change in cardiometabolic risk over the same 10‐year period. Replacing 30 min/day of sedentary time with 30 min/day of light‐intensity physical activity at year 20 was associated with a lower composite risk score (−0.01 SD [95% CI, −0.02, −0.00]) at year 30, characterized by lower waist circumference (0.15 cm [95% CI, −0.27, 0.02]), insulin (0.20 μU/mL [95% CI, −0.35, −0.04]), and higher high‐density lipoprotein cholesterol (0.20 mg/dL [95% CI, 0.00, 0.40]; all P

Rural school districts face different challenges than urban and suburban districts. In fact, several Rural Systemic Initiatives (RSIs) have been established around the country to isolate and address rural school district issues (Harmon & Smith, 2012). In order to improve the effectiveness of transition services in rural schools, feedback from stakeholders in the process is vital. Directors of special education, specifically, must work to facilitate a quality and seamless process for transition despite challenges, and those working in rural settings may face additional obstacles. This study examines the perspectives of these front-line providers in order to begin to understand the difficulties that rural school districts, in particular, must overcome. The challenges and suggestions expressed by directors of special education impact the trajectory of improvements that need to be made in rural education transition services. These improvements will not only streamline processes for rural educators and staff involved in transition, but will ultimately benefit the families they serve.

Coupled fire-atmosphere models are increasingly being used to study low-intensity fires, such as those that are used in prescribed fire applications. Thus, the need arises to evaluate these models for their ability to accurately represent fire spread in marginal burning conditions. In this study, wind and fuel data collected during the Prescribed Fire Combustion and Atmospheric Dynamics Research Experiments (RxCADRE) fire campaign were used to generate initial and boundary conditions for coupled fire-atmosphere simulations. We present a novel method to obtain fuels representation at the model grid scale using a combination of imagery, machine learning, and field sampling. Several methods to generate wind input conditions for the model from eight different anemometer measurements are explored. We find a strong sensitivity of fire outcomes to wind inputs. This result highlights the critical need to include variable wind fields as inputs in modeling marginal fire conditions. This work highlights the complexities of comparing physics-based model results against observations, which are more acute in marginal burning conditions, where stronger sensitivities to local variability in wind and fuels drive fire outcomes.

BackgroundMedical devices are critical to providing high-quality, hospital-based newborn care, yet many of these devices are unavailable in low- and middle-income countries (LMIC) and are not designed to be suitable for these settings. Target Product Profiles (TPPs) are often utilised at an early stage in the medical device development process to enable user-defined performance characteristics for a given setting. TPPs can also be applied to assess the profile and match of existing devices for a given context.MethodsWe developed initial TPPs for 15 newborn product categories for LMIC settings. A Delphi-like process was used to develop the TPPs. Respondents completed an online survey where they scored their level of agreement with each of the proposed performance characteristics for each of the 15 devices. Characteristics with  75% agreement. Areas of disagreement were voted on by 69 participants at an in-person consensus meeting, with consensus achieved for 648 (97%) performance characteristics. Only 20 (3%) performance characteristics did not achieve consensus, most (15/20) relating to quality management systems. UNICEF published the 15 TPPs in April 2020, accompanied by a report detailing the online survey results and consensus meeting discussion, which has been viewed 7,039 times (as of January 2023).ConclusionsThese 15 TPPs can inform developers and enable implementers to select neonatal care products for LMIC. Over 2,400 medical devices and diagnostics meeting these TPPs have been installed in 65 hospitals in Nigeria, Tanzania, Kenya, and Malawi through the NEST360 Alliance. Twenty-three medical devices identified and qualified by NEST360 meet nearly all performance characteristics across 11 of the 15 TPPs. Eight of the 23 qualified medical devices are available in the UNICEF Supply Catalogue. Some developers have adjusted their technologies to meet these TPPs. There is potential to adapt the TPP process beyond newborn care.

