Recombinant Flag-tagged E1E2 glycoproteins from three hepatitis C virus genotypes are biologically functional and elicit cross-reactive neutralizing antibodies in mice

Hepatitis C virus (HCV) is a globally disseminated human pathogen for which no vaccine is currently available. HCV is highly diverse genetically and can be classified into 7 genotypes and multiple sub-types. Due to this antigenic variation, the induction of cross-reactive and at the same time neutralizing antibodies is a challenge in vaccine production. Here we report the analysis of immunogenicity of recombinant HCV envelope glycoproteins from genotypes 1a, 1b and 2a, with a Flag tag inserted in the hypervariable region 1 of E2. This modification did not affect protein expression or conformation or its capacity to bind the crucial virus entry factor, CD81. Importantly, in immunogenicity studies on mice, the purified E2-Flag mutants elicited high-titer, cross-reactive antibodies that were able to neutralize HCV infectious particles from two genotypes tested (1a and 2a). These findings indicate that E1E2-Flag envelope glycoproteins could be important immunogen candidates for vaccine aiming to induce broad HCV-neutralizing responses

Temporal and spatiotemporal autocorrelation of daily concentrations of Alnus, Betula, and Corylus pollen in Poland

The aim of the study was to determine the characteristics of temporal and space–time autocorrelation of pollen counts of Alnus, Betula, and Corylus in the air of eight cities in Poland. Daily average pollen concentrations were monitored over 8 years (2001–2005 and 2009–2011) using Hirst-designed volumetric spore traps. The spatial and temporal coherence of data was investigated using the autocorrelation and cross-correlation functions. The calculation and mathematical modelling of 61 correlograms were performed for up to 25 days back. The study revealed an association between temporal variations in Alnus, Betula, and Corylus pollen counts in Poland and three main groups of factors such as: (1) air mass exchange after the passage of a single weather front (30–40 % of pollen count variation); (2) long-lasting factors (50–60 %); and (3) random factors, including diurnal variations and measurements errors (10 %). These results can help to improve the quality of forecasting models

Resistance to autosomal dominant Alzheimer's disease in an APOE3 Christchurch homozygote: a case report.

We identified a PSEN1 (presenilin 1) mutation carrier from the world's largest autosomal dominant Alzheimer's disease kindred, who did not develop mild cognitive impairment until her seventies, three decades after the expected age of clinical onset. The individual had two copies of the APOE3 Christchurch (R136S) mutation, unusually high brain amyloid levels and limited tau and neurodegenerative measurements. Our findings have implications for the role of APOE in the pathogenesis, treatment and prevention of Alzheimer's disease

Validation of salivary uric acid remote self-monitoring for early prediction of hypertensive disorders of pregnancy: study protocol for a prospective, observational, multicentre cohort study

Introduction Hypertensive disorders of pregnancy (HDP), including gestational hypertension and pre-eclampsia, affect approximately 10% of pregnancies worldwide and contribute significantly to fetal and maternal morbidity and mortality. Early identification of HDP would facilitate targeted surveillance and personalised care in order to mitigate the severity of complications and improve pregnancy outcomes. Uric acid is a marker of oxidative stress, inflammation and endothelial dysfunction, and has been proposed as a predictor of hypertensive disease. Salurate is a salivary uric acid test that has the potential to identify pregnant women at risk of developing HDP several weeks before clinical manifestation. Methods and analysis This is a prospective, multicentre, observational, cohort study with health economics evaluation. Women aged 16 and above, with a viable singleton pregnancy at <16 weeks gestation and a combined first trimester pre-eclampsia risk of >1:300 will be eligible for recruitment. Participants will perform weekly remote salivary uric acid testing from enrolment until the conclusion of pregnancy and upload results of colourimetric paper tests via a smartphone application. We will validate a predictive algorithm that analyses colour data from several consecutive samples to detect patterns that predict whether HDP is likely to occur. The primary outcome is test performance for the prediction of HDP. Secondary outcomes include adherence to sampling and test performance for predicting gestational diabetes, stillbirth and fetal growth restriction. Data on pregnancy outcomes will be collected from the medical notes, compared with the predictions made by the algorithm and subjected to statistical analysis. Ethics and dissemination Approval has been obtained from Cambridge East Research Ethics Committee (REC reference 24/EE/0123), Medicines and Healthcare products Regulatory Agency (CI/2024/0038/GB) and Health Research Authority (IRAS ID 337290). Results of the study will be published in peer-reviewed journals and presented at national and international conferences. Trial registration number ISRCTN17992452. Protocol version 4, 4 July 2024

