A machine learning predictive model for recurrence of resected distal cholangiocarcinoma: Development and validation of predictive model using artificial intelligence.

INTRODUCTION: Distal Cholangiocarcinoma (dCCA) represents a challenge in hepatobiliary oncology, that requires nuanced post-resection prognostic modeling. Conventional staging criteria may oversimplify dCCA complexities, prompting the exploration of novel prognostic factors and methodologies, including machine learning algorithms. This study aims to develop a machine learning predictive model for recurrence after resected dCCA. MATERIAL AND METHODS: This retrospective multicentric observational study included patients with dCCA from 13 international centers who underwent curative pancreaticoduodenectomy (PD). A LASSO-regularized Cox regression model was used to feature selection, examine the path of the coefficient and create a model to predict recurrence. Internal and external validation and model performance were assessed using the C-index score. Additionally, a web application was developed to enhance the clinical use of the algorithm. RESULTS: Among 654 patients, LNR (Lymph Node Ratio) 15, neural invasion, N stage, surgical radicality, and differentiation grade emerged as significant predictors of disease-free survival (DFS). The model showed the best discrimination capacity with a C-index value of 0.8 (CI 95 %, 0.77%-0.86 %) and highlighted LNR15 as the most influential factor. Internal and external validations showed the model's robustness and discriminative ability with an Area Under the Curve of 92.4 % (95 % CI, 88.2%-94.4 %) and 91.5 % (95 % CI, 88.4%-93.5 %), respectively. The predictive model is available at https://imim.shinyapps.io/LassoCholangioca/. CONCLUSIONS: This study pioneers the integration of machine learning into prognostic modeling for dCCA, yielding a robust predictive model for DFS following PD. The tool can provide information to both patients and healthcare providers, enhancing tailored treatments and follow-up.

Phosphorus-Based Flame-Retardant Acrylonitrile Butadiene Styrene Copolymer with Enhanced Mechanical Properties by Combining Ultrahigh Molecular Weight Silicone Rubber and Ethylene Methyl Acrylate Copolymer.

The present work proposes to investigate the effect of an ultrahigh molecular weight silicone rubber (UHMW-SR) and two ethylene methyl acrylate copolymers (EMA) with different methyl acrylate (MA) content on the mechanical and fire performance of a fireproof acrylonitrile butadiene styrene copolymer (ABS) composite, with an optimum amount of ammonium polyphosphate (APP) and aluminum diethyl phosphinate (AlPi). ABS formulations with a global flame retardant weight content of 20 wt.% (ABS P) were melt-compounded, with and without EMA and UHMW-SR, in a Brabender mixer. During this batch process, ABS P formulations with UHMW-SR and/or EMA registered lower torque values than those of ABS P. By means of scanning electron microscopy (SEM), it was possible to observe that all ABS composites exhibited a homogenous structure without phase separation or particle agglomeration. Slightly improved interfacial interaction between the well-dispersed flame-retardant particles in the presence of EMA and/or UHMW-SR was also noticed. Furthermore, synergies in mechanical properties by adding both EMA and UHMW-SR into ABS P were ascertained. An enhancement of molecular mobility that contributed to the softening of ABS P was observed under dynamic mechanical thermal analysis (DMTA). An improvement of its flexibility, ductility and toughness were also registered under three-point-bending trials, and even more remarkable synergies were noticed in Charpy notched impact strength. Particularly, a 212% increase was achieved when 5 wt.% of EMA with 29 wt.% of MA and 2 wt.% of UHMW-SR in ABS P (ABS E29 S P) were added. Thermogravimetric analysis (TGA) showed that the presence of EMA copolymers in ABS P formulations did not interfere with its thermal decomposition, whereas UHMW-SR presence decreased its thermal stability at the beginning of the decomposition. Although the addition of EMA or UHMW-SR, as well as the combination of both in ABS P increased the pHRR in cone calorimetry, UL 94 V-0 classification was maintained for all flame-retarded ABS composites. In addition, through SEM analysis of cone calorimetry sample residue, a more cohesive surface char layer, with Si-O-C network formation confirmed by Fourier transform infrared (FTIR), was shown in ABS P formulations with UHMW-SR.