Retinal implant devices are becoming an increasingly realizable way to improve the vision of patients blinded by photoreceptor degeneration. As an electrode material that can improve restored visual acuity, carbon nanotubes (CNTs) excel due to their nanoscale topography, flexibility, surface chemistry, and double-layer capacitance. If vertically aligned carbon nanotubes (VACNTs) are biocompatible with retinal neurons and mechanically robust, they can further improve visual acuity—most notably in subretinal implants—because they can be patterned into high-aspect-ratio, micrometer-size electrodes. We investigated the role of an aluminum (Al) underlayer beneath an iron (Fe) catalyst layer used in the growth of VACNTs by chemical vapor deposition (CVD). In particular, we cultured dissociated retinal cells for three days in vitro (DIV) on unfunctionalized and oxygen plasma functionalized VACNTs grown from a Fe catalyst (Fe and Fe+Pl preparations, where Pl signifies the plasma functionalization) and an Fe catalyst with an Al underlayer (Al/Fe and Al/Fe+Pl preparations). The addition of the Al layer increased the mechanical integrity of the VACNT interface and enhanced retinal neurite outgrowth over the Fe preparation. Unexpectedly, the extent of neurite outgrowth was significantly greater in the Al/Fe than in the Al/Fe+Pl preparation, suggesting plasma functionalization can negatively impact biocompatibility for some VACNT preparations. Additionally, we show our VACNT growth process for the Al/Fe preparation can support neurite outgrowth for up to 7 DIV. By demonstrating the retinal neuron biocompatibility, mechanical integrity, and pattern control of our VACNTs, this work offers VACNT electrodes as a solution for improving the restored visual acuity provided by modern retinal implants.

Abstract Introduction Despite strong recommendations, only 40.6% of pregnant women attending two prenatal clinics were vaccinated against influenza during the 2009 pandemic. We tested whether an opting-out approach would improve vaccine uptake. Methods We conducted a randomized quality improvement (QI) trial to compare opting-out with conventional opting-in consent for influenza immunization. Women age ≥ 18 years attending the University of Texas Health Science Center at Houston (UTHealth) or UT-Medical Branch (UTMB) prenatal clinics during the 2010–2011 influenza season, were eligible. Results We enrolled 280 women (140 UTHealth, 140 UTMB). Both groups had similar mean age (26.0 ± 5.5 years), mean gestational age (19.4 ± 9.5 weeks), and percent with underlying health conditions (20.7%). Vaccination rates with opting-in and opting-out were similar among all (83 vs. 84%), UTHealth (87 vs. 93%), and UTMB patients (79 vs.76%) (p > 0.05). In subsamples of patients assessed, consent strategy did not significantly affect maternal recall of information provided. Conclusion While prenatal influenza vaccination uptake doubled from the 2009–2010 influenza season, opting-out did not perform better than opting-in, a conclusion opposite that we would have reached had this been a nonconcurrent trial. Vaccination rates dropped posttrial; hence, continued research is needed to increase the prenatal influenza immunizations.

Understanding cell–nanoparticle interactions is critical to developing effective nanosized drug delivery systems. Nanoparticles have already advanced the treatment of several challenging conditions including cancer and human immunodeficiency virus (HIV), yet still hold the potential to improve drug delivery to elusive target sites. Even though most nanoparticles will encounter blood at a certain stage of their transport through the body, the interactions between nanoparticles and blood cells is still poorly understood and the importance of evaluating nanoparticle hemocompatibility is vastly understated. In contrast to most review articles that look at the interference of nanoparticles with the intricate coagulation cascade, this review will explore nanoparticle hemocompatibility from a cellular angle. The most important functions of the three cellular components of blood, namely erythrocytes, platelets and leukocytes, in hemostasis are highlighted. The potential deleterious effects that nanoparticles can have on these cells are discussed and insight is provided into some of the complex mechanisms involved in nanoparticle–blood cell interactions. Throughout the review, emphasis is placed on the importance of undertaking thorough, all-inclusive hemocompatibility studies on newly engineered nanoparticles to facilitate their translation into clinical application.

