Phage therapy combats pan drug-resistant Acinetobacter baumannii infection safely and efficiently.

Phage therapy offers a promising approach to combat the growing threat of antimicrobial resistance. Yet, key questions remain regarding dosage, administration routes, combination therapy, and the causes of therapeutic failure. In this study, we focused on a novel lytic phage, ФAb4B, which specifically targeted the Acinetobacter baumannii strains with KL160 capsular polysaccharide, including the pan-drug resistant A. baumannii YQ4. ФAb4B exhibited the ability to effectively inhibit biofilm formation and eradicate mature biofilms independently of dosage. Additionally, it demonstrated a wide spectrum of antibiotic-phage synergy and did not show any cytotoxic or haemolytic effects. Continuous phage injections, both intraperitoneally and intravenously over 7 d, showed no acute toxicity in vivo. Importantly, phage therapy significantly improved neutrophil counts, outperforming ciprofloxacin. However, excessive phage injections suppressed neutrophil levels. The combinatorial treatment of phage-ciprofloxacin rescued 91% of the mice, a superior outcome compared to phage alone (67%). The efficacy of the combinatorial treatment was independent of phage dosage. Notably, prophylactic administration of the combinatorial regimen provided no protection, but even when combined with a delayed therapeutic regimen, it saved all the mice. Bacterial resistance to the phage was not a contributing factor to treatment failure. Our preclinical study systematically describes the lytic phage's effectiveness in both in vitro and in vivo settings, filling in crucial details about phage treatment against bacteriemia caused by A. baumannii, which will provide a robust foundation for the future of phage therapy.

Engineered endolysin of Klebsiella pneumoniae phage is a potent and broad-spectrum bactericidal agent against "ESKAPEE" pathogens.

The rise of antimicrobial resistance in ESKAPEE pathogens poses significant clinical challenges, especially in polymicrobial infections. Bacteriophage-derived endolysins offer promise in combating this crisis, but face practical hurdles. Our study focuses on engineering endolysins from a Klebsiella pneumoniae phage, fusing them with ApoE23 and COG133 peptides. We assessed the resulting chimeric proteins' bactericidal activity against ESKAPEE pathogens in vitro. ApoE23-Kp84B (CHU-1) reduced over 3 log units of CFU for A. baumannii, E. faecalis, K. pneumoniae within 1 h, while COG133-Kp84B (CHU-2) showed significant efficacy against S. aureus. COG133-L1-Kp84B, with a GS linker insertion in CHU-2, exhibited outstanding bactericidal activity against E. cloacae and P. aeruginosa. Scanning electron microscopy revealed alterations in bacterial morphology after treatment with engineered endolysins. Notably, CHU-1 demonstrated promising anti-biofilm and anti-persister cell activity against A. baumannii and E. faecalis but had limited efficacy in a bacteremia mouse model of their coinfection. Our findings advance the field of endolysin engineering, facilitating the customization of these proteins to target specific bacterial pathogens. This approach holds promise for the development of personalized therapies tailored to combat ESKAPEE infections effectively.

High-toughness, extensile and self-healing PDMS elastomers constructed by decuple hydrogen bonding.

Elastomers are widely used in traditional industries and new intelligent fields. However, they are inevitably damaged by electricity, heat, force, etc. during the working process. With the continuous improvement of reliability and environmental protection requirements in human production and living, it is vital to develop elastomer materials with good mechanical properties that are not easily damaged and can self-heal after being damaged. Nevertheless, there are often contradictions between mechanical properties and self-healing as well as toughness, strength, and ductility. Herein, a strong and dynamic decuple hydrogen bonding based on carbon hydrazide (CHZ) is reported, accompanied with soft polydimethylsiloxane (PDMS) chains to prepare self-healing (efficiency 98.7%), recyclable, and robust elastomers (CHZ-PDMS). The strategy of decuple hydrogen bonding will significantly impact the study of the mechanical properties of elastomers. High stretchability (1731%) and a high toughness of 23.31 MJ m-3 are achieved due to the phase-separated structure and energy dissipation. The recyclability of CHZ-PDMS further supports the concept of environmental protection. The application of CHZ-PDMS as a flexible strain sensor exhibited high sensitivity.

Hyperglycemia promotes myocardial dysfunction via the ERS-MAPK10 signaling pathway in db/db mice.

