Showing papers by "David A. Cooper published in 2023"

Neutralization of BA.4–BA.5, BA.4.6, BA.2.75.2, BQ.1.1, and XBB.1 with Bivalent Vaccine

Abstract: circulating omicron sublineages. These findings support the use of the current bivalent vaccine and underscore the importance of monitoring real-world effec-tiveness

Bivalent Omicron BA.1–Adapted BNT162b2 Booster in Adults Older than 55 Years

Abstract: Abstract Background The emergence of immune-escape variants of severe acute respiratory syndrome coronavirus 2 warrants the use of sequence-adapted vaccines to provide protection against coronavirus disease 2019. Methods In an ongoing phase 3 trial, adults older than 55 years who had previously received three 30-μg doses of the BNT162b2 vaccine were randomly assigned to receive 30 μg or 60 μg of BNT162b2, 30 μg or 60 μg of monovalent B.1.1.529 (omicron) BA.1–adapted BNT162b2 (monovalent BA.1), or 30 μg (15 μg of BNT162b2+15 μg of monovalent BA.1) or 60 μg (30 μg of BNT162b2+30 μg of monovalent BA.1) of BA.1–adapted BNT162b2 (bivalent BA.1). Primary objectives were to determine superiority (with respect to 50% neutralizing titer [NT50] against BA.1) and noninferiority (with respect to seroresponse) of the BA.1-adapted vaccines to BNT162b2 (30 μg). A secondary objective was to determine noninferiority of bivalent BA.1 to BNT162b2 (30 μg) with respect to neutralizing activity against the ancestral strain. Exploratory analyses assessed immune responses against omicron BA.4, BA.5, and BA.2.75 subvariants. Results A total of 1846 participants underwent randomization. At 1 month after vaccination, bivalent BA.1 (30 μg and 60 μg) and monovalent BA.1 (60 μg) showed neutralizing activity against BA.1 superior to that of BNT162b2 (30 μg), with NT50 geometric mean ratios (GMRs) of 1.56 (95% confidence interval [CI], 1.17 to 2.08), 1.97 (95% CI, 1.45 to 2.68), and 3.15 (95% CI, 2.38 to 4.16), respectively. Bivalent BA.1 (both doses) and monovalent BA.1 (60 μg) were also noninferior to BNT162b2 (30 μg) with respect to seroresponse against BA.1; between-group differences ranged from 10.9 to 29.1 percentage points. Bivalent BA.1 (either dose) was noninferior to BNT162b2 (30 μg) with respect to neutralizing activity against the ancestral strain, with NT50 GMRs of 0.99 (95% CI, 0.82 to 1.20) and 1.30 (95% CI, 1.07 to 1.58), respectively. BA.4–BA.5 and BA.2.75 neutralizing titers were numerically higher with 30-μg bivalent BA.1 than with 30-μg BNT162b2. The safety profile of either dose of monovalent or bivalent BA.1 was similar to that of BNT162b2 (30 μg). Adverse events were more common in the 30-μg monovalent-BA.1 (8.5%) and 60-μg bivalent-BA.1 (10.4%) groups than in the other groups (3.6 to 6.6%). Conclusions The candidate monovalent or bivalent omicron BA.1–adapted vaccines had a safety profile similar to that of BNT162b2 (30 μg), induced substantial neutralizing responses against ancestral and omicron BA.1 strains, and, to a lesser extent, neutralized BA.4, BA.5, and BA.2.75 strains. (Funded by BioNTech and Pfizer; ClinicalTrials.gov number, NCT04955626.)

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

Abstract: 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.).

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

Abstract: 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.).