Anaplastic thyroid cancer (ATC) is a rare and lethal human malignancy with no known effective therapies in the majority of cases. Despite the use of conventional treatments such as chemotherapy, radiation and surgical resection, this disease remains almost universally fatal. In the present study, we identified the JAK2 inhibitor Lestaurtinib as a potent compound when testing against 13 ATC cell lines. Lestaurtinib demonstrated a potent antiproliferative effect in vitro at nanomolar concentrations. Furthermore, Lestaurtinib impeded cell migration and the ability to form colonies from single cells using scratch-wound and colony formation assays, respectively. Flow cytometry was used for cell cycle analysis following drug treatment and demonstrated arrest at the G2/M phase of the cell cycle, indicative of a cytostatic effect. In vivo studies using the chick chorioallantoic membrane xenograft models demonstrated that treatment with Lestaurtinib resulted in a significant decrease in endpoint tumor volume and vascularity using power Doppler ultrasound imaging. Overall, this study provides evidence that Lestaurtinib is a potent antiproliferative agent with potential antiangiogenic activity that warrants further investigation as a targeted therapy for ATC.

Purpose. To investigate the association of automated visual field (VF) reliability indices (false positive [FP], false negative [FN], and fixation loss [FL]) and sleep quality, VF experience, and age. Methods. Prospective, cross-sectional study. Adult patients (age ≥ 18 years) completing automated VF testing were invited to participate. Baseline participant characteristics were obtained, and all participants were asked to complete the Pittsburgh Sleep Quality Index (PSQI) questionnaire. Nonparametric Spearman correlations and logistical regression models were performed. Results. 63 patients were enrolled. Lower PSQI score was correlated with higher percentage (%) FL in the right eye (p=0.03). Fewer prior VF was significantly correlated with higher %FP in the right eye (p=0.008). Older age was significantly correlated with higher %FN in the left eye (p=0.01). Greater mean deviation (MD) and pattern standard deviation (PSD) were strongly correlated with higher %FN in the right (p=0.02 and 0.002, resp.) and left eyes (p=0.01 and 0.02, resp.). Conclusion. In this prospective, cross-sectional study, worse MD and PSD are strongly correlated with increased FN in both eyes. Increased FN in the left eye associated with older age might be attributable to test fatigue. Worse sleep quality is associated with decreased FL in the right eye.

Characterizing the mechanisms underlying follicle development in the ovary is crucial to understanding female fertility and is an area of increasing research interest. The RNA binding protein Musashi is essential for post-transcriptional regulation of oocyte maturation in Xenopus and is expressed during ovarian development in Drosophila. In mammals Musashi is important for spermatogenesis and male fertility, but its role in the ovary has yet to be characterized. In this study we determined the expression of mammalian Musashi proteins MSI1 and MSI2 during mouse folliculogenesis, and through the use of a MSI2-specific knockout mouse model we identified that MSI2 is essential for normal follicle development. Time-course characterization of MSI1 and MSI2 revealed distinct differences in steady-state mRNA levels and protein expression/localization at important developmental time-points during folliculogenesis. Using a gene-trap mouse model that inactivates Msi2, we observed a significant decrease in ovarian mass, and change in follicle-stage composition due to developmental blocking of antral stage follicles and pre-antral follicle loss through atresia. We also confirmed that hormonally stimulated Msi2-deficient mice produce significantly fewer MII oocytes (60.9% less than controls, p < 0.05). Furthermore, the majority of these oocytes are of poor viability (62.2% non-viable/apoptotic, p < 0.05), which causes a reduction in female fertility evidenced by decreased litter size in Msi2-deficient animals (33.1% reduction to controls, p < 0.05). Our findings indicate that MSI1 and MSI2 display distinct expression profiles during mammalian folliculogenesis and that MSI2 is required for pre-antral follicle development.

