Breathing Exercises for Patients with Asthma in Specialist Care:A Multicenter Randomized Clinical Trial

RATIONALE: Moderate to severe asthma is associated with impaired asthma control and quality of life (QoL) despite access to specialist care and modern pharmacotherapy. Breathing exercises (BrEX) improve QoL in incompletely controlled mild asthma, but impact in moderate to severe asthma is unknown. OBJECTIVES: To investigate the effectiveness of BrEX as adjuvant treatment on QoL in patients with uncontrolled moderate to severe asthma. METHODS: Adult patients with incompletely controlled asthma attending respiratory specialist clinics were randomized to usual specialist care (UC) or UC and BrEX (UC + BrEX) with three individual physiotherapist-delivered sessions and home exercises. Primary outcome was asthma-related QoL (Mini-Asthma Quality of Life Questionnaire [Mini-AQLQ]) at 6 months on the basis of intention-to-treat analysis. Secondary outcomes: Mini-AQLQ at 12 months, lung function, 6-minute-walk test, physical activity level, Nijmegen Questionnaire, Hospital Anxiety and Depression Scale, and adverse events. Repeated-measures mixed-effects models were used to analyze data. Poisson regression models were used to analyze adverse event incidence rate ratio. RESULTS: A total of 193 participants were allocated to UC + BrEX (n = 94) or UC (n = 99). UC + BrEX was superior in the primary outcome (adjusted mean change difference, 0.35; 95% confidence interval [CI], 0.07 to 0.62). Superiority in Mini-AQLQ was sustained at 12 months (0.38; 95% CI, 0.12 to 0.65). A minor improvement in Hospital Anxiety and Depression Scale depression score at 6 months favoring UC + BrEX (−0.90; 95% CI, −1.67 to −0.14) was observed. Asthma-related adverse events occurred similarly in UC + BrEX and UC participants: 14.9% versus 18.1% (P = 0.38). CONCLUSIONS: BrEX as add-on to usual care improve asthma-related QoL in incompletely controlled asthma regardless of severity and with no evidence of harm. Clinical trial registered with www.clinicaltrials.gov (NCT 03127059)

Social disconnectedness, loneliness, and mental health among adolescents in Danish high schools : a nationwide cross-sectional study

Background: Previous research has suggested that social disconnectedness experienced at school is linked to mental health problems, however, more research is needed to investigate (1) whether the accumulation of various types of social disconnectedness is associated with risk for mental health problems, and (2) whether loneliness is a mechanism that explains these associations. Methods: Using data from the Danish National Youth Study 2019 (UNG19), nation-wide cross-sectional data from 29,086 high school students in Denmark were analyzed to assess associations between social disconnectedness experienced at school (lack of classmate support, lack of teacher support, lack of class social cohesion, and not being part of the school community) and various mental health outcomes, as well as the mediating role of loneliness for each type of disconnectedness. Multilevel regression analyses were conducted to assess the associations. Results: Descriptive analyses suggest that 27.5% of Danish high school students experience at least one type of social disconnectedness at school. Each type of social disconnectedness was positively associated with mental health problems (depression symptoms, anxiety symptoms, stress, sleep problems, suicidal ideation, non-suicidal self-injury, eating disorder, body dissatisfaction, and low self-esteem) and negatively associated with mental well-being. In all cases, loneliness significantly mediated the associations. We found a clear dose-response pattern, where each addition in types of social disconnectedness was associated with (1) stronger negative coefficients with mental well-being and (2) stronger positive coefficients with mental health problems. Conclusion: Our results add to a large evidence-base suggesting that mental health problems among adolescents may be prevented by promoting social connectedness at school. More specifically, fostering social connectedness at school may prevent loneliness, which in turn may promote mental well-being and prevent mental health problems during the developmental stages of adolescence. It is important to note that focusing on single indicators of school social connectedness/disconnectedness would appear to be insufficient. Implications for practices within school settings to enhance social connectedness are discussed

