Efficacy and Safety of an mRNA-Based RSV PreF Vaccine in Older Adults.

BACKGROUND: Respiratory syncytial virus (RSV) can cause substantial morbidity and mortality among older adults. An mRNA-based RSV vaccine, mRNA-1345, encoding the stabilized RSV prefusion F glycoprotein, is under clinical investigation. METHODS: In this ongoing, randomized, double-blind, placebo-controlled, phase 2-3 trial, we randomly assigned, in a 1:1 ratio, adults 60 years of age or older to receive one dose of mRNA-1345 (50 µg) or placebo. The two primary efficacy end points were the prevention of RSV-associated lower respiratory tract disease with at least two signs or symptoms and with at least three signs or symptoms. A key secondary efficacy end point was the prevention of RSV-associated acute respiratory disease. Safety was also assessed. RESULTS: Overall, 35,541 participants were assigned to receive the mRNA-1345 vaccine (17,793 participants) or placebo (17,748). The median follow-up was 112 days (range, 1 to 379). The primary analyses were conducted when at least 50% of the anticipated cases of RSV-associated lower respiratory tract disease had occurred. Vaccine efficacy was 83.7% (95.88% confidence interval [CI], 66.0 to 92.2) against RSV-associated lower respiratory tract disease with at least two signs or symptoms and 82.4% (96.36% CI, 34.8 to 95.3) against the disease with at least three signs or symptoms. Vaccine efficacy was 68.4% (95% CI, 50.9 to 79.7) against RSV-associated acute respiratory disease. Protection was observed against both RSV subtypes (A and B) and was generally consistent across subgroups defined according to age and coexisting conditions. Participants in the mRNA-1345 group had a higher incidence than those in the placebo group of solicited local adverse reactions (58.7% vs. 16.2%) and of systemic adverse reactions (47.7% vs. 32.9%); most reactions were mild to moderate in severity and were transient. Serious adverse events occurred in 2.8% of the participants in each trial group. CONCLUSIONS: A single dose of the mRNA-1345 vaccine resulted in no evident safety concerns and led to a lower incidence of RSV-associated lower respiratory tract disease and of RSV-associated acute respiratory disease than placebo among adults 60 years of age or older. (Funded by Moderna; ConquerRSV ClinicalTrials.gov number, NCT05127434.).

Vertical flow paper-based plasmonic device for cysteine detection.

Cystinuria, is an autosomal recessive genetic disorder involving increasingly high levels of poorly soluble cysteine in urine leading to formation of stones. Developing a facile, low-cost, point-of-care and selective sensor for diagnosis of cysteine is imperative. Accordingly, for the detection of cysteine, the present study demonstrates an inexpensive colorimetric, paper-based vertical flow plasmonic micro-well device with a two-minute turn-around time. The method encompasses the use of microbially-synthesized silver nanoparticles (AgNPs) that change from light brown / yellow to dark brown upon binding with Sulphur present in cysteine. This technique allows for visual detection up to 1 × 10-5 mM cysteine and can be easily offered as a rapid diagnostic test even at setups with minimal resources.

Performance of intraclass correlation coefficient (ICC) as a reliability index under various distributions in scale reliability studies.

Many published scale validation studies determine inter-rater reliability using the intra-class correlation coefficient (ICC). However, the use of this statistic must consider its advantages, limitations, and applicability. This paper evaluates how interaction of subject distribution, sample size, and levels of rater disagreement affects ICC and provides an approach for obtaining relevant ICC estimates under suboptimal conditions. Simulation results suggest that for a fixed number of subjects, ICC from the convex distribution is smaller than ICC for the uniform distribution, which in turn is smaller than ICC for the concave distribution. The variance component estimates also show that the dissimilarity of ICC among distributions is attributed to the study design (ie, distribution of subjects) component of subject variability and not the scale quality component of rater error variability. The dependency of ICC on the distribution of subjects makes it difficult to compare results across reliability studies. Hence, it is proposed that reliability studies should be designed using a uniform distribution of subjects because of the standardization it provides for representing objective disagreement. In the absence of uniform distribution, a sampling method is proposed to reduce the non-uniformity. In addition, as expected, high levels of disagreement result in low ICC, and when the type of distribution is fixed, any increase in the number of subjects beyond a moderately large specification such as n = 80 does not have a major impact on ICC.