Development of a high-throughput scale-down model in Ambr® 250 HT for plasmid DNA fermentation processes.

Recent advances in messenger ribonucleic acid (mRNA) vaccines and gene therapy vectors have increased the need for rapid plasmid DNA (pDNA) screening and production within the biopharmaceutical industry. High-throughput (HT) fermentor systems, such as the Ambr® 250 HT, can significantly accelerate process development timelines of pDNA upstream processes compared to traditional bench-scale glass fermentors or small-scale steam-in-place (SIP) fermentors. However, such scale-down models must be qualified to ensure that they are representative of the larger scale process similar to traditional small-scale models. In the current study, we developed a representative scale-down model of a Biostat® D-DCU 30 L pDNA fermentation process in Ambr® 250 HT fermentors using three cell lines producing three different constructs. The Ambr scale-down model provided comparable process performance and pDNA quality as the 30 L SIP fermentation process. In addition, we demonstrated the predictive value of the Ambr model by two-way qualification, first by accurately reproducing the prior trends observed in a 30 L process, followed by predicting new process trends that were then successfully reproduced in the 30 L process. The representative and predictive scale-down Ambr model developed in this study would enable a faster and more efficient approach to strain/clone/host-cell screening, pDNA process development and characterization studies, process scale-up studies, and manufacturing support.

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.).

Efficacy and Safety of a Bivalent RSV Prefusion F Vaccine in Older Adults.

BACKGROUND: Respiratory syncytial virus (RSV) infection causes considerable illness in older adults. The efficacy and safety of an investigational bivalent RSV prefusion F protein-based (RSVpreF) vaccine in this population are unknown. METHODS: In this ongoing, phase 3 trial, we randomly assigned, in a 1:1 ratio, adults (≥60 years of age) to receive a single intramuscular injection of RSVpreF vaccine at a dose of 120 µg (RSV subgroups A and B, 60 µg each) or placebo. The two primary end points were vaccine efficacy against seasonal RSV-associated lower respiratory tract illness with at least two or at least three signs or symptoms. The secondary end point was vaccine efficacy against RSV-associated acute respiratory illness. RESULTS: At the interim analysis (data-cutoff date, July 14, 2022), 34,284 participants had received RSVpreF vaccine (17,215 participants) or placebo (17,069 participants). RSV-associated lower respiratory tract illness with at least two signs or symptoms occurred in 11 participants in the vaccine group (1.19 cases per 1000 person-years of observation) and 33 participants in the placebo group (3.58 cases per 1000 person-years of observation) (vaccine efficacy, 66.7%; 96.66% confidence interval [CI], 28.8 to 85.8); 2 cases (0.22 cases per 1000 person-years of observation) and 14 cases (1.52 cases per 1000 person-years of observation), respectively, occurred with at least three signs or symptoms (vaccine efficacy, 85.7%; 96.66% CI, 32.0 to 98.7). RSV-associated acute respiratory illness occurred in 22 participants in the vaccine group (2.38 cases per 1000 person-years of observation) and 58 participants in the placebo group (6.30 cases per 1000 person-years of observation) (vaccine efficacy, 62.1%; 95% CI, 37.1 to 77.9). The incidence of local reactions was higher with vaccine (12%) than with placebo (7%); the incidences of systemic events were similar (27% and 26%, respectively). Similar rates of adverse events through 1 month after injection were reported (vaccine, 9.0%; placebo, 8.5%), with 1.4% and 1.0%, respectively, considered by the investigators to be injection-related. Severe or life-threatening adverse events were reported in 0.5% of vaccine recipients and 0.4% of placebo recipients. Serious adverse events were reported in 2.3% of participants in each group through the data-cutoff date. CONCLUSIONS: RSVpreF vaccine prevented RSV-associated lower respiratory tract illness and RSV-associated acute respiratory illness in adults (≥60 years of age), without evident safety concerns. (Funded by Pfizer; RENOIR ClinicalTrials.gov number, NCT05035212; EudraCT number, 2021-003693-31.).