Why Are Outcomes Different for Registry Patients Enrolled Prospectively and Retrospectively? Insights from the Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF).

Background: Retrospective and prospective observational studies are designed to reflect real-world evidence on clinical practice, but can yield conflicting results. The GARFIELD-AF Registry includes both methods of enrolment and allows analysis of differences in patient characteristics and outcomes that may result. Methods and Results: Patients with atrial fibrillation (AF) and ≥1 risk factor for stroke at diagnosis of AF were recruited either retrospectively (n = 5069) or prospectively (n = 5501) from 19 countries and then followed prospectively. The retrospectively enrolled cohort comprised patients with established AF (for a least 6, and up to 24 months before enrolment), who were identified retrospectively (and baseline and partial follow-up data were collected from the emedical records) and then followed prospectively between 0-18 months (such that the total time of follow-up was 24 months; data collection Dec-2009 and Oct-2010). In the prospectively enrolled cohort, patients with newly diagnosed AF (≤6 weeks after diagnosis) were recruited between Mar-2010 and Oct-2011 and were followed for 24 months after enrolment. Differences between the cohorts were observed in clinical characteristics, including type of AF, stroke prevention strategies, and event rates. More patients in the retrospectively identified cohort received vitamin K antagonists (62.1% vs. 53.2%) and fewer received non-vitamin K oral anticoagulants (1.8% vs . 4.2%). All-cause mortality rates per 100 person-years during the prospective follow-up (starting the first study visit up to 1 year) were significantly lower in the retrospective than prospectively identified cohort (3.04 [95% CI 2.51 to 3.67] vs . 4.05 [95% CI 3.53 to 4.63]; p = 0.016). Conclusions: Interpretations of data from registries that aim to evaluate the characteristics and outcomes of patients with AF must take account of differences in registry design and the impact of recall bias and survivorship bias that is incurred with retrospective enrolment. Clinical Trial Registration: - URL: http://www.clinicaltrials.gov . Unique identifier for GARFIELD-AF (NCT01090362)

Impact of hypertensive disorders on disease progression in pregnancies affected by early‐onset fetal growth restriction

