This integrated analysis reveals a deep impact of the timing between immunizations, and highlights the importance of early but also late innate responses involving phenotypical changes, in shaping humoral immunity.Rift Valley fever virus (RVFV) is a mosquito-borne bunyavirus that causes severe and recurrent outbreaks on the African continent and the Arabian Peninsula and continues to expand its habitat. RVFV induces severe disease in newborns and abortion in pregnant ruminants. The viral genome consists of a small (S), medium (M) and large (L) RNA segment of negative polarity. The M segment encodes a glycoprotein precursor protein that is co-translationally cleaved into the two structural glycoproteins Gn and Gc, which are involved in receptor attachment and cell entry. We previously constructed a four-segmented RVFV (RVFV-4s) by splitting the M genome segment into two M-type segments encoding either Gn or Gc. RVFV-4s replicates efficiently in cell culture but was shown to be completely avirulent in mice, lambs and pregnant ewes. Here, we show that a RVFV-4s candidate vaccine for veterinary use (vRVFV-4s) does not disseminate in vaccinated animals, is not shed or spread to the environment and does not revert to virulence. Furthermore, a single vaccination of lambs, goat kids and calves was shown to induce protective immunity against a homologous challenge. Finally, the vaccine was shown to provide full protection against a genetically distinct RVFV strain. Altogether, we demonstrate that vRVFV-4s optimally combines efficacy with safety, holding great promise as a next-generation RVF vaccine.The ventricular arrhythmia (VA)-chronic obstructive pulmonary disease (COPD) association and related risk factors remain unclear. Using 2001-2012 data from National Health Insurance Research Database, we retrospectively reviewed 71,838 patients diagnosed as having COPD and 71,838 age- and sex-matched controls. After adjustments for comorbidities, medication, urbanization level, and monthly income, patients with COPD had higher incidence rates of VA than did the controls (adjusted hazard ratio [aHR] [95% confidence interval (CI)] 1.45 [1.25-1.68]). More hospitalization or emergency visits because of acute COPD exacerbation (aHRs [95% CIs] for first, second, and third visits 1.28 [1.08-1.50], 1.75 [1.32-2.32], and 1.88 [1.46-2.41], respectively) and asthma-COPD overlap (aHR [95% CI] 1.49 [1.25-1.79]) were associated with high VA risk in patients with COPD. In the multivariate analysis, heart failure (aHR [95% CI] 2.37 [1.79-3.14]), diabetes (aHR [95% CI]1.64 [1.29-2.08]), age ≥75 (aHR [95% CI] 2.48 [1.68-3.67]), male (aHR [95% CI] 1.69[1.34-2.12]), and class III antiarrhythmic drug use (aHR [95% CI] 2.49 [1.88-3.28]) are the most significant risk factors of new onset of VA in patients with COPD.The RSV Fusion (F) protein is a target for neutralizing antibody responses and is a focus for vaccine discovery; however, the process of RSV entry requires F to adopt a metastable prefusion form and transition to a more stable postfusion form, which displays less potent neutralizing epitopes. mRNA vaccines encode antigens that are translated by host cells following vaccination, which may allow conformational transitions similar to those observed during natural infection to occur. Here we evaluate a panel of chemically modified mRNA vaccines expressing different forms of the RSV F protein, including secreted, membrane associated, prefusion-stabilized, and non-stabilized structures, for conformation, immunogenicity, protection, and safety in rodent models. Vaccination with mRNA encoding native RSV F elicited antibody responses to both prefusion- and postfusion-specific epitopes, suggesting that this antigen may adopt both conformations in vivo. Incorporating prefusion stabilizing mutations further shifts the immune response toward prefusion-specific epitopes, but does not impact neutralizing antibody titer. https://www.selleckchem.com/Androgen-Receptor.html mRNA vaccine candidates expressing either prefusion stabilized or native forms of RSV F protein elicit robust neutralizing antibody responses in both mice and cotton rats, similar to levels observed with a comparable dose of adjuvanted prefusion stabilized RSV F protein. In contrast to the protein subunit vaccine, mRNA-based vaccines elicited robust CD4+ and CD8+ T-cell responses in mice, highlighting a potential advantage of the technology for vaccines requiring a cellular immune response for efficacy.The gold-standard cognitive-behavioral therapy (CBT) for psychosis offers at best modest effects. With advances in technology, virtual reality (VR) therapies for auditory verbal hallucinations (AVH), such as AVATAR therapy (AT) and VR-assisted therapy (VRT), are amid a new wave of relational approaches that may heighten effects. Prior trials have shown greater effects of these therapies on AVH up to a 24-week follow-up. However, no trial has compared them to a recommended active treatment with a 1-year follow-up. We performed a pilot randomized comparative trial evaluating the short- and long-term efficacy of VRT over CBT for patients with treatment-resistant schizophrenia. Patients were randomized to VRT (n = 37) or CBT (n = 37). Clinical assessments were administered before and after each intervention and at follow-up periods up to 12 months. Between and within-group changes in psychiatric symptoms were assessed using linear mixed-effects models. Short-term findings showed that both interventions produced significant improvements in AVH severity and depressive symptoms. Although results did not show a statistically significant superiority of VRT over CBT for AVH, VRT did achieve larger effects particularly on overall AVH (d = 1.080 for VRT and d = 0.555 for CBT). Furthermore, results suggested a superiority of VRT over CBT on affective symptoms. VRT also showed significant results on persecutory beliefs and quality of life. Effects were maintained up to the 1-year follow-up. VRT highlights the future of patient-tailored approaches that may show benefits over generic CBT for voices. A fully powered single-blind randomized controlled trial comparing VRT to CBT is underway.