Bivalent Prefusion F Vaccine in Pregnancy to Prevent RSV Illness in Infants.

BACKGROUND: Whether vaccination during pregnancy could reduce the burden of respiratory syncytial virus (RSV)-associated lower respiratory tract illness in newborns and infants is uncertain. METHODS: In this phase 3, double-blind trial conducted in 18 countries, we randomly assigned, in a 1:1 ratio, pregnant women at 24 through 36 weeks' gestation to receive a single intramuscular injection of 120 µg of a bivalent RSV prefusion F protein-based (RSVpreF) vaccine or placebo. The two primary efficacy end points were medically attended severe RSV-associated lower respiratory tract illness and medically attended RSV-associated lower respiratory tract illness in infants within 90, 120, 150, and 180 days after birth. A lower boundary of the confidence interval for vaccine efficacy (99.5% confidence interval [CI] at 90 days; 97.58% CI at later intervals) greater than 20% was considered to meet the success criterion for vaccine efficacy with respect to the primary end points. RESULTS: At this prespecified interim analysis, the success criterion for vaccine efficacy was met with respect to one primary end point. Overall, 3682 maternal participants received vaccine and 3676 received placebo; 3570 and 3558 infants, respectively, were evaluated. Medically attended severe lower respiratory tract illness occurred within 90 days after birth in 6 infants of women in the vaccine group and 33 infants of women in the placebo group (vaccine efficacy, 81.8%; 99.5% CI, 40.6 to 96.3); 19 cases and 62 cases, respectively, occurred within 180 days after birth (vaccine efficacy, 69.4%; 97.58% CI, 44.3 to 84.1). Medically attended RSV-associated lower respiratory tract illness occurred within 90 days after birth in 24 infants of women in the vaccine group and 56 infants of women in the placebo group (vaccine efficacy, 57.1%; 99.5% CI, 14.7 to 79.8); these results did not meet the statistical success criterion. No safety signals were detected in maternal participants or in infants and toddlers up to 24 months of age. The incidences of adverse events reported within 1 month after injection or within 1 month after birth were similar in the vaccine group (13.8% of women and 37.1% of infants) and the placebo group (13.1% and 34.5%, respectively). CONCLUSIONS: RSVpreF vaccine administered during pregnancy was effective against medically attended severe RSV-associated lower respiratory tract illness in infants, and no safety concerns were identified. (Funded by Pfizer; MATISSE ClinicalTrials.gov number, NCT04424316.).

Analysis of volatile compounds production kinetics: A study of the impact of nitrogen addition and temperature during alcoholic fermentation.

Among the different compounds present in the must, nitrogen is an essential nutrient for the management of fermentation kinetics, also playing a major role in the synthesis of fermentative aromas. Fermentation temperature is yet another variable that affects fermentation duration and the production of fermentative aromas in wine. The main objective of this study was thus to evaluate the combined effects of nitrogen addition-at the start of the fermentation process or during the stationary phase-at different fermentation temperatures on both fermentation kinetics and aroma synthesis kinetics. To study the impact of these three parameters simultaneously, we used an innovative transdisciplinary approach associating an online GC-MS system with an original modeling approach: a Box-Behnken experimental design combined with response surface modeling and GAM modeling. Our results indicated that all three factors studied had significant effects on fermentation and aroma production kinetics. These parameters did not impact in the same way the different families of volatile compounds. At first, obtained data showed that reduction of ester accumulation in the liquid phase at high temperature was mainly due to important losses by evaporation but also to modifications of yeast metabolic capabilities to synthetize these compounds. In a noticeable way, optimal temperature changed for liquid accumulation of the two classes of esters-23°C for acetate ester and 18°C for ethyl esters-because biological impact of temperature was different for the two chemical families. Moreover, the study of these three factors simultaneously allowed us to show that propanol is not only a marker of the presence of assimilable nitrogen in the medium but above all a marker of cellular activity. Finally, this work enabled us to gain a deeper understanding of yeast metabolism regulation. It also underlines the possibility to refine the organoleptic profile of a wine by targeting the ideal combination of fermentation temperature with initial and added nitrogen concentrations. Such observation was particularly true for isoamyl acetate for which interactions between the three factors were very strong.