One-year outcomes from the international multicenter study of the Zenith Alpha Thoracic Endovascular Graft for thoracic endovascular repair.

OBJECTIVE: This study evaluated the safety and effectiveness of the Zenith Alpha Thoracic Endovascular Graft (Cook Medical, Bloomington, Ind) for the treatment of descending thoracic aortic aneurysms and large ulcers. METHODS: The Zenith Alpha Thoracic Endovascular Graft, with a 16F to 20F delivery system, was developed to address vascular access issues associated with larger-profile devices and to increase conformability in tortuous anatomy. This prospective, nonrandomized, multicenter study was conducted in Europe, Japan, and the United States. The main anatomical inclusion criteria included proximal neck seal zone of ≥20 mm, aortic arch radius of ≥20 mm, and a neck diameter of 15 to 42 mm. Patients were evaluated preprocedure, predischarge, and postdischarge 1, 6, and 12 months and yearly thereafter through 5 years. RESULTS: Between March 2010 and January 2013, 110 patients (64 men and 46 women; mean age, 72 ± 10 years) were enrolled in the study for the treatment of descending thoracic aortic aneurysms (n = 90) or ulcers (n = 20). Access was percutaneous in 36% (40 of 110) of patients. The study device was successfully implanted in all but two patients (both due to inability to gain access or advance to the target treatment site). There was no 30-day mortality. Five deaths occurred ≤1 year (only one was aneurysm-related by independent adjudication), resulting in a 95% freedom from all-cause mortality and a 99% freedom from thoracic aortic aneurysm-related mortality. At one or more time points ≤1 year, type I endoleak (all distal) was observed in 4 patients, type III endoleak in 2, and aneurysm growth in 4. Five patients experienced stroke ≤1 year (2 procedure-related). No aortic rupture, paraplegia, paralysis, or permanent spinal cord injury was observed ≤1 year. CONCLUSIONS: Early outcomes after Zenith Alpha implantation appear promising and suggest expanded thoracic endovascular aortic repair applicability in patients with smaller access vessels. Longer-term follow-up is ongoing.

Five-year results of thoracic endovascular aortic repair with the Zenith TX2.

BACKGROUND: This trial evaluated thoracic endovascular aortic repair (TEVAR) compared with open surgical repair of descending thoracic aortic aneurysms and large ulcers at 42 international sites. Whereas several studies demonstrate early safety and utility advantages with TEVAR, longer follow-up is important because of concerns about durability of TEVAR. METHODS: This prospective, nonrandomized study enrolled 160 TEVAR patients treated with the Cook Zenith TX2 and 70 open surgical repair patients. RESULTS: Although follow-up was limited, 5-year mortality rate was similar at 37% for both groups. Aneurysm-related mortality rate was 5.9% with TEVAR compared with 12% with open surgical repair (P = .11). There were no ruptures of the treated aneurysms in either group or open conversions in the TEVAR group. Predefined severe morbidity occurred at a significantly lower rate in TEVAR (21%) compared with open surgical repair (39%; P < .001). Aneurysm growth was seen by core laboratory in 5.9% of patients and endoleak in 5.7% of patients. Secondary intervention rates were similar between TEVAR (8%) and open surgical repair (12%; P = .49) patients. CONCLUSIONS: Five-year results indicate similar all-cause mortality and aneurysm-related mortality with TEVAR compared with open repair. There was a persistent reduction of severe complications with TEVAR. Reinterventions occurred with similar frequency. TEVAR with the TX2 is a safe and effective alternative to open surgical repair for the treatment of anatomically suitable descending thoracic aortic aneurysms and ulcers.

Evaluation of neuroimmunomodulatory activity of recombinant human interferon α.