ABSTRACT The ongoing concurrent outbreaks of Zika, Chikungunya, and dengue viruses in Latin America and the Caribbean highlight the need for development of broad-spectrum antiviral treatments. The type I interferon (IFN) system has evolved in vertebrates to generate tissue responses that actively block replication of multiple known and potentially zoonotic viruses. As such, its control and activation through pharmacological agents may represent a novel therapeutic strategy for simultaneously impairing growth of multiple virus types and rendering host populations resistant to virus spread. In light of this strategy’s potential, we undertook a screen to identify novel interferon-activating small molecules. Here, we describe 1-(2-fluorophenyl)-2-(5-isopropyl-1,3,4-thiadiazol-2-yl)-1,2-dihydrochromeno[2,3-c]pyrrole-3,9-dione, which we termed AV-C. Treatment of human cells with AV-C activates innate and interferon-associated responses that strongly inhibit replication of Zika, Chikungunya, and dengue viruses. By utilizing genome editing, we investigated the host proteins essential to AV-C-induced cellular states. This showed that the compound requires a TRIF-dependent signaling cascade that culminates in IFN regulatory factor 3 (IRF3)-dependent expression and secretion of type I interferon to elicit antiviral responses. The other canonical IRF3-terminal adaptor proteins STING and IPS-1/MAVS were dispensable for AV-C-induced phenotypes. However, our work revealed an important inhibitory role for IPS-1/MAVS, but not TRIF, in flavivirus replication, implying that TRIF-directed viral evasion may not occur. Additionally, we show that in response to AV-C, primary human peripheral blood mononuclear cells secrete proinflammatory cytokines that are linked with establishment of adaptive immunity to viral pathogens. Ultimately, synthetic innate immune activators such as AV-C may serve multiple therapeutic purposes, including direct antimicrobial responses and facilitation of pathogen-directed adaptive immunity. IMPORTANCE The type I interferon system is part of the innate immune response that has evolved in vertebrates as a first line of broad-spectrum immunological defense against an unknowable diversity of microbial, especially viral, pathogens. Here, we characterize a novel small molecule that artificially activates this response and in so doing generates a cellular state antagonistic to growth of currently emerging viruses: Zika virus, Chikungunya virus, and dengue virus. We also show that this molecule is capable of eliciting cellular responses that are predictive of establishment of adaptive immunity. As such, this agent may represent a powerful and multipronged therapeutic tool to combat emerging and other viral diseases.

Background: There is a lack of evidence examining the role of physical therapy (PT) to address movement dysfunction for individuals with essential tremor (ET).Case Report: A 61-year-old male with ET and prolonged bilateral deep brain stimulation (DBS) completed 14 sessions of outpatient PT that emphasized balance, functional movements, and proximal stability training with an integration of principles of body awareness training and visual motor coordination. Improvements were noted in all outcome measures.Discussion: This report describes a novel PT approach that offers a promising means of improving functional mobility and balance while decreasing falls risk in patients with ET.

Background. Vaginal stones may form in the setting of mesh exposure with urinary incontinence. This report serves to help understand the presentation, evaluation, and management of vaginal urinary stones. Case. A 68-year-old female presented with a vaginal calculus. She had a history of anterior and posterior polypropylene mesh placement for prolapse 7 years earlier and urinary incontinence. The stone was identified on a portion of exposed mesh and removed in office. Pathology confirmed urinary etiology. The exposed mesh resolved with topical estrogen. Cystourethroscopy excluded urinary fistula and bladder mesh erosion. Conclusions. When identified, a vaginal calculus should be removed and evaluated for composition. Cystourethroscopy should be performed to assess potential urinary tract fistulas and mesh erosion. Additional imaging should be considered.