Acrylonitrile Butadiene Styrene-Based Composites with Permalloy with Tailored Magnetic Response.

This work reports on tailoring the magnetic properties of acrylonitrile butadiene styrene (ABS)-based composites for their application in magnetoactive systems, such as magnetic sensors and actuators. The magnetic properties of the composites are provided by the inclusion of varying permalloy (Py-Ni75Fe20Mo5) nanoparticle content within the ABS matrix. Composites with Py nanoparticle content up to 80 wt% were prepared and their morphological, mechanical, thermal, dielectric and magnetic properties were evaluated. It was found that ABS shows the capability to include high loads of the filler without negatively influencing its thermal and mechanical properties. In fact, the thermal properties of the ABS matrix are basically unaltered with the inclusion of the Py nanoparticles, with the glass transition temperatures of pristine ABS and its composites remaining around 105 °C. The mechanical properties of the composites depend on filler content, with the Young's modulus ranging from 1.16 GPa for the pristine ABS up to 1.98 GPa for the sample with 60 wt% filler content. Regarding the magnetic properties, the saturation magnetization of the composites increased linearly with increasing Py content up to a value of 50.9 emu/g for the samples with 80 wt% of Py content. A numerical model has been developed to support the findings about the magnetic behavior of the NP within the ABS. Overall, the slight improvement in the mechanical properties and the magnetic properties provides the ABS composites new possibilities for applications in magnetoactive systems, including magnetic sensors, actuators and magnetic field shielding.

COVID-19 Convalescent Plasma Outpatient Therapy to Prevent Outpatient Hospitalization: A Meta-analysis of Individual Participant Data From Five Randomized Trials

BackgroundMonoclonal antibody and antiviral treatments for COVID-19 disease remain largely unavailable worldwide, and existing monoclonal antibodies may be less active against circulating omicron variants. Although treatment with COVID-19 convalescent plasma (CCP) is promising, randomized clinical trials (RCTs) among outpatients have shown mixed results. MethodsWe conducted an individual participant data meta-analysis from all outpatient CCP RCTs to assess the overall risk reduction for all-cause hospitalizations by day 28 in all participants who had transfusion initiated. Relevant trials were identified by searching MEDLINE, Embase, MedRxiv, WHO, Cochrane Library, and Web of Science from January 2020 to September 2022. ResultsFive included studies from four countries enrolled and transfused 2,620 adult patients. Comorbidities were present in 1,795 (69%). The anti-Spike or virus neutralizing antibody titer range across all trials was broad. 160 (12.2%) of 1315 control patients were hospitalized, versus 111 (8.5%) of 1305 CCP-treated patients, yielding a 3.7% (95%CI: 1.3%-6.0%; p=.001) ARR and 30.1% RRR for all-cause hospitalization. The effect size was greatest in those with both early transfusion and high titer with a 7.6% ARR (95%CI: 4.0%-11.1%; p=.0001) accompanied by at 51.4% RRR. No significant reduction in hospitalization was seen with treatment > 5 days after symptom onset or in those receiving CCP with antibody titers below the median titer. ConclusionsAmong outpatients with COVID-19, treatment with CCP reduced the rate of all-cause hospitalization. CCP may be most effective when given within 5 days of symptom onset and when antibody titer is higher. Key PointsWhile the outpatient COVID-19 randomized controlled trial meta-analysis indicated heterogeneity in participant risk factors and convalescent plasma, the combined CCP efficacy for reducing hospitalization was significant, improving with transfusion within 5 days of symptom onset and high antibody neutralization levels.