Recent studies have demonstrated that hyperglycemia is a major risk factor for the development and exacerbation of cardiovascular disease (CVD). However, the molecular mechanisms involved in diabetic cardiomyopathy (DCM) have not been fully elucidated. In this study, we focused on the underlying mechanism of DCM. Leptin receptor-deficient db/db mice were used to model a type 2 diabetes mellitus (T2DM) model in our study. WT mice and db/db mice received 4-phenylbutyric acid (4-PBA) (25 mg/kg/day) and saline by intraperitoneal injection every other day for 4 weeks. WT and db/db mice were given tail vein injections of 100 µL of rAAV9-Sh-MAPK10 and rAAV9-Sh-GFP at the age of 6-8 weeks. Echocardiography was performed to measure cardiac function, histological examinations were used to evaluate ventricular hypertrophy and fibrosis. Quantitative RT-qPCR was used to assess the mRNA expression of Jun N-terminal kinase 3 (JNK3, MAPK10), atrial natriuretic factor (ANF), brain natriuretic peptide (BNP), and collagen I and III. Immunoblotting was performed to measure the levels of cardiac hypertrophy-related proteins, fibrosis-related proteins, endoplasmic reticulum stress (ERS)-related proteins and apoptosis-related proteins. TUNEL staining was performed to examine cardiomyocyte apoptosis. In contrast to 12-week-old db/db mice, 16-week-old db/db mice showed the most severe myocardial dysfunction. The DCM induced by hyperglycemia was largely alleviated by 4-PBA (25 mg/kg/day, intraperitoneal injection). Similarly, tail vein injection of rAAV9-Sh-MAPK10 reversed the phenotype of the heart in db/db mice including cardiac hypertrophy and apoptosis in db/db mice. The mechanistic findings suggested that hyperglycemia initiated the ERS response through the negative regulation of sirtuin 1 (SIRT1), leading to the occurrence of myocardial dysfunction, and specific knockdown of MAPK10 in the heart directly reversed myocardial dysfunction induced by hyperglycemia. We demonstrated that hyperglycemia promotes DCM in db/db mice through the ERS-MAPK10 signaling pathway in diabetic mice.

Effectiveness of Telemonitoring for Reducing Exacerbation Occurrence in COPD Patients With Past Exacerbation History: A Systematic Review and Meta-Analysis.

Background: Although an increasing number of studies have reported that telemonitoring (TM) in patients with chronic obstructive pulmonary disease (COPD) can be useful and efficacious for hospitalizations and quality of life, its actual utility in detecting and managing acute exacerbation of COPD (AECOPD) is less established. This meta-analysis aimed to identify the best available evidence on the effectiveness of TM targeting the early and optimized management of AECOPD in patients with a history of past AECOPD compared with a control group without TM intervention. Methods: We systematically searched PubMed, Embase, and the Cochrane Library for randomized controlled trials published from 1990 to May 2020. Primary endpoints included emergency room visits and exacerbation-related readmissions. P-values, risk ratios, odds ratios, and mean differences with 95% confidence intervals were calculated. Results: Of 505 identified citations, 17 original articles with both TM intervention and a control group were selected for the final analysis (N = 3,001 participants). TM was found to reduce emergency room visits [mean difference (MD) -0.70, 95% confidence interval (CI) -1.36 to -0.03], exacerbation-related readmissions (risk ratio 0.74, 95% CI 0.60-0.92), exacerbation-related hospital days (MD -0.60, 95% CI -1.06 to -0.13), mortality (odds ratio 0.71, 95% CI 0.54-0.93), and the St. George's Respiratory Questionnaire (SGRQ) score (MD -3.72, 95% CI -7.18 to -0.26) but did not make a difference with respect to all-cause readmissions, the rate of exacerbation-related readmissions, all-cause hospital days, time to first hospital readmission, anxiety and depression, and exercise capacity. Furthermore, the subgroup analysis by observation period showed that longer TM (≥12 months) was more effective in reducing readmissions. Conclusions: TM can reduce emergency room visits and exacerbation-related readmissions, as well as acute exacerbation (AE)-related hospital days, mortality, and the SGRQ score. The implementation of TM intervention is thus a potential protective therapeutic strategy that could facilitate the long-term management of AECOPD. Systematic Review Registration: This systematic review and meta-analysis is reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement and was registered at International Prospective Register of Systematic Reviews (number: CRD42020181459).