SummaryIn metazoans, tissues experiencing proteotoxic stress induce “transcellular chaperone signaling” (TCS) that activates molecular chaperones, such as hsp-90, in distal tissues. How this form of inter-tissue communication is mediated to upregulate systemic chaperone expression and whether it can be utilized to protect against protein misfolding diseases remain open questions. Using C. elegans, we identified key components of a systemic stress signaling pathway that links the innate immune response with proteostasis maintenance. We show that mild perturbation of proteostasis in the neurons or the intestine activates TCS via the GATA zinc-finger transcription factor PQM-1. PQM-1 coordinates neuron-activated TCS via the innate immunity-associated transmembrane protein CLEC-41, whereas intestine-activated TCS depends on the aspartic protease ASP-12. Both TCS pathways can induce hsp-90 in muscle cells and facilitate amelioration of Aβ3-42-associated toxicity. This may have powerful implications for the treatment of diseases related to proteostasis dysfunction.

Background The cell-propagated inactivated quadrivalent influenza vaccine (ccIIV4) may offer improved protection in seasons where egg-derived influenza viruses undergo mutations that affect antigenicity. This study estimated the relative vaccine effectiveness (rVE) of ccIIV4 versus egg-derived inactivated quadrivalent influenza vaccine (eIIV4) in preventing influenza-related medical encounters in the 2018-2019 U.S. season. Methods A dataset linking primary care electronic medical records with medical claims data was used to conduct a retrospective cohort study among individuals ≥4 years vaccinated with ccIIV4 or eIIV4 during the 2018-2019 season. Adjusted odds ratios (ORs) were derived from a doubly robust inverse probability of treatment-weighted approach adjusting for age, sex, race, ethnicity, geographic region, vaccination week, and health status. Relative vaccine effectiveness (rVE) was estimated by (1-OR)*100 and presented with 95% confidence intervals (CI). Results Following the application of inclusion/exclusion criteria, the study cohort included 2,125,430 ccIIV4 and 8,000,903 eIIV4 recipients. Adjusted analyses demonstrated a greater reduction in influenza-related medical encounters with ccIIV4 versus eIIV4, with the following rVE: overall, 7.6% (95% CI 6.5-8.6); age 4-17 years, 3.9% (0.9-7.0); 18-64 years, 6.5% (5.2-7.9); 18-49 years, 7.5% (5.7-9.3); 50-64 years, 5.6% (3.6-7.6); and ≥65 years, -2.2% (-5.4 to 0.9). Conclusions Adjusted analyses demonstrated statistically significantly greater reduction in influenza-related medical encounters in individuals vaccinated with ccIIV4 vs eIIV4 in the 2018-2019 U.S. influenza season. These results support ccIIV4 as a potentially more effective public health measure against influenza than an egg-based equivalent.

Background The effectiveness of standard, egg-derived quadrivalent influenza vaccines (IIV4) may be reduced in adults ≥65 years of age, largely due to immunosenescence. An MF59®-adjuvanted trivalent influenza vaccine (aIIV3) and a high-dose trivalent influenza vaccine (HD-IIV3) offer older adults enhanced protection versus standard vaccines. This study compared the relative effectiveness of aIIV3 to IIV4 and HD-IIV3 in preventing influenza-related medical encounters over two US influenza seasons. Methods This retrospective cohort study included US patients ≥65 years vaccinated with aIIV3, IIV4, or HD-IIV3. The outcome of interest was the occurrence of influenza-related medical encounters. Data were derived from a large dataset comprised of primary and specialty care electronic medical records linked with pharmacy and medical claims. Adjusted odds ratios (OR) were derived from an inverse probability of treatment-weighted sample adjusted for age, sex, race, ethnicity, geographic region, vaccination week, and health status. Relative vaccine effectiveness (rVE) was determined using the formula (% VE =1-ORadjusted)*100. Results In 2017-2018, cohorts included: aIIV3, n=524,223; IIV4, n=917,609; HD-IIV3, n=3,377,860. After adjustment, 2017-2018 rVE of aIIV3 vs. IIV4 was 18.2 (95% confidence interval [CI] 15.8 to 20.5); aIIV3 vs. HD-IIV3 was 7.7 (2.3 to 12.8). In 2018-2019, cohorts included: aIIV3, n=1,031,145; IIV4, n=915,380; HD-IIV3, n=3,809,601, with adjusted rVEs of aIIV3 vs. IIV4 of 27.8 (25.7 to 29.9) and vs. HD-IIV3 of 6.9 (3.1 to 10.6). Conclusion In the 2017-2018 and 2018-2019 influenza seasons in the US, aIIV3 demonstrated greater reduction in influenza-related medical encounters than IIV4 and HD-IIV3 in adults ≥65 years.