Telerehabilitation Readiness, Knowledge, and Acceptance of Future Physiatrists in the Philippines: An Online Survey During the COVID-19 Pandemic.

Background: Clinical, educational, and research interest in telerehabilitation has not been widely explored until the COVID-19 pandemic. Amid the enduring pandemic, telerehabilitation remains part of the daily service, academic, and research responsibilities of residents in various training institutions worldwide. Objective: To determine the Rehabilitation Medicine residents' current levels of telerehabilitation readiness, knowledge, and acceptance, their pattern of beliefs about telerehabilitation, and the factors affecting their readiness. Methods: All bona fide residents from all training institutions in the Philippines were invited to participate in an online survey evaluating the following constructs: technological readiness (using the Technological Readiness Index or TRI 2.0); telerehabilitation knowledge (using an original multiple-choice examination); and telerehabilitation acceptance (using the Unified Theory of Acceptance and Use of Technology questionnaire). A pre-test and pilot test were conducted. The TRI responses were classified according to technology adoption segments to determine the respondents' pattern of beliefs about telerehabilitation. Results: Sixty-two residents participated (86.1% response rate). They had good telerehabilitation readiness (3.3 ± 0.4 out of 5), fair telerehabilitation knowledge (2.1 ± 1.1 out of 5), and excellent telerehabilitation acceptance (4.5 ± 0.6 out of 5). The majority were classified either as telerehabilitation skeptics (38.7%), pioneers (19.4%), or explorers (19.4%). The factors that significantly influenced telerehabilitation readiness were optimism, innovativeness, discomfort, and insecurity (p < 0.05). Conclusion: Despite having favorable levels of telerehabilitation readiness and acceptance, the Rehabilitation Medicine residents showed fair telerehabilitation knowledge. Our results suggest the need for formal education and training on virtual rehabilitation care during residency.

Lymph Node Ratio Nomogram-Based Prognostic Model for Resected Distal Cholangiocarcinoma.

BACKGROUND: Several variables have been described as prognostic factors for resected distal cholangiocarcinoma (dCC), including lymph node metastases (N status) and lymph node ratio (LNR). The present study aimed to evaluate the prognostic value of LNR on survival and to establish a novel prognostic nomogram to predict the cancer-specific recurrence-free survival (RFS) of dCC. STUDY DESIGN: Between December 2006 and September 2020, 415 consecutive patients who underwent pancreaticoduodenectomy (PD) for dCC in 10 centers were identified. Multivariate Cox analysis was used to identify all independent risk factors among several prognostic factors. A nomogram was then developed and assessed by integrating the independent prognostic factors into the model, and the concordance index (C-index) was used to evaluate its performance. RESULTS: According to Cox regression multivariate analysis, a nomogram based on independent prognostic factor for RFS was performed including LNR 15 (hazard ratio [HR] 2.442, 95% CI 1.348-4.425, p = 0.003), perineural invasion (HR 3.100, 95% CI 1.183-8.122, p = 0.025), differentiation grade (HR 2.100, 95% CI 1.172-4.143, p = 0.021), and radicality of PD (HR 2.276, 95% CI 1.223-4.234, p = 0.009). The C-index of the nomogram, tailored based on the previous significant factors, was 0.8. CONCLUSIONS: LNR15 yields a high prognostic efficiency for RFS. The nomogram based on LNR can provide an accurate prognosis assessment for patients with resected dCC.

Efficacy and Safety of a Recombinant Plant-Based Adjuvanted Covid-19 Vaccine.