Evaluation of BNT162b2 Covid-19 Vaccine in Children Younger than 5 Years of Age

Abstract: Abstract Background Safe and effective vaccines against coronavirus disease 2019 (Covid-19) are urgently needed in young children. Methods We conducted a phase 1 dose-finding study and are conducting an ongoing phase 2–3 safety, immunogenicity, and efficacy trial of the BNT162b2 vaccine in healthy children 6 months to 11 years of age. We present results for children 6 months to less than 2 years of age and those 2 to 4 years of age through the data-cutoff dates (April 29, 2022, for safety and immunogenicity and June 17, 2022, for efficacy). In the phase 2–3 trial, participants were randomly assigned (in a 2:1 ratio) to receive two 3-μg doses of BNT162b2 or placebo. On the basis of preliminary immunogenicity results, a third 3-μg dose (≥8 weeks after dose 2) was administered starting in January 2022, which coincided with the emergence of the B.1.1.529 (omicron) variant. Immune responses at 1 month after doses 2 and 3 in children 6 months to less than 2 years of age and those 2 to 4 years of age were immunologically bridged to responses after dose 2 in persons 16 to 25 years of age who received 30 μg of BNT162b2 in the pivotal trial. Results During the phase 1 dose-finding study, two doses of BNT162b2 were administered 21 days apart to 16 children 6 months to less than 2 years of age (3-μg dose) and 48 children 2 to 4 years of age (3-μg or 10-μg dose). The 3-μg dose level was selected for the phase 2–3 trial; 1178 children 6 months to less than 2 years of age and 1835 children 2 to 4 years of age received BNT162b2, and 598 and 915, respectively, received placebo. Immunobridging success criteria for the geometric mean ratio and seroresponse at 1 month after dose 3 were met in both age groups. BNT162b2 reactogenicity events were mostly mild to moderate, with no grade 4 events. Low, similar incidences of fever were reported after receipt of BNT162b2 (7% among children 6 months to <2 years of age and 5% among those 2 to 4 years of age) and placebo (6 to 7% among children 6 months to <2 years of age and 4 to 5% among those 2 to 4 years of age). The observed overall vaccine efficacy against symptomatic Covid-19 in children 6 months to 4 years of age was 73.2% (95% confidence interval, 43.8 to 87.6) from 7 days after dose 3 (on the basis of 34 cases). Conclusions A three-dose primary series of 3-μg BNT162b2 was safe, immunogenic, and efficacious in children 6 months to 4 years of age. (Funded by BioNTech and Pfizer; ClinicalTrials.gov number, NCT04816643.)

Xenotransplantation: A historical–ethical account of viewpoints

Abstract: Formal clinical trials of pig‐to‐human organ transplant—known asxenotransplantation—may begin this decade, with the first trials likely to consist of either adult renal transplants or pediatric cardiac transplant patients. Xenotransplantation as a systematic scientific study only reaches back to the latter half of the 20th century, with episodic xenotransplantation events occurring prior to that. As the science of xenotransplantation has progressed in the 20th and 21st centuries, the public's knowledge of the potential therapy has also increased. With this, there have been shifting ethical stances toward xenotransplantation in key areas, such as religious and public viewpoints towards xenotransplantation, animal rights, and public health concerns. This review provides a historical–ethical account of xenotransplantation and details if or how viewpoints have shifted over time.

Divalent siRNAs are bioavailable in the lung and efficiently block SARS-CoV-2 infection

Abstract: Significance Vaccines and repurposed drugs have been critical in preventing and treating SARS-CoV-2 infections; however, the virus’s ability to evolve rapidly requires alternative strategies that can keep pace with this pandemic pathogen. We performed the first comprehensive screening of siRNA chemical architectures and identified an effective multimeric platform for local lung delivery. Using this platform, we designed and screened over 200 siRNAs and antisense oligonucleotides targeting highly conserved regions within the SARS-CoV-2 genome. We identified four compounds targeting all clinically relevant variants, including delta and omicron, and are fully protective in a mouse model of SARS-CoV-2 infection. Our agile platform is adaptable for multiple diseases by changing the nucleic acid sequence, promising broad and deep impact in pulmonary medicine.

