The prevention of bleeding with adequately sustained levels of clotting factor, after a single therapeutic intervention and without the need for further medical intervention, represents an important ...goal in the treatment of hemophilia.
We infused a single-stranded adeno-associated viral (AAV) vector consisting of a bioengineered capsid, liver-specific promoter and factor IX Padua (factor IX-R338L) transgene at a dose of 5×10
vector genomes per kilogram of body weight in 10 men with hemophilia B who had factor IX coagulant activity of 2% or less of the normal value. Laboratory values, bleeding frequency, and consumption of factor IX concentrate were prospectively evaluated after vector infusion and were compared with baseline values.
No serious adverse events occurred during or after vector infusion. Vector-derived factor IX coagulant activity was sustained in all the participants, with a mean (±SD) steady-state factor IX coagulant activity of 33.7±18.5% (range, 14 to 81). On cumulative follow-up of 492 weeks among all the participants (range of follow-up in individual participants, 28 to 78 weeks), the annualized bleeding rate was significantly reduced (mean rate, 11.1 events per year range, 0 to 48 before vector administration vs. 0.4 events per year range, 0 to 4 after administration; P=0.02), as was factor use (mean dose, 2908 IU per kilogram range, 0 to 8090 before vector administration vs. 49.3 IU per kilogram range, 0 to 376 after administration; P=0.004). A total of 8 of 10 participants did not use factor, and 9 of 10 did not have bleeds after vector administration. An asymptomatic increase in liver-enzyme levels developed in 2 participants and resolved with short-term prednisone treatment. One participant, who had substantial, advanced arthropathy at baseline, administered factor for bleeding but overall used 91% less factor than before vector infusion.
We found sustained therapeutic expression of factor IX coagulant activity after gene transfer in 10 participants with hemophilia who received the same vector dose. Transgene-derived factor IX coagulant activity enabled the termination of baseline prophylaxis and the near elimination of bleeding and factor use. (Funded by Spark Therapeutics and Pfizer; ClinicalTrials.gov number, NCT02484092 .).
Chronic conditions are an increasing challenge for individuals and the health care system. Smartphones and health apps are potentially promising tools to change health-related behaviors and manage ...chronic conditions.
The aim of this study was to explore (1) the extent of smartphone and health app use, (2) sociodemographic, medical, and behavioral correlates of smartphone and health app use, and (3) associations of the use of apps and app characteristics with actual health behaviors.
A population-based survey (N=4144) among Germans, aged 35 years and older, was conducted. Sociodemographics, presence of chronic conditions, health behaviors, quality of life, and health literacy, as well as the use of the Internet, smartphone, and health apps were assessed by questionnaire at home visit. Binary logistic regression models were applied.
It was found that 61.25% (2538/4144) of participants used a smartphone. Compared with nonusers, smartphone users were younger, did more research on the Internet, were more likely to work full-time and more likely to have a university degree, engaged more in physical activity, and less in low fat diet, and had a higher health-related quality of life and health literacy. Among smartphone users, 20.53% (521/2538) used health apps. App users were younger, less likely to be native German speakers, did more research on the Internet, were more likely to report chronic conditions, engaged more in physical activity, and low fat diet, and were more health literate compared with nonusers who had a smartphone. Health apps focused on smoking cessation (232/521, 44.5%), healthy diet (201/521, 38.6%), and weight loss (121/521, 23.2%). The most common app characteristics were planning (264/521, 50.7%), reminding (188/521, 36.1%), prompting motivation (179/521 34.4%), and the provision of information (175/521, 33.6%). Significant associations were found between planning and the health behavior physical activity, between feedback or monitoring and physical activity, and between feedback or monitoring and adherence to doctor's advice.
Although there were many smartphone and health app users, a substantial proportion of the population was not engaged. Findings suggest age-related, socioeconomic-related, literacy-related, and health-related disparities in the use of mobile technologies. Health app use may reflect a user's motivation to change or maintain health behaviors. App developers and researchers should take account of the needs of older people, people with low health literacy, and chronic conditions.