BACKGROUND: Coronavirus-like particles (CoVLP) that are produced in plants and display the prefusion spike glycoprotein of the original strain of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are combined with an adjuvant (Adjuvant System 03 [AS03]) to form the candidate vaccine. METHODS: In this phase 3, multinational, randomized, placebo-controlled trial conducted at 85 centers, we assigned adults (≥18 years of age) in a 1:1 ratio to receive two intramuscular injections of the CoVLP+AS03 vaccine or placebo 21 days apart. The primary objective of the trial was to determine the efficacy of the CoVLP+AS03 vaccine in preventing symptomatic coronavirus disease 2019 (Covid-19) beginning at least 7 days after the second injection, with the analysis performed after the detection of at least 160 cases. RESULTS: A total of 24,141 volunteers participated in the trial; the median age of the participants was 29 years. Covid-19 was confirmed by polymerase-chain-reaction assay in 165 participants in the intention-to-treat population; all viral samples that could be sequenced contained variants of the original strain. Vaccine efficacy was 69.5% (95% confidence interval [CI], 56.7 to 78.8) against any symptomatic Covid-19 caused by five variants that were identified by sequencing. In a post hoc analysis, vaccine efficacy was 78.8% (95% CI, 55.8 to 90.8) against moderate-to-severe disease and 74.0% (95% CI, 62.1 to 82.5) among the participants who were seronegative at baseline. No severe cases of Covid-19 occurred in the vaccine group, in which the median viral load for breakthrough cases was lower than that in the placebo group by a factor of more than 100. Solicited adverse events were mostly mild or moderate and transient and were more frequent in the vaccine group than in the placebo group; local adverse events occurred in 92.3% and 45.5% of participants, respectively, and systemic adverse events in 87.3% and 65.0%. The incidence of unsolicited adverse events was similar in the two groups up to 21 days after each dose (22.7% and 20.4%) and from day 43 through day 201 (4.2% and 4.0%). CONCLUSIONS: The CoVLP+AS03 vaccine was effective in preventing Covid-19 caused by a spectrum of variants, with efficacy ranging from 69.5% against symptomatic infection to 78.8% against moderate-to-severe disease. (Funded by Medicago; ClinicalTrials.gov number, NCT04636697.).

The Timing of Nitrogen Addition Impacts Yeast Genes Expression and the Production of Aroma Compounds During Wine Fermentation.

Among the different compounds present in the must, nitrogen is an essential nutrient for the management of fermentation kinetics but also plays an important role in the synthesis of fermentative aromas. To address the problems related to nitrogen deficiencies, nitrogen additions during alcoholic fermentation have been implemented. The consequences of such additions on the main reaction are well known. However, their impact on aromas synthesis is still poorly understood. So, the main objective of this study was to determine the impact of nitrogen addition during the stationary phase on both the fermentation kinetics and aroma synthesis. To reach this goal, we used a transdisciplinary approach combining statistical modeling (Box-Behnken design and response surface modeling) and gene expression study (transcriptomic analysis). Our results indicated that nitrogen metabolism, central carbon metabolism (CCM), fermentation kinetics and aroma production were significantly impacted by nitrogen addition. The most remarkable point was the different regulation of the bioconversion of higher alcohols into acetate esters on one hand and of fatty acids into ethyl esters on the other hand. We highlighted that the conversion of higher alcohols into acetate esters was maximum when nitrogen was added at the beginning of the stationary phase. Conversely, the highest conversion of acids into ethyl esters was reached when nitrogen was added close to the end of the stationary phase. Moreover, even if the key element in the production of these two ester families appeared to be the enzymatic activity responsible for their production, rather than the availability of the corresponding precursors, these enzymatic activities were differently regulated. For acetate esters, the regulation occurred at gene level: the ATF2 gene was overexpressed following nitrogen addition during the stationary phase. On the opposite, no induction of gene expression was noted for ethyl esters; it seemed that there was an allosteric regulation.