OBJECTIVE: Recombinant human interferon (rhIFN)-α is a potent immunoregulator having a wide range of therapeutic applications. In the present study, rhIFN-α was evaluated for its neuroimmunomodulatory activity. METHOD: Dose-dependent gene expression of cytokines and chemokines in the brain of rhIFN-administered mice was studied using real-time SYBR green PCR. RESULTS: Statistically significant increase in expression levels of tumor necrosis factor-α, interleukin (IL)-6, IL-1ß and IFN-γ were observed. CONCLUSION: The findings indicate that rhIFN-α may be used at an optimized dose to cause appropriate neuromodulation of cytokine/chemokine secretion that can aid in the development of therapeutic approaches for many infectious diseases of the central nervous system for which therapies are lacking.

A-kinase anchoring proteins are enriched in the central pair microtubules of motile cilia in Chlamydomonas reinhardtii.

Cilia are microtubule-based sensory organelles present in a number of eukaryotic cells. Mutations in the genes encoding ciliary proteins cause ciliopathies in humans. A-kinase anchoring proteins (AKAPs) tether ciliary signaling proteins such as protein kinase A (PKA). The dimerization and docking domain (D/D) on the RIIα subunit of PKA interacts with AKAPs. Here, we show that AKAP240 from the central-pair microtubules of Chlamydomonas reinhardtii cilia uses two C-terminal amphipathic helices to bind to its partner FAP174, an RIIα-like protein with a D/D domain at the N-terminus. Co-immunoprecipitation using anti-FAP174 antibody with an enriched central-pair microtubule fraction isolated seven interactors whose mass spectrometry analysis revealed proteins from the C2a (FAP65, FAP70, and FAP147) and C1b (CPC1, HSP70A, and FAP42) microtubule projections and FAP75, a protein whose sub-ciliary localization is unknown. Using RII D/D and FAP174 as baits, we identified two additional AKAPs (CPC1 and FAP297) in the central-pair microtubules.

Impact of Modifying Abicipar Manufacturing Process in Patients with Neovascular Age-Related Macular Degeneration: MAPLE Study Results.

Purpose: To evaluate the impact of modifying the abicipar pegol (abicipar) manufacturing process on the safety and treatment effect of abicipar in patients with neovascular age-related macular degeneration (nAMD). Methods: A new process for manufacturing abicipar was developed to reduce host cell impurities. In a prospective, Phase 2, multicenter, open-label, 28-week clinical trial, patients (n=123) with active nAMD received intravitreal injections of abicipar 2 mg at baseline (day 1) and weeks 4, 8, 16, and 24. Outcome measures included proportion of patients with stable vision (<15-letter loss from baseline; primary endpoint), change from baseline in best-corrected visual acuity (BCVA) and central retinal thickness (CRT), and adverse events. Results: Overall, 8.9% (11/123) of patients experienced intraocular inflammation (IOI) and discontinued treatment. IOI cases were assessed as mild (2.4% [3/123]), moderate (4.9% [6/123]), or severe (1.6% [2/123]) and resolved with steroid treatment. Visual acuity in most patients with IOI (8 of 11) recovered to baseline BCVA or better by study end. No cases of endophthalmitis or retinal vasculitis were reported. Stable vision was maintained for ≥95.9% (≥118/123) of patients at all study visits. At week 28, treatment-naïve patients showed a greater mean improvement from baseline in BCVA compared with previously treated patients (4.4 vs 1.8 letters) and a larger mean CRT reduction from baseline (98.5 vs 45.5 µm). Conclusion: Abicipar produced using a modified manufacturing process showed a moderately lower incidence and severity of IOI compared with Phase 3 abicipar studies. Beneficial effects of treatment were demonstrated.

Omicron BA.1-containing mRNA-1273 boosters compared with the original COVID-19 vaccine in the UK: a randomised, observer-blind, active-controlled trial.