To investigate the outcomes of childhood glaucoma suspects.Retrospective case series.Records of childhood glaucoma suspects were identified using financial claims data; medical history, baseline biometric and exam findings were recorded. Conversion from suspect to glaucoma was determined based on the Childhood Glaucoma Research Network criteria. The study adheres to the tenets of the Declarations of Helsinki.214 subjects were enrolled, with median age at initial presentation of 6.37 years (interquartertile range: Q1 = 2.46, Q3 = 8.90). 22 (10.2%) subjects developed glaucoma, 64 (29.9%) had ocular hypertension but no glaucoma, 9 (4.2%) had high-risk condition or syndrome without either ocular hypertension or glaucoma after a mean follow up of 39 +/- 34 months. Neither a family history of glaucoma nor patient gender was significantly different between the groups. 40.2% of subjects (86 of 214) had two or more episodes of intraocular pressure (IOP) > 21 mmHg, among which 25.6% (22 of 86) developed glaucoma after a mean duration of 32.8 +/- 33.5 months.Up to 25% of children with 2 or more episodes of elevated IOP may develop glaucoma. In 50% of suspects who converted to glaucoma, elevated IOP was not present at the initial evaluation. There is no significant difference in gender, family history, or baseline central corneal thickness between suspects who developed glaucoma compared to the rest. While suspects who converted to glaucoma had higher average, maximum and minimum IOP measurements, there is no clear cutoff between the groups.

BackgroundInterleukin-2 (IL-2) has an essential role in the expansion and function of CD4+ regulatory T cells (Tregs). Tregs reduce tissue damage by limiting the immune response following infection and regulate autoreactive CD4+ effector T cells (Teffs) to prevent autoimmune diseases, such as type 1 diabetes (T1D). Genetic susceptibility to T1D causes alterations in the IL-2 pathway, a finding that supports Tregs as a cellular therapeutic target. Aldesleukin (Proleukin; recombinant human IL-2), which is administered at high doses to activate the immune system in cancer immunotherapy, is now being repositioned to treat inflammatory and autoimmune disorders at lower doses by targeting Tregs.Methods and findingsTo define the aldesleukin dose response for Tregs and to find doses that increase Tregs physiologically for treatment of T1D, a statistical and systematic approach was taken by analysing the pharmacokinetics and pharmacodynamics of single doses of subcutaneous aldesleukin in the Adaptive Study of IL-2 Dose on Regulatory T Cells in Type 1 Diabetes (DILT1D), a single centre, non-randomised, open label, adaptive dose-finding trial with 40 adult participants with recently diagnosed T1D. The primary endpoint was the maximum percentage increase in Tregs (defined as CD3+CD4+CD25highCD127low) from the baseline frequency in each participant measured over the 7 d following treatment. There was an initial learning phase with five pairs of participants, each pair receiving one of five pre-assigned single doses from 0.04 × 106 to 1.5 × 106 IU/m2, in order to model the dose-response curve. Results from each participant were then incorporated into interim statistical modelling to target the two doses most likely to induce 10% and 20% increases in Treg frequencies. Primary analysis of the evaluable population (n = 39) found that the optimal doses of aldesleukin to induce 10% and 20% increases in Tregs were 0.101 × 106 IU/m2 (standard error [SE] = 0.078, 95% CI = -0.052, 0.254) and 0.497 × 106 IU/m2 (SE = 0.092, 95% CI = 0.316, 0.678), respectively. On analysis of secondary outcomes, using a highly sensitive IL-2 assay, the observed plasma concentrations of the drug at 90 min exceeded the hypothetical Treg-specific therapeutic window determined in vitro (0.015-0.24 IU/ml), even at the lowest doses (0.040 × 106 and 0.045 × 106 IU/m2) administered. A rapid decrease in Treg frequency in the circulation was observed at 90 min and at day 1, which was dose dependent (mean decrease 11.6%, SE = 2.3%, range 10.0%-48.2%, n = 37), rebounding at day 2 and increasing to frequencies above baseline over 7 d. Teffs, natural killer cells, and eosinophils also responded, with their frequencies rapidly and dose-dependently decreased in the blood, then returning to, or exceeding, pretreatment levels. Furthermore, there was a dose-dependent down modulation of one of the two signalling subunits of the IL-2 receptor, the β chain (CD122) (mean decrease = 58.0%, SE = 2.8%, range 9.8%-85.5%, n = 33), on Tregs and a reduction in their sensitivity to aldesleukin at 90 min and day 1 and 2 post-treatment. Due to blood volume requirements as well as ethical and practical considerations, the study was limited to adults and to analysis of peripheral blood only.ConclusionsThe DILT1D trial results, most notably the early altered trafficking and desensitisation of Tregs induced by a single ultra-low dose of aldesleukin that resolves within 2-3 d, inform the design of the next trial to determine a repeat dosing regimen aimed at establishing a steady-state Treg frequency increase of 20%-50%, with the eventual goal of preventing T1D.Trial registrationISRCTN Registry ISRCTN27852285; ClinicalTrials.gov NCT01827735.