Efficacy and Safety of a Plant-Based Virus-Like Particle Vaccine for COVID-19 Adjuvanted with AS03

BackgroundSeveral COVID-19 vaccines are currently being deployed but supply constraints, concerns over durability of immune responses, solidifying vaccine hesitancy/resistance and vaccine efficacy in the face of emerging variants mean that new vaccines continue to be needed to fight the ongoing pandemic. The vaccine described here is an enveloped, coronavirus-like particle produced in plants (CoVLP) that displays the prefusion-stabilized spike (S) glycoprotein of SARS-CoV-2 (ancestral Wuhan strain) and is adjuvanted with AS03 (CoVLP+AS03). MethodsThis Phase 3 randomized, observer-blind, placebo-controlled trial was conducted at 85 centers in Argentina, Brazil, Canada, Mexico, the UK, and the USA. Adults [≥]18 years of age including those at high risk for COVID-19 complications were randomly assigned 1:1 to receive two intramuscular injections of CoVLP (3.75 g) adjuvanted with AS03 or placebo, 21 days apart. The primary efficacy endpoint was prevention of symptomatic ([≥] 1 symptom), PCR-confirmed SARS-CoV-2 infection with onset at least 7 days after the second injection and was triggered by the identification of [≥]160 virologically-confirmed cases. Tolerability and safety of CoVLP+AS03 were also determined. ResultsA total of 24,141 volunteers were randomly assigned 1:1 to receive vaccine or placebo (N= 12,074 and 12,067, respectively: median age 29, range 18 to 86 years). Overall, 83% received both doses. 14.8% were SARS-CoV-2 seropositive at baseline. Symptomatic SARS-CoV-2 infection was confirmed in 165 study participants in the intention to treat (ITT) set and 157 in the per-protocol population (PP) set. Of the 157 in the PP set, 118 COVID-19 cases were in the placebo group and 39 COVID-19 cases were in the CoVLP+AS03 group for an overall vaccine efficacy (VE) of 71.0% (95% confidence interval (CI) 58.6, 80.0). Moderate-to-severe COVID-19 occurred in 8 and 32 participants in the CoVLP+AS03 and placebo groups, respectively: VE 78.1% (95% CI: 53.9, 90.5) in the PP set overall and 84.5% (95% CI: 62.0, 94.7) in those seronegative at recruitment. To date, 100% of the sequenced strains (122/165 cases: 73.39%) were variants, dominated by Delta (45.9%) and Gamma (43.4%) strains. Vaccine efficacy by variant was 75.3% (95% CI 52.8, 87.9) against Delta and 88.6% (95% CI 74.6, 95.6) against Gamma. Cross-protection was also observed against Alpha, Lambda and Mu variants; although fewer cases were identified, all were in the placebo group. At diagnosis, viral loads in the CoVLP+AS03 breakthrough cases were >100-fold lower than in the placebo cases. Reactogenicity data for solicited adverse events (AEs) was analysed for a subset (N=4,136 in vaccine arm and N=3,683 for placebo) of participants. Reactogenicity was mostly mild to moderate, and transient, and occurred more frequently in the CoVLP+AS03 group. The safety analysis set used for unsolicited AE assessment comprised 24,076 participants who received at least one study injection: 12,036 received CoVLP+AS03 and 12,040 received placebo. All serious adverse events were assessed as unrelated, except two events reported in the same subject in the placebo group. No significant imbalance or safety concern was noted in medically attended AEs (MAAEs), adverse event of special interest (AESIs), AEs leading to withdrawal, deaths, or adverse events potentially associated with currently authorized vaccines. ConclusionsThe CoVLP+AS03 vaccine candidate conferred an efficacy of 71.0% in preventing symptomatic SARS-CoV-2 infection caused by a spectrum of variants. Vaccine efficacy of 78.1% was observed against moderate and severe disease, while variant-specific efficacy ranged from 75.3% to 100%. Markedly lower viral loads in the CoVLP+AS03 group at the time of diagnosis suggests a significant virologic impact of vaccination even in the breakthrough cases. CoVLP+AS03 vaccine candidate was well tolerated, and no safety concerns were identified during the study. If approved by regulators, this more traditional protein+adjuvant vaccine produced using the novel plant-based platform may be able to make an important contribution to the global struggle against the increasingly complex family of SARS-CoV-2 viruses (Funded by Medicago with grants from the governments of Quebec and Canada; NCT04636697).