Introduction Fetal growth restriction is a leading cause of perinatal morbidity, often linked to placental insufficiency. Hypertensive disorders frequently coexist with fetal growth restriction and may alter its clinical course. The objective of this study is to examine how hypertensive disorders influence the onset, progression, and timing of birth in pregnancies affected by fetal growth restriction. Secondary outcomes were indications for delivery and neonatal outcomes. Material and Methods A retrospective cohort study of pregnancies diagnosed with fetal growth restriction prior to 36 weeks' gestation and monitored under the TRUFFLE protocol between January 2013 and July 2024 at a tertiary fetal medicine unit in the UK. Pregnancies were stratified by maternal blood pressure status: normotensive, hypertensive disorder of pregnancy, or preexisting chronic hypertension. Clinical characteristics, antenatal surveillance findings, delivery indications, and neonatal outcomes were compared between groups. Results One hundred and ninety‐six singleton pregnancies met the inclusion criteria. 68% of the cohort were affected by chronic hypertension or new‐onset hypertensive disorders of pregnancy. Hypertensive pregnancies had significantly shorter intervals from fetal growth restriction diagnosis to delivery (9 days (IQR 5–19) for chronic hypertension, 12 days (IQR 3–24) for hypertensive disorders of pregnancy, 23 days (IQR 8–35) in normotensive pregnancies (p = 0.001)) and earlier gestational age at delivery (29 + 5 weeks (IQR 27 + 3–32 + 3) for chronic hypertension and 30 + 5 weeks (IQR 28 + 4–32 + 6) for hypertensive disorders of pregnancy — versus 32 + 0 weeks (IQR 29 + 1–33 + 6) in normotensive cases; p = 0.023). A higher proportion of hypertensive pregnancies were delivered for maternal indications (37.5% hypertensive disorders of pregnancy, 39.5% chronic hypertension) compared to 14.5% in normotensive pregnancies (p = 0.004), while normotensive pregnancies were more frequently delivered due to abnormal umbilical artery Dopplers (29.0% vs. 14.6% hypertensive disorders of pregnancy, 13.2% chronic hypertension; p = 0.041). Neonates of mothers with chronic hypertension had higher birthweight centiles (p = 0.004), but neonatal outcomes were comparable across all groups. Conclusions Incidence of hypertension in the context of fetal growth restriction significantly impacts timing and gestational age of delivery and birthweight centile. An integrated approach to combine maternal and fetal monitoring in these pregnancies is required to optimize birth outcomes

Considerations for a European animal welfare standard to evaluate adverse phenotypes in teleost fish

No abstract available

Quest for barley canopy architecture genes in the hortillus population and whealbi germplasm collection

Barley grains are predominantly used for animal feed and malting, and breeding traditionally focused on increase of grain yield by partitioning biomass from straw to grains. The increasing demand for renewable energy sources makes straw, and specially barley straw characterized by the largest content of carbohydrates among the cereals, a valuable product for its potential conversion into biofuels and other products. The BarPLUS project aims at finding genes, alleles and candidate lines related to barley canopy architecture and photosynthesis, to maximize barley biomass and yield (https://barplus.wordpress.com/). In this framework, our research group focuses on identifying genes and alleles controlling tillering, leaf size and leaf angle traits in barley by exploiting both induced and natural allelic variation. Using a forward genetics approach, we screened the HorTILLUS population (Szurman-Zubrzycka et al., 2018) under both field and controlled conditions, identifying 5 mutants with increased tillering and/or erect leaves. After crossing with four reference cultivars, pools of F2 wild-type and mutant plants were selected to map and identify the underlying genes by exome sequencing (Mascher et al., 2014). In parallel, TILLING of the HorTILLUS population identified four lines carrying mutations in the LBO (Lateral branching oxidoreductase) gene involved in tiller number. In order to explore also natural genetic variation, we are taking advantage of the \u2018WHEALBI\u2019 germplasm collection, which includes 403 exome sequenced diverse accessions (BustosKorts et al., 2019): a field trial on a subset of 240 lines (Fiorenzuola d\u2019Arda, Italy) allowed us to conduct a preliminary genome wide association study based on high-throughput phenotyping for leaf angle (PocketPlant3D smartphone app) and quantitative image-analysis for leaf size. Results will be compared with those from a greenhouse experiment on the same 240 accessions to analyze a wide range of morphological traits and identify associated markers and genomic regions

Exploring natural and induced variations for the genetic improvement of barley biomass and yield