Peatlands have been artificially drained and degraded over 100s of years and have released huge amounts of carbon dioxide (CO2) as a result. In organic grassland soils, raising the water table to ...prevent such emissions is being proposed to meet national greenhouse gas emission targets for the land use sector. At present, all of these soils (335,000 ha) are assumed to be drained (as no information has been available on their drainage status) within national emission inventory reporting and are therefore responsible for significant emissions (8–9 million tonnes CO2-equivalent annually). The objective of the present study was to collate studies relating to the drainage status of peat soils in Ireland to present alternative scenarios with regard to actual drainage status of organic soils and their estimated emissions. From a drainage design perspective, evidence suggests that relatively small proportions of the grassland peat area was drained effectively using optimal in-field drain spacings required to control the water table at 0.4–0.5 m. Open drains excavated on such soils have limited capacity to laterally control the water table depth beyond short distances. Furthermore, the lack of long-term routine maintenance post installation ensures the redundancy of many drainage systems over time. New drainage installations are therefore likely replacing existing infrastructure and not necessarily increasing the drained area at any given time. This evidence supports literature from the 1980s which state that relatively low proportions of the grassland peat area has been subjected to effective drainage. Scenario testing results showed that likely emissions from the most probable scenario (with total area drained equating to 90,000–120,000 ha) are 3.6–4.7 million tonnes CO2-equivalent, approximately 40–53% of current national emission inventory estimates. The incorporation of such a refinement into the national inventory could offer a significant reduction in estimated GHG emissions from the grassland land use sector in national emission inventory reporting.
•In Ireland, it is assumed that all 335,000 ha of mapped grassland peat soils are drained.•This estimate results in assumed GHG emissions of 8–9 million tonnes CO2-e per year.•The proportion of grassland peat soils actually drained is much lower than the current estimate.•Evidence shows that drainage works on peat soils are limited in extent and effectiveness.•Scenarios based on updated drainage status result in emission savings of up to 60%.
Cannabis use in pregnancy is associated with adverse perinatal outcomes, which are likely mediated by the placenta. However, the underlying mechanisms and specific vasoactive effects of cannabis on ...the placenta are unknown. Our objective was to determine the impact of chronic prenatal delta-tetrahydrocannabinol (THC, main psychoactive component of cannabis) exposure on placental function and development in a rhesus macaque model using advanced imaging. Animals were divided into two groups, control (CON, n = 5) and THC-exposed (THC, n = 5). THC-exposed animals received a THC edible daily pre-conception and throughout pregnancy. Animals underwent serial ultrasound and MRI at gestational days 85 (G85), G110, G135 and G155 (full term is ~ G168). Animals underwent cesarean delivery and placental collection at G155 for histologic and RNA-Seq analysis. THC-exposed pregnancies had significantly decreased amniotic fluid volume (p < 0.001), placental perfusion (p < 0.05), and fetal oxygen availability (p < 0.05), all indicators of placental insufficiency. Placental histological analysis demonstrated evidence of ischemic injury with microinfarctions present in THC-exposed animals only. Bulk RNA-seq demonstrated that THC alters the placental transcriptome and pathway analysis suggests dysregulated vasculature development and angiogenesis pathways. The longer-term consequences of these adverse placental findings are unknown, but they suggest that use of THC during pregnancy may deleteriously impact offspring development.
Prenatal cannabis use is associated with adverse offspring neurodevelopmental outcomes, however the underlying mechanisms are relatively unknown. We sought to determine the impact of chronic ...delta-9-tetrahydrocannabinol (THC) exposure on fetal neurodevelopment in a rhesus macaque model using advanced imaging combined with molecular and tissue studies. Animals were divided into two groups, control (n = 5) and THC-exposed (n = 5), which received a daily THC edible pre-conception and throughout pregnancy. Fetal T2-weighted MRI was performed at gestational days 85 (G85), G110, G135 and G155 to assess volumetric brain development. At G155, animals underwent cesarean delivery with collection of fetal cerebrospinal fluid (CSF) for microRNA (miRNA) studies and fetal tissue for histologic analysis. THC exposure was associated with significant age by sex interactions in brain growth, and differences in fetal brain histology suggestive of brain dysregulation. Two extracellular vesicle associated-miRNAs were identified in THC-exposed fetal CSF; pathway analysis suggests that these miRNAs are associated with dysregulated axonal guidance and netrin signaling. This data is indicative of subtle molecular changes consistent with the observed histological data, suggesting a potential role for fetal miRNA regulation by THC. Further studies are needed to determine whether these adverse findings correlate with long-term offspring neurodevelopmental health.
Maternal malnutrition increases fetal and neonatal morbidity, partly by affecting placental function and morphology, but its impact on placental hemodynamics are unknown. Our objective was to define ...the impact of maternal malnutrition on placental oxygen reserve and perfusion in vivo in a rhesus macaque model of protein restriction (PR) using advanced imaging. Animals were fed control (CON, 26% protein), 33% PR diet (17% protein), or a 50% PR diet (13% protein, n = 8/group) preconception and throughout pregnancy. Animals underwent Doppler ultrasound and fetal biometry followed by MRI at gestational days 85 (G85) and 135 (G135; term is G168). Pregnancy loss rates were 0/8 in CON, 1/8 in 33% PR, and 3/8 in 50% PR animals. Fetuses of animals fed a 50% PR diet had a smaller abdominal circumference (G135, p < 0.01). On MRI, placental blood flow was decreased at G135 (p < 0.05) and placental oxygen reserve was reduced (G85, p = 0.05; G135, p = 0.01) in animals fed a 50% PR diet vs. CON. These data demonstrate that a 50% PR diet reduces maternal placental perfusion, decreases fetal oxygen availability, and increases fetal mortality. These alterations in placental hemodynamics may partly explain human growth restriction and stillbirth seen with severe PR diets in the developing world.