The microbiome is important in the evolution of the immune system in children; however, information is lacking regarding the composition of the pediatric ocular microbiome and its surrounding structures. A prospective, cross-sectional study of the ocular microbiome was conducted in children t-test, diversity indices, and principal coordinate analysis. A total of 15 children were enrolled. The ocular surface microbiome was predominantly composed of Proteobacteria, whereas Bacteroidetes dominated the eyelid margin, and Firmicutes dominated the periocular skin. Despite these variations, no statistically significant compositional differences were found with Bray-Curtis analysis. The conjunctiva had the lowest Shannon diversity index with a value of 2.3, which was significantly lower than those of the eyelid margin (3.4, p = 0.01) and the periocular skin (3.5, p = 0.001). However, the evenness of the species using Faith’s phylogenetic diversity index was similar at all sites. Overall, the ocular surface microbiome is dominated by Proteobacteria in children. The niche is similar to the surrounding structures in terms of composition, but has a lower number and relative abundance of species.

Full breastfeeding (FBF) is promoted as effective for losing pregnancy weight during the postpartum period. This study evaluated whether longer FBF is associated with lower maternal postpartum weight retention (PPWR) as compared to a shorter FBF duration. The MILK (Mothers and Infants Linked for Healthy Growth) study is an ongoing prospective cohort of 370 mother−infant dyads, all of whom fully breastfed their infants for at least 1 month. Breastfeeding status was subsequently self-reported by mothers at 3 and 6 months postpartum. Maternal PPWR was calculated as maternal weight measured at 1, 3, and 6 months postpartum minus maternal prepregnancy weight. Using linear mixed effects models, by 6 months postpartum, adjusted means ± standard errors for weight retention among mothers who fully breastfed for 1−3 (3.40 ± 1.16 kg), 3−6 (1.41 ± 0.69 kg), and ≥6 months (0.97 ± 0.32 kg) were estimated. Compared to mothers who reported FBF for 1−3 months, those who reported FBF for 3−6 months and ≥6 months both had lower PPWR over the period from 1 to 6 months postpartum (p = 0.04 and p < 0.01, respectively). However, PPWR from 3 to 6 months was not significantly different among those who reported FBF for 3−6 versus ≥6 months (p > 0.05). Interventions to promote FBF past 3 months may increase the likelihood of postpartum return to prepregnancy weight.

Maternal pregnancy nutrition influences fetal growth. Evidence is limited, however, on the relationship of maternal diet during pregnancy and lactation on infant postnatal growth and adiposity. Our purpose was to examine associations between maternal diet quality during pregnancy and lactation with offspring growth and body composition from birth to six months. Maternal diet quality was serially assessed in pregnancy and at one and three months postpartum, using the Healthy Eating Index–2015 in a cohort of 354 fully breastfeeding mother–infant dyads. Infant length-for-age (LAZ), weight-for-age (WAZ), and weight-for-length (WLZ) Z-scores were assessed at birth, one, three, and six months. Infant body fat percent (BF%), fat mass (FM), and fat-free mass (FFM) were measured at six months using dual-energy X-ray absorptiometry. Higher maternal diet quality from pregnancy through three months postpartum was associated with lower infant WLZ from birth to six months (p = 0.02) and BF% at six months (p ≤ 0.05). Higher maternal diet quality at one and three months postpartum was also associated with lower infant FM at six months (p < 0.01). In summary, maternal diet quality during pregnancy and lactation was inversely associated with infant relative weight and adiposity in early postnatal life. Additional research is needed to explore whether associations persist across the life course.

