Potential of mannan or dextrin nanogels as vaccine carrier/adjuvant systems

Polymeric nanogels have been sophisticatedly designed promising a new generation of vaccine delivery/adjuvant systems capable of boosting immune response, a strategic priority in vaccine design. Here, nanogels made of mannan or dextrin were evaluated for their potential as carriers/adjuvants in vaccine formulations. Since lymph nodes are preferential target organs for vaccine delivery systems, nanogels were biotin-labeled, injected in the footpad of rats, and their presence in draining lymph nodes was assessed by immunofluorescence. Nanogels were detected in the popliteal and inguinal lymph nodes by 24h upon subcutaneous administration, indicating entrapment in lymphatic organs. Moreover, the model antigen ovalbumin was physically encapsulated within nanogels and physicochemically characterized concerning size, zeta potential, ovalbumin loading, and entrapment efficiency. The immunogenicity of these formulations was assessed in mice intradermally immunized with ovalbuminmannan or ovalbumindextrin by determining ovalbumin-specific antibody serum titers. Intradermal vaccination using ovalbuminmannan elicited a humoral immune response in which ovalbumin-specific IgG1 levels were significantly higher than those obtained with ovalbumin alone, indicating a TH2-type response. In contrast, dextrin nanogel did not show adjuvant potential. Altogether, these results indicate that mannan nanogel is a material that should be explored as a future antigen delivery system.The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work is supported by the Fundação para a Ciência e a Tecnologia (FCT) Portugal, post-doc grant SFRH/BPD/70524/2010 and the International Iberian Nanotechnology Laboratory (INL), PhD grant. The authors thank the Portuguese Foundation for Science and Technology (FCT) under the scope of the strategic funding of UID/BIO/04469/2013 unit and COMPETE 2020 (POCI-01-0145-FEDER-006684). The authors also acknowledge the Project RECI/BBB-EBI/0179/2012 (FCOMP-01-0124-FEDER-027462)

Deep learning enables genetic analysis of the human thoracic aorta

Genome-wide association analyses identify variants associated with thoracic aortic diameter. A polygenic score for ascending aortic diameter was associated with a diagnosis of thoracic aortic aneurysm in independent samples. Enlargement or aneurysm of the aorta predisposes to dissection, an important cause of sudden death. We trained a deep learning model to evaluate the dimensions of the ascending and descending thoracic aorta in 4.6 million cardiac magnetic resonance images from the UK Biobank. We then conducted genome-wide association studies in 39,688 individuals, identifying 82 loci associated with ascending and 47 with descending thoracic aortic diameter, of which 14 loci overlapped. Transcriptome-wide analyses, rare-variant burden tests and human aortic single nucleus RNA sequencing prioritized genes including SVIL, which was strongly associated with descending aortic diameter. A polygenic score for ascending aortic diameter was associated with thoracic aortic aneurysm in 385,621 UK Biobank participants (hazard ratio = 1.43 per s.d., confidence interval 1.32-1.54, P = 3.3 x 10(-20)). Our results illustrate the potential for rapidly defining quantitative traits with deep learning, an approach that can be broadly applied to biomedical images

Alcohol Use Disorders (AUD) among Tuberculosis Patients: A Study from Chennai, South India

BACKGROUND: Alcohol Use Disorders (AUDs) among tuberculosis (TB) patients are associated with nonadherence and poor treatment outcomes. Studies from Tuberculosis Research Centre (TRC), Chennai have reported that alcoholism has been one of the major reasons for default and mortality in under the DOTS programme in South India. Hence, it is planned to conduct a study to estimate prevalence of alcohol use and AUDs among TB patients attending the corporation health centres in Chennai, India. METHODOLOGY: This is a cross-sectional cohort study covering 10 corporation zones at Chennai and it included situational assessment followed by screening of TB patients by a WHO developed Alcohol Use Disorders Identification Test AUDIT scale. Four zones were randomly selected and all TB patients treated during July to September 2009 were screened with AUDIT scale for alcohol consumption. RESULTS: Out of 490 patients, 66% were males, 66% were 35 years and above, 57% were married, 58% were from the low monthly income group of <Rs 5000 per month. No females reported alcohol use. Overall, out of 490 TB pts, 29% (141) were found to consume alcohol. Among 141 current drinkers 52% (73) had an AUDIT score of >8. Age (>35 years), education (less educated), income (<Rs 5000 per month), marital status (separated/divorced) and treatment category (Category 2) were statistically significant for TB patients with alcohol use than those TB patients without alcohol use. CONCLUSIONS: AUD among TB patients needs to be addressed urgently and the findings suggest the importance of integrating alcohol treatment into TB care

Effectiveness of influenza vaccine against laboratory-confirmed influenza, in the late 2011-2012 season in Spain, among population targeted for vaccination