The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection during pregnancy on the developing fetal brain is poorly understood. Other antenatal infections such as influenza ...have been associated with adverse neurodevelopmental outcomes in offspring. Although vertical transmission has been rarely observed in SARS-CoV-2 to date, given the potential for profound maternal immune activation (MIA), impact on the developing fetal brain is likely. Here we review evidence that SARS-CoV-2 and other viral infections during pregnancy can result in maternal, placental, and fetal immune activation, and ultimately in offspring neurodevelopmental morbidity. Finally, we highlight the need for cellular models of fetal brain development to better understand potential short- and long-term impacts of maternal SARS-CoV-2 infection on the next generation.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in pregnancy is known to confer a risk of increased morbidity and mortality for the mother, but data are lacking regarding the impact of maternal SARS-CoV-2 infection on the developing fetal brain.Placental and fetal infection with SARS-CoV-2 have been rare to date; SARS-CoV-2 infection in pregnancy appears most likely to impact fetal brain development via maternal and placental immune activation.Maternal, placental, and fetal immune activation have been observed in SARS-CoV-2 infection during pregnancy, and adverse neurodevelopmental outcomes have been reported in early follow-up studies of offspring.Maternal and placental immune activation may impact the placenta and developing fetal brain via induction of immune activation and proinflammatory cytokine production, dysregulation of serotonin/other neurotransmitter signaling, and increased oxidative stress.
With the growing availability of cannabis and the popularization of additional routes of cannabis use beyond smoking, including edibles, the prevalence of cannabis use in pregnancy is rapidly ...increasing. However, the potential effects of prenatal cannabis use on fetal developmental programming remain unknown.
We designed this study to determine whether the use of edible cannabis during pregnancy is deleterious to the fetal and placental epigenome. Pregnant rhesus macaques consumed a daily edible containing either delta-9-tetrahydrocannabinol (THC) (2.5 mg/7 kg/day) or placebo. DNA methylation was measured in 5 tissues collected at cesarean delivery (placenta, lung, cerebellum, prefrontal cortex, and right ventricle of the heart) using the Illumina MethylationEPIC platform and filtering for probes previously validated in rhesus macaque. In utero exposure to THC was associated with differential methylation at 581 CpGs, with 573 (98%) identified in placenta. Loci differentially methylated with THC were enriched for candidate autism spectrum disorder (ASD) genes from the Simons Foundation Autism Research Initiative (SFARI) database in all tissues. The placenta demonstrated greatest SFARI gene enrichment, including genes differentially methylated in placentas from a prospective ASD study.
Overall, our findings reveal that prenatal THC exposure alters placental and fetal DNA methylation at genes involved in neurobehavioral development that may influence longer-term offspring outcomes. The data from this study add to the limited existing literature to help guide patient counseling and public health polices focused on prenatal cannabis use in the future.
Trypanosoma cruzi is an intracellular protozoan parasite capable of infecting through mucosal surfaces. Our laboratory has previously elucidated the anatomical routes of infection after both ...conjunctival and gastric challenge in mice. We have shown that chronically infected mice develop strong immune responses capable of protecting against subsequent rechallenge with virulent parasites through gastric, conjunctival, and systemic routes of infection. We have also shown that intranasal immunizations with the unique T. cruzi trans-sialidase (TS) antigen protect against gastric and systemic T. cruzi challenge. In the current work we have investigated the ability of purified TS adjuvanted with CpG-containing oligonucleotides to induce immunity against conjunctival T. cruzi challenge. We confirm that intranasal vaccinations with TS plus CpG induce TS-specific T-cell and secretory IgA responses. TS-specific secretory IgA was detectable in the tears of vaccinated mice, the initial body fluid that contacts the parasite during infectious conjunctival exposures. We further show that intranasal vaccinations with TS plus CpG protect against conjunctival T. cruzi challenge, limiting local parasite replication at the site of mucosal invasion and systemic parasite dissemination. We also provide the first direct evidence that mucosal antibodies induced by intranasal TS vaccination can inhibit parasite invasion.