Cost of Type 2 Diabetes Patients with Chronic Kidney Disease Based on Real-World Data: An Observational Population-Based Study in Spain.

This study analyzed the prevalence, costs and economic impact of chronic kidney disease CKD in patients with T2D in a Spanish Health District using real-world data. Observational cross-sectional study in adult patients with T2D was through data extracted from the information systems of the Valencia Clínico-La Malvarrosa Health District in the year 2015. Patients were stratified with the KDIGO classification for CKD. Additionally, patients were assigned to Clinical Risk Groups (CRGs) according to multimorbidity. Direct costs of primary and specialized care, and medication were estimated. The prevalence of T2D in the database population (n = 28,345) was 10.8% (mean age (SD) = 67.8 years (13.9); 51.5% male). Up to 14.935 patients (52.6%) had data on kidney function. According to the KDIGO classification, 66.2% of the patients were at low risk of CKD, 20.6% at moderately increased risk, 7.9% at high risk, and 5.2% at very high risk. The average healthcare costs associated with these four risk groups were EUR 3437, EUR 4936, EUR 5899 and EUR 7389, respectively. The large number of T2D patients with CKD in the early stages of the disease generated a significant increase in direct healthcare costs. The economic impact could be mitigated by early and comprehensive therapeutic approaches.

Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine through 6 Months.

BACKGROUND: BNT162b2 is a lipid nanoparticle-formulated, nucleoside-modified RNA vaccine encoding a prefusion-stabilized, membrane-anchored severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) full-length spike protein. BNT162b2 is highly efficacious against coronavirus disease 2019 (Covid-19) and is currently approved, conditionally approved, or authorized for emergency use worldwide. At the time of initial authorization, data beyond 2 months after vaccination were unavailable. METHODS: In an ongoing, placebo-controlled, observer-blinded, multinational, pivotal efficacy trial, we randomly assigned 44,165 participants 16 years of age or older and 2264 participants 12 to 15 years of age to receive two 30-µg doses, at 21 days apart, of BNT162b2 or placebo. The trial end points were vaccine efficacy against laboratory-confirmed Covid-19 and safety, which were both evaluated through 6 months after vaccination. RESULTS: BNT162b2 continued to be safe and have an acceptable adverse-event profile. Few participants had adverse events leading to withdrawal from the trial. Vaccine efficacy against Covid-19 was 91.3% (95% confidence interval [CI], 89.0 to 93.2) through 6 months of follow-up among the participants without evidence of previous SARS-CoV-2 infection who could be evaluated. There was a gradual decline in vaccine efficacy. Vaccine efficacy of 86 to 100% was seen across countries and in populations with diverse ages, sexes, race or ethnic groups, and risk factors for Covid-19 among participants without evidence of previous infection with SARS-CoV-2. Vaccine efficacy against severe disease was 96.7% (95% CI, 80.3 to 99.9). In South Africa, where the SARS-CoV-2 variant of concern B.1.351 (or beta) was predominant, a vaccine efficacy of 100% (95% CI, 53.5 to 100) was observed. CONCLUSIONS: Through 6 months of follow-up and despite a gradual decline in vaccine efficacy, BNT162b2 had a favorable safety profile and was highly efficacious in preventing Covid-19. (Funded by BioNTech and Pfizer; ClinicalTrials.gov number, NCT04368728.).