Peptide-oligonucleotide conjugates as nanoscale building blocks for assembly of an artificial three-helix protein mimic

Peptide-based structures can be designed to yield artificial proteins with specific folding patterns and functions. Template-based assembly of peptide units is one design option, but the use of two orthogonal self-assembly principles, oligonucleotide triple helix and a coiled coil protein domain formation have never been realized for de novo protein design. Here, we show the applicability of peptide–oligonucleotide conjugates for self-assembly of higher-ordered protein-like structures. The resulting nano-assemblies were characterized by ultraviolet-melting, gel electrophoresis, circular dichroism (CD) spectroscopy, small-angle X-ray scattering and transmission electron microscopy. These studies revealed the formation of the desired triple helix and coiled coil domains at low concentrations, while a dimer of trimers was dominating at high concentration. CD spectroscopy showed an extraordinarily high degree of α-helicity for the peptide moieties in the assemblies. The results validate the use of orthogonal self-assembly principles as a paradigm for de novo protein design

A brain-targeting lipidated peptide for neutralizing RNA-mediated toxicity in Polyglutamine Diseases

Abstract Polyglutamine (PolyQ) diseases are progressive neurodegenerative disorders caused by both protein- and RNA-mediated toxicities. We previously showed that a peptidyl inhibitor, P3, which binds directly to expanded CAG RNA can inhibit RNA-induced nucleolar stress and suppress RNA-induced neurotoxicity. Here we report a N-acetylated and C-amidated derivative of P3, P3V8, that showed a more than 20-fold increase in its affinity for expanded CAG RNA. The P3V8 peptide also more potently alleviated expanded RNA-induced cytotoxicity in vitro, and suppressed polyQ neurodegeneration in Drosophila with no observed toxic effects. Further N-palmitoylation of P3V8 (L1P3V8) not only significantly improved its cellular uptake and stability, but also facilitated its systemic exposure and brain uptake in rats via intranasal administration. Our findings demonstrate that concomitant N-acetylation, C-amidation and palmitoylation of P3 significantly improve both its bioactivity and pharmacological profile. L1P3V8 possesses drug/lead-like properties that can be further developed into a lead inhibitor for the treatment of polyQ diseases

Genetic and antigenic characterization of complete genomes of Type 1 Porcine Reproductive and Respiratory Syndrome viruses (PRRSV) isolated in Denmark over a period of 10 years

AbstractPorcine Reproductive and Respiratory Syndrome (PRRS) caused by the PRRS virus (PRRSV) is considered one of the most devastating swine diseases worldwide. PRRS viruses are divided into two major genotypes, Type 1 and Type 2, with pronounced diversity between and within the genotypes. In Denmark more than 50% of the herds are infected with Type 1 and/or Type 2 PRRSV. The main objective of this study was to examine the genetic diversity and drift of Type 1 viruses in a population with limited introduction of new animals and semen. A total of 43 ORF5 and 42 ORF7 nucleotide sequences were obtained from viruses collected from 2003 to February 2013. Phylogenetic analysis of ORF5 nucleotide sequences showed that the Danish isolates formed two major clusters within the subtype 1. The nucleotide identity to the subtype 1 protogenotype Lelystad virus (LV) spanned 84.9–98.8% for ORF5 and 90.7–100% for ORF7. Among the Danish viruses the pairwise nucleotide identities in ORF5 and ORF7 were 81.2–100% and 88.9–100%, respectively. Sequencing of the complete genomes, including the 5′- and 3′-end nucleotides, of 8 Danish PRRSV Type 1 showed that the genome lengths differed from 14,876 to 15,098 nucleotides and the pairwise nucleotide identity among the Danish viruses was 86.5–97.3% and the identity to LV was 88.7–97.9%. The study strongly indicated that there have been at least two independent introductions of Type 1 PRRSV in Denmark and analysis of the full genomes revealed a significant drift in several regions of the virus