BACKGROUND: The omicron BA.1 bivalent booster is used globally. Previous open-label studies of the omicron BA.1 (Moderna mRNA-1273.214) booster showed superior neutralising antibody responses against omicron BA.1 and other variants compared with the original mRNA-1273 booster. We aimed to compare the safety and immunogenicity of omicron BA.1 monovalent and bivalent boosters with the original mRNA-1273 vaccine in a large, randomised controlled trial. METHODS: In this large, randomised, observer-blind, active-controlled, phase 3 trial in the UK (28 hospital and vaccination clinic sites), individuals aged 16 years or older who had previously received two injections of any authorised or approved COVID-19 vaccine, with or without an mRNA vaccine booster (third dose), were randomly allocated (1:1) using interactive response technology to receive 50 µg omicron BA.1 monovalent or bivalent vaccines or 50 µg mRNA-1273 administered as boosters via deltoid intramuscular injection. The primary outcomes were safety and immunogenicity at day 29, including prespecified non-inferiority and superiority of booster immune responses, based on the neutralising antibody geometric mean concentration (GMC) ratios of the monovalent and bivalent boosters compared with mRNA-1273. Safety was assessed in all participants who received first or second boosters, and primary immunogenicity outcomes were assessed in all participants who received the planned booster dose, had pre-booster and day 29 antibody data, had no major protocol deviations, and who were SARS-CoV-2-negative. The study is registered with EudraCT (2022-000063-51) and ClinicalTrials.gov (NCT05249829) and is ongoing. FINDINGS: Between Feb 16 and March 24, 2022, 724 participants were randomly allocated to receive omicron BA.1 monovalent (n=366) or mRNA-1273 (n=357), and between April 2 and June 17, 2022, 2824 participants were randomly allocated to receive omicron BA.1 bivalent (n=1418) or mRNA-1273 (n=1395) vaccines as second boosters. Median durations (months) between the most recent COVID-19 vaccine and study boosters were similar for omicron BA.1 monovalent (4·0 months [IQR 3·6-4·7]) and mRNA-1273 (4·1 [3·5-4·7]), and for the omicron BA.1 bivalent (5·5 [4·8-6·2]) and mRNA-1273 (5·4 [4·8-6·2]) boosters. The omicron BA.1 monovalent and bivalent boosters elicited superior neutralising GMCs against the omicron BA.1 variant compared with mRNA-1273, with GMC ratios of 1·68 (99% CI 1·45-1·95) and 1·53 (1·41-1·67) at day 29 post-booster doses in participants without previous SARS-CoV-2 infection. Both boosters induced non-inferior ancestral SARS-CoV-2 (Asp614Gly) immune responses with GMCs that were similar for the bivalent (2987·2 [95% CI 2814·9-3169·9]) versus mRNA-1273 (2911·3 [2750·9-3081·0]) and lower for the monovalent (2699·7 [2431·3-2997·7] vs 3020·6 [2776·5-3286·2]) boosters, with respective GMC ratios of 1·05 (99% CI 0·96-1·15) and 0·82 (95% CI 0·74-0·91). Results were comparable regardless of previous SARS-CoV-2 infection status. Incidences of solicited adverse reactions with the omicron BA.1 monovalent (335 [91·3%] of 367 participants) and omicron BA.1 bivalent (1285 [90·4%] of 1421 participants) boosters were similar to those observed previously for mRNA-1273, with no new safety concerns identified and no occurrences of fatal adverse events. INTERPRETATION: Omicron-containing booster vaccines generated superior immunogenicity against omicron BA.1 and comparable immunogenicity against the original strain with no new safety concerns. It remains important to continuously monitor the immune responses and real-world vaccine effectiveness as divergent SARS-CoV-2 variants emerge. FUNDING: Moderna.

Environmental impacts of animal-based food supply chains with market characteristics.

Animal-based food supply chains lead to significant environmental impacts, which can be influenced by production systems, distribution networks and consumption patterns. To develop strategy aimed at reducing the environmental impact of animal-based food supply chains, the common environmental hotspots among different types of food, the role of transport logistics and the consequence of end market need to be better understood. Life cycle assessment was adopted to model three types of animal-based food chains (beef, butter and salmon), with specific technologies, high spatial-resolution logistics and typical consumption patterns for three markets: local, regional (intra-European) and international. The results confirmed that the farm production stage usually had the greatest environmental impact, except when air transport was used for distribution. Potentially, the role of end market also can significantly influence the environmental impacts. To understand more, three improvement options were examined in detail with regard to hotspots for climate change: novel feed ingredients (farm production stage), sustainable aviation fuel (transport and logistics stage) and reduction of wasted food (consumption and end of life stage). Significant reduction was achieved in the salmon system by sustainable aviation fuel (64%) and novel feed (15%). Minimizing food waste drove the greatest reduction in the beef supply chain (23%) and the international butter supply chain can reduce 50% of GHG mission by adopting sustainable aviation fuel. Combined interventions could reduce GHG emission of animal-based food supply chains by 15% to 82%, depending on market, transport and food waste behaviour. The results show that eco-efficiency information of animal-based foods should include the full supply chain. The effective mitigation strategy to achieve the greatest reduction should not only consider the impacts on-farm, but also detail of the downstream impacts, such as food distribution network and consumption patterns.