This manuscript shares how one teacher education program is working to interrupt racist, xenophobic, homophobic, antisemitic, ableist, and sexist microaggressions and other forms of discrimination that occur in P-12 field experiences. In this article, we share our context, actions, and examples (i.e., critical cases) of microaggressions from pre-service social studies teachers' field experiences. Drawing upon microaggressions theory, we frame our work with equity literacy to analyze pre-service teachers' field experiences and connect to microinterventions. We argue that teacher education programs must prepare teachers to respond to and interrupt microaggressions, and move toward curricular interventions in the social studies in an effort to transform schools to be more equitable in the curriculum and institutionally. We hope practitioners will engage with the ideas and practices presented and reflect on connections and applications to their schools, communities, and contexts.

Hydrozirconation of 1-hexyne, the addition to in situ prepared N-acyliminium species, and ring-closing metathesis (RCM) were key steps in the preparation of a tricyclic isoindolinone scaffold. An unusual alkene isomerization process during the RCM was identified and studied in some detail. Chemical diversification for library synthesis was achieved by a subsequent alkene epoxidation and zinc-mediated aminolysis reaction. The resulting library products provided selective hits among a large number of high-throughput screens reported in PubChem, thus illustrating the utility of the novel scaffold.

Pharmacologic stimulation of innate immune processes represents an attractive strategy to achieve multiple therapeutic outcomes including inhibition of virus replication, boosting antitumor immunity, and enhancing vaccine immunogenicity. In light of this we sought to identify small molecules capable of activating the type I interferon (IFN) response by way of the transcription factor IFN regulatory factor 3 (IRF3). A high throughput in vitro screen yielded 4-(2-chloro-6-fluorobenzyl)-N-(furan-2-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide (referred to herein as G10), which was found to trigger IRF3/IFN-associated transcription in human fibroblasts. Further examination of the cellular response to this molecule revealed expression of multiple IRF3-dependent antiviral effector genes as well as type I and III IFN subtypes. This led to the establishment of a cellular state that prevented replication of emerging Alphavirus species including Chikungunya virus, Venezuelan Equine Encephalitis virus, and Sindbis virus. To define cellular proteins essential to elicitation of the antiviral activity by the compound we employed a reverse genetics approach that utilized genome editing via CRISPR/Cas9 technology. This allowed the identification of IRF3, the IRF3-activating adaptor molecule STING, and the IFN-associated transcription factor STAT1 as required for observed gene induction and antiviral effects. Biochemical analysis indicates that G10 does not bind to STING directly, however. Thus the compound may represent the first synthetic small molecule characterized as an indirect activator of human STING-dependent phenotypes. In vivo stimulation of STING-dependent activity by an unrelated small molecule in a mouse model of Chikungunya virus infection blocked viremia demonstrating that pharmacologic activation of this signaling pathway may represent a feasible strategy for combating emerging Alphaviruses.

Protein kinase D (PKD) belongs to a family of serine/threonine kinases that play an important role in basic cellular processes and are implicated in the pathogenesis of several diseases. Progress in our understanding of the biological functions of PKD has been limited due to the lack of a PKD-specific inhibitor. The benzoxoloazepinolone CID755673 was recently reported as the first potent and kinase-selective inhibitor for this enzyme. For structure-activity analysis purposes, a series of analogs was prepared and their in vitro inhibitory potency evaluated.