Background: In Spain, the influenza vaccine effectiveness (VE) was estimated in the last three seasons using the observational study cycEVA conducted in the frame of the existing Spanish Influenza Sentinel Surveillance System. The objective of the study was to estimate influenza vaccine effectiveness (VE) against medically attended, laboratory-confirmed influenza-like illness (ILI) among the target groups for vaccination in Spain in the 2011-2012 season. We also studied influenza VE in the early (weeks 52/2011-7/2012) and late (weeks 8-14/2012) phases of the epidemic and according to time since vaccination. Methods: Medically attended patients with ILI were systematically swabbed to collect information on exposure, laboratory outcome and confounding factors. Patients belonging to target groups for vaccination and who were swabbed 4 months, respectively, since vaccination. A decrease in VE with time since vaccination was only observed in individuals aged ≥ 65 years. Regarding the phase of the season, decreasing point estimates were only observed in the early phase, whereas very low or null estimates were obtained in the late phase for the shortest time interval. Conclusions: The 2011-2012 influenza vaccine showed a low-to-moderate protective effect against medically attended, laboratory-confirmed influenza in the target groups for vaccination, in a late season and with a limited match between the vaccine and circulating strains. The suggested decrease in influenza VE with time since vaccination was mostly observed in the elderly population. The decreasing protective effect of the vaccine in the late part of the season could be related to waning vaccine protection because no viral changes were identified throughout the season

Responsiveness of the Early Childhood Oral Health Impact Scale (ECOHIS) is related to dental treatment complexity

Abstract\ud \ud Background\ud The responsiveness of the Early Childhood Oral Health Impact Scale (ECOHIS) has varied greatly across studies; hence, we hypothesized that this discrepancy could be related to the complexity of dental treatment received. Thus, we aimed to evaluate the responsiveness of the ECOHIS to changes in oral health-related quality of life (OHRQoL) following dental treatments of varying complexity in preschool children.\ud \ud \ud Methods\ud Preschool children aged 3 to 6 years were selected; their parents responded to the ECOHIS at baseline. The parents responded to the ECOHIS again and a global transition question 30 days after the children were treated. The type of treatment received by the children was categorized according to complexity, as follows: 1) non-operative treatment only, 2) restorative treatment, and 3) endodontic treatment and/or tooth extraction. Change scores and effect sizes (ES) were calculated for total scores, as well as considering the different treatment types and global transition question responses.\ud \ud \ud Results\ud Of the 152 children who completed the study, the ECOHIS yielded large ES for total scores (0.89). The children showed increasing ES values associated with better perception of improvement, assessed by the global transition question. The magnitude of ES after treatment was related to treatment complexity (0.53, 0.92 and 1.43, for children who received non-operative treatment only, restorative treatment, and endodontic treatment and/or tooth extraction, respectively).\ud \ud \ud Conclusions\ud Parents whose children required more complex dental treatment are more likely to perceive treatment-related changes to OHRQoL assessed with the ECOHIS.The study was funded by Conselho Nacional de Desenvolvimento Científico\ud e Tecnológico – CNPq (Grants # 471817/2012–0 and 306,304/2015–5),\ud Fundação de Amparo à Pesquisa do Estado de São Paulo – FAPESP (Grant #\ud 2012/24243–7), and Coordenação de Aperfeiçoamento de Pessoal de Nível\ud Superior (CAPES)

Hippocampal biomarkers of fear memory in an animal model of generalized anxiety disorder

Generalized anxiety disorder (GAD) is highly prevalent and incapacitating. Here we used the Carioca High-Conditioned Freezing (CHF) rats, a previously validated animal model for GAD, to identify biomarkers and structural changes in the hippocampus that could be part of the underlying mechanisms of their high-anxiety profile. Spatial and fear memory was assessed in the Morris water maze and passive avoidance test. Serum corticosterone levels, immunofluorescence for glucocorticoid receptors (GR) in the dentate gyrus (DG), and western blotting for hippocampal brain derived neurotrophic factor (BDNF) were performed. Immunohistochemistry for markers of cell proliferation (bromodeoxiuridine/Ki-67), neuroblasts (doublecortin), and cell survival were undertaken in the DG, along with spine staining (Golgi) and dendritic arborization tracing. Hippocampal GABA release was assessed by neurochemical assay. Fear memory was higher among CHF rats whilst spatial learning was preserved. Serum corticosterone levels were increased, with decreased GR expression. No differences were observed in hippocampal cell proliferation/survival, but the number of newborn neurons was decreased, along with their number and length of tertiary dendrites. Increased expression of proBDNF and dendritic spines was observed; lower ratio of GABA release in the hippocampus was also verified. These findings suggest that generalized anxiety/fear could be associated with different hippocampal biomarkers, such as increased spine density, possibly as a compensatory mechanism for the decreased hippocampal number of neuroblasts and dendritic arborization triggered by high corticosterone. Disruption of GABAergic signaling and BDNF impairment are also proposed as part of the hippocampal mechanisms possibly underlying the anxious phenotype of this model