Use of rapid fluorescent focus inhibition test (RFFIT) for in vitro evaluation of anti-rabies activity.

Even in the twenty-first century, rabies remains one of the most dreaded diseases in many parts of the world. An effective chemotherapeutic still remains elusive. The present study was aimed at in vitro evaluation of crude extracts of Allamanda cathartica and Cynodon dactylon for their potential anti-rabies activity based on the principle of immunofluorescence. The extracts were tested for cytotoxicity and screened for the presence of phytochemicals. While A. cathartica extracts were found to be non-toxic, the CC50 of C. dactylon (water and methanol) cold extracts were found to be 8.17 and 9.20 mg/mL respectively on BHK-21 cell line. Rapid Fluorescent Focus Inhibition Test (RFFIT) was used to evaluate anti-rabies activities of these plants against the rabies challenge virus standard strain. We observed 50% inhibition of 10 TCID50 CVS at 5 mg/mL (IC50) whereas florescence (no inhibition) was observed with A. cathartica extracts. The present study highlights the use of modified RFFIT as a method of choice for testing anti-rabies activity over assays based on evaluation of cytopathic effect.

Pathway Analysis of Proteomics Profiles in Rabies Infection: Towards Future Biomarkers?

Rabies is a zoonotic viral disease that invariably leads to fatal encephalitis, which can be prevented provided post-exposure prophylaxis is initiated timely. Ante-mortem diagnostic tests are inconclusive, and rabies is nontreatable once the clinical signs appear. A large number of host factors are responsible for the altered neuronal functions observed in rabies; however their precise role remains uninvestigated. We therefore used two-dimensional electrophoresis and mass spectrometry analysis to identify differentially expressed host proteins in an experimental murine model of rabies. We identified 143 proteins corresponding to 45 differentially expressed spots (p < 0.05) in neuronal tissues of Swiss albino mice in response to infection with neurovirulent rabies strains. Time series analyses revealed that a majority of the alterations occur at 4 to 6 days post infection, in particular affecting the host's cytoskeletal architecture. Extensive pathway analysis and protein interaction studies using the bioinformatic tools such as Ingenuity Pathway Analysis and STRING revealed novel pathways and molecules (e.g., protein ubiquitination) unexplored hitherto. Further activation/inhibition studies of these pathway molecular leads would be relevant to identify novel biomarkers and mechanism-based therapeutics for rabies, a disease that continues to severely impact global health.

Postgenomics biomarkers for rabies­the next decade of proteomics.

Rabies is one of the oldest diseases known to mankind. The pathogenic mechanisms by which rabies virus infection leads to development of neurological disease and death are still poorly understood. Analysis of rabies-infected proteomes may help identify novel biomarkers for antemortem diagnosis of the disease and target molecules for therapeutic intervention. This article offers a literature synthesis and critique of the differentially expressed proteins that have been previously reported from various in vitro/in vivo model systems and naturally infected clinical specimens. The emerging data collectively indicate that, in addition to the obvious alterations in proteins involved in synapse and neurotransmission, a majority of cytoskeletal proteins are relevant as well, providing evidence of neuronal degeneration. An interesting observation is that certain molecules, such as KPNA4, could be potential diagnostic markers for rabies. Importantly, proteomic studies with body fluids such as cerebrospinal fluid provide newer insights into antemortem diagnosis. In order to develop a complete integrative biology picture, it is essential to analyze the entire CNS (region-wise) and in particular, the brain. We suggest the use of laboratory animal models over cell culture systems using a combinatorial proteomics approach, as the former is a closer match to the actual host response. While most studies have focused on the terminal stages of the disease in mice, a time-series analysis could provide deeper insights for therapy. Postgenomics technologies such as proteomics warrant more extensive applications in rabies and similar diseases impacting public health around the world.