With the increasing demands for renewable energy sources, plant biomass such as cereal straw is becoming more attractive. The BarPLUS project aims at finding genes, alleles, and candidate lines related to barley architecture and photosynthesis to maximize barley biomass and yield (https://barplus.wordpress.com/). The major focus of our research group is to identify genes and alleles controlling tillering, leaf size and angle exploiting both induced and natural allelic variation. Using a forward genetics approach, we screened the HorTillus population derived from chemical mutagenesis of the barley cultivar “Sebastian” under both field and controlled conditions and identified mutants with increased tillering and/or erect leaves. The selected candidate lines were crossed with two reference cultivars and the mapping populations are being targeted for mapping- by-sequencing to isolate the underlying genes. We also utilized genome wide association on a set of 240 diverse barley accessions with exome capture data provided by the WHEALBI consortium (http://www.whealbi.eu/) in order to dissect natural allelic variation in leaf size and angle. Data were collected from the WHEALBI field trial for precision phenotyping of canopy development (Fiorenzuola d’Arda, Italy). High-throughput protocols based on the PocketPlant3D smartphone app for leaf angle and quantitative image-analysis for leaf size were exploited. Strong positive correlations were observed between leaf size parameters. In addition, leaf width and area had moderate to weak negative correlations with leaf angle, respectively. Noteworthy, 6-row barleys had higher values than 2-row barleys for leaf size parameters whereas leaf angle was higher in 2- row barleys, indicating the effect of row-type on the traits. High heritability values supported the existence of genetic factors for both traits, and several markers potentially associated with leaf size and angle were detected and are under evaluation for validation and analysis of potential candidate genes. In parallel, based on previous knowledge in model plants, a total of 48 candidate genes involved in canopy architecture and photosynthesis were selected for allele mining analyses. Taking advantage of WHEALBI exome capture data, in silico analysis of the corresponding sequences revealed the presence of several variants with potential effects on protein function. Finally, using reverse genetics approach, we targeted a subset of candidate genes for TILLING and identified several interesting mutations: the candidate lines are currently growing under controlled condition to confirm their phenotypes. Together, this research will provide valuable knowledge and resources for potential improvement of barley biomass and yield

Patient-reported outcomes in CodeBreaK 200 : Sotorasib versus docetaxel for previously treated advanced NSCLC with KRAS G12C mutation

In the CodeBreaK 200 phase III, open-label trial, sotorasib significantly improved efficacy versus docetaxel in previously treated KRAS G12C-mutated advanced non-small cell lung cancer (NSCLC). Patient-reported outcomes (PROs) for global health status, physical functioning, dyspnea, and cough favored sotorasib over docetaxel. Here, we report sotorasib's additional impact on quality of life (QOL). In CodeBreaK 200, 345 patients who had progressed after prior therapy received sotorasib (960 mg orally daily) or docetaxel (75 mg/m intravenously every 3 weeks). Validated questionnaires captured patients' perception of their QOL and symptom burden for key secondary and exploratory PRO endpoints, including the European Organisation for Research and Treatment of Cancer Quality-of-life Questionnaire Core 30 (EORTC QLQ-C30) and Quality-of-life Questionnaire Lung Cancer 13 (EORTC QLQ-LC13), question GP5 from the Functional Assessment of Cancer Therapy Tool General Form (FACT-G GP5), PRO-Common Terminology Criteria for Adverse Events (PRO-CTCAE), and 5-level EuroQOL-5 dimensions (EQ-5D-5L) including visual analog scale (EQ-5D VAS). Change from baseline to week 12 was assessed with generalized estimating equations for ordinal outcomes. Patients receiving sotorasib were less bothered by treatment side effects than those receiving docetaxel (odds ratio [OR] 5.7) and experienced symptoms at lower severity (pain: OR 2.9; aching muscles: OR 4.4; aching joints: OR 4.2; mouth or throat sores: OR 4.3). Further, patients' symptoms interfered less with usual/daily activities (pain: OR 3.2; aching muscles: OR 3.9; aching joints: OR 10.7). QOL remained stable with sotorasib but worsened with docetaxel (change from baseline in EQ-5D VAS score: 1.5 vs -8.4 at cycle 1 day 5 and 2.2 vs -5.8 at week 12). Patients receiving sotorasib reported less severe symptoms than those receiving docetaxel. In addition to improving clinical efficacy outcomes, sotorasib maintained QOL versus docetaxel, suggesting sotorasib may be a more tolerable treatment option for patients with pretreated, KRAS G12C-mutated advanced NSCLC