We describe experiments and modeling for the deposition of silver lines and films via the impaction of a silver nanoparticle aerosol delivered through a supersonic jet. The aerosol gas dynamics of the jet flow field, nanoparticle acceleration in the jet, and deposition by impaction onto the substrate were modeled for both a flat-plate nozzle and for a conical nozzle designed to obtain higher impaction velocities. We modeled nanoparticle dynamics for He, Ar, and N2 gasses, all initially at room temperature and 1 atm pressure, flowing through a 250 μm orifice into vacuum with a pressure ratio of ~5000. Experiments were conducted to deposit silver nanoparticle aerosols under the same conditions as were modeled. The silver nanoparticles were generated by laser ablation of a flowing microparticle aerosol entrained in either He or Ar that produced nanoparticles 5−10 and 15−20 nm in diameter, respectively. Deposition was made onto an unheated substrate in vacuum. The morphology of the deposited films was determined by scanning electron microscope cross-section images and crystallite size was determined by x-ray diffraction analysis. The morphological features and crystallite size were correlated with the nanoparticle impaction velocity and impaction energy derived from the model. We found that, for a given gas type, the size of the grains and morphological features within the impacted films were similar to the size of the nanoparticles from which the films were formed. The density and the degree of consolidation of the films were highly dependent on the nanoparticle impaction velocity/energy and were highest for helium. Control of film morphology, grain size, and film density during supersonic impaction of nanoparticle aerosols are discussed in light of these results.

Background Age-related immunosenescence may impair the immune response to vaccination in older adults. Adjuvanted influenza vaccines are designed to overcome immune senescence in older adults. This study estimated the relative vaccine effectiveness (rVE) of MF59®-adjuvanted trivalent inactivated influenza vaccine (aIIV3) versus egg-derived quadrivalent inactivated influenza vaccine (IIV4e) and high-dose trivalent inactivated influenza vaccine (HD-IIV3) in preventing influenza-related medical encounters in the 2019-2020 US season. Methods This retrospective cohort study used electronic medical records linked to pharmacy and medical claims data. The study population included adults age ≥65 years with a record of aIIV3, IIV4e, or HD-IIV3 vaccination. A doubly robust inverse probability of treatment weighting model was used to derive adjusted odds ratios (OR). rVE was calculated by (1–ORadjusted)*100 and was determined overall and separately for age subgroups. An exploratory analysis evaluated the outcome separately in inpatient and outpatient settings. Results Subjects received aIIV3 (n=936,508), IIV3e (n=651,034), and HD-IIV3 (n=1,813,819) and influenza-related medical encounters were recorded in 0.5%, 0.9%, 0.7% of each cohort, respectively. Overall, rVE of aIIV3 was 27.5% (95% CI, 24.4 to 30.5) versus IIV4e and 13.9% (95% CI 10.7 to 17.0) vs versus HD-IIV3. aIIV3 had a more favorable rVE in inpatient and outpatient settings. Findings remained consistent across age subgroups and during alternative seasonal dates. Conclusions Adults ≥65 years vaccinated with aIIV3 had fewer influenza-related medical encounters compared with IIV4e or HD-IIV3 during the 2019-2020 US influenza season.