Effects of Anacetrapib in Patients with Atherosclerotic Vascular Disease

BACKGROUND: Patients with atherosclerotic vascular disease remain at high risk for cardiovascular events despite effective statin-based treatment of low-density lipoprotein (LDL) cholesterol levels. The inhibition of cholesteryl ester transfer protein (CETP) by anacetrapib reduces LDL cholesterol levels and increases high-density lipoprotein (HDL) cholesterol levels. However, trials of other CETP inhibitors have shown neutral or adverse effects on cardiovascular outcomes. METHODS: We conducted a randomized, double-blind, placebo-controlled trial involving 30,449 adults with atherosclerotic vascular disease who were receiving intensive atorvastatin therapy and who had a mean LDL cholesterol level of 61 mg per deciliter (1.58 mmol per liter), a mean non-HDL cholesterol level of 92 mg per deciliter (2.38 mmol per liter), and a mean HDL cholesterol level of 40 mg per deciliter (1.03 mmol per liter). The patients were assigned to receive either 100 mg of anacetrapib once daily (15,225 patients) or matching placebo (15,224 patients). The primary outcome was the first major coronary event, a composite of coronary death, myocardial infarction, or coronary revascularization. RESULTS: During the median follow-up period of 4.1 years, the primary outcome occurred in significantly fewer patients in the anacetrapib group than in the placebo group (1640 of 15,225 patients [10.8%] vs. 1803 of 15,224 patients [11.8%]; rate ratio, 0.91; 95% confidence interval, 0.85 to 0.97; P=0.004). The relative difference in risk was similar across multiple prespecified subgroups. At the trial midpoint, the mean level of HDL cholesterol was higher by 43 mg per deciliter (1.12 mmol per liter) in the anacetrapib group than in the placebo group (a relative difference of 104%), and the mean level of non-HDL cholesterol was lower by 17 mg per deciliter (0.44 mmol per liter), a relative difference of -18%. There were no significant between-group differences in the risk of death, cancer, or other serious adverse events. CONCLUSIONS: Among patients with atherosclerotic vascular disease who were receiving intensive statin therapy, the use of anacetrapib resulted in a lower incidence of major coronary events than the use of placebo. (Funded by Merck and others; Current Controlled Trials number, ISRCTN48678192 ; ClinicalTrials.gov number, NCT01252953 ; and EudraCT number, 2010-023467-18 .)

BacHBerry: BACterial Hosts for production of Bioactive phenolics from bERRY fruits

BACterial Hosts for production of Bioactive phenolics from bERRY fruits (BacHBerry) was a 3-year project funded by the Seventh Framework Programme (FP7) of the European Union that ran between November 2013 and October 2016. The overall aim of the project was to establish a sustainable and economically-feasible strategy for the production of novel high-value phenolic compounds isolated from berry fruits using bacterial platforms. The project aimed at covering all stages of the discovery and pre-commercialization process, including berry collection, screening and characterization of their bioactive components, identification and functional characterization of the corresponding biosynthetic pathways, and construction of Gram-positive bacterial cell factories producing phenolic compounds. Further activities included optimization of polyphenol extraction methods from bacterial cultures, scale-up of production by fermentation up to pilot scale, as well as societal and economic analyses of the processes. This review article summarizes some of the key findings obtained throughout the duration of the project

Search for eccentric black hole coalescences during the third observing run of LIGO and Virgo

Despite the growing number of confident binary black hole coalescences observed through gravitational waves so far, the astrophysical origin of these binaries remains uncertain. Orbital eccentricity is one of the clearest tracers of binary formation channels. Identifying binary eccentricity, however, remains challenging due to the limited availability of gravitational waveforms that include effects of eccentricity. Here, we present observational results for a waveform-independent search sensitive to eccentric black hole coalescences, covering the third observing run (O3) of the LIGO and Virgo detectors. We identified no new high-significance candidates beyond those that were already identified with searches focusing on quasi-circular binaries. We determine the sensitivity of our search to high-mass (total mass M&gt;70 M⊙) binaries covering eccentricities up to 0.3 at 15 Hz orbital frequency, and use this to compare model predictions to search results. Assuming all detections are indeed quasi-circular, for our fiducial population model, we place an upper limit for the merger rate density of high-mass binaries with eccentricities 0&lt;e≤0.3 at 0.33 Gpc−3 yr−1 at 90\% confidence level