Magnetic Shielding Analysis of Bonding in [1.1.1]Propellane

Abstract: The bonding in [1.1.1]propellane, bicyclo[1.1.0]butane, bicyclo[1.1.1]pentane, tetrahedrane, and cyclopropane is investigated by analyzing changes in the off-nucleus isotropic magnetic shielding within the space surrounding each of these molecules and, for [1.1.1]propellane, by examining also the diamagnetic and paramagnetic contributions to this shielding. Any shielding arising from the two “exo” sp3-like hybrid atomic orbitals on the bridgehead carbon atoms that have been used to support the idea of an inverted bond between these two atoms is found to be almost entirely contained within the [1.1.1]propellane cage and to contribute to a strongly shielded central region. This strongly shielded region suggests the establishment of a mainly covalent bonding interaction involving all carbon atoms that cannot be straightforwardly decomposed into contributions from individual carbon–carbon bonds. The emergence of the strongly shielding central region is traced by comparing the shielding variations in and around molecules with one three-membered carbon ring (cyclopropane), two fused three-membered carbon rings (bicyclo[1.1.0]butane), and three fused three-membered carbon rings ([1.1.1]propellane).

Hydrological dynamics and associated greenhouse gas fluxes in a mountain peatland under different climate scenarios

Abstract: Peatlands have sequestered atmospheric carbon dioxide (CO2) for millennia and can also act as significant sources of atmospheric methane (CH4). Hydrological processes that control water table dynamics, and climatic conditions such as air temperature, play important roles in mediating peatland–atmosphere exchange of these greenhouse gases. These controls are likely to be impacted by climate change, particularly for those peatlands found in cold environments, including mountain regions. In this study, we developed empirical models to simulate hydrological dynamics and ecosystem–atmosphere C exchange in a mountain peatland under three climate scenarios (2012 air temperatures, +2°C and +4°C). Observed water table dynamics and air temperature were used to model ecosystem–atmosphere C exchange during the 2012 growing season. Modelled snowmelt dynamics were used to predict water table position at the beginning of the growing season for warming scenarios, and the subsequent water table dynamics and increased air temperature were used to drive the same C exchange models during the growing seasons. Increased air temperatures led to earlier snowmelt and water table decline, causing water tables to drop by 10 and 19 cm for the +2 and +4°C scenarios, respectively. This led to roughly a two‐fold decrease in growing season net ecosystem production (NEP) in both warming scenarios, as a result of increased ecosystem respiration relative to gross primary production. Methane efflux was positively correlated with NEP and therefore decreased under the warming scenarios, albeit to a lesser degree. These results indicate that reductions in NEP and CH4 efflux are possible in low‐elevation mountain peatlands that are dependent on snowpack‐derived hydrologic inputs. These ecosystems are found at elevations where future winter precipitation will increasingly fall as rain rather than snow and melting of snowpack will occur earlier under warmer conditions.

Vegetation response to Rocky Mountain National Park’s elk and vegetation management plan: Analysis of 2008–2018 data

Abstract: Rocky Mountain National Park (RMNP) developed the Elk and Vegetation Management Plan (EVMP) to address well-documented declines in the ecological condition of aspen stands and riparian communities from high levels of elk herbivory. The EVMP aims to reduce the impacts of elk on vegetation and restore the natural range of variability in the elk population and affected plant communities, including preventing the loss of aspen clones within high elk-use areas, restoring montane riparian willow cover and height within suitable habitat, and reducing of levels of elk grazing on herbaceous vegetation. The EVMP described a range of management actions including reductions in the size of the elk herd and the installation of fencing to reduce herbivory levels and facilitate recovery in degraded communities. The EVMP established a monitoring protocol in focal communities to assess progress towards these vegetation goals and facilitate adaptive management. RMNP has collected data quantifying biomass offtake in upland herbaceous and riparian communities, willow height and cover, and aspen stand structure and regeneration periodically since implementation of the plan began in 2008. This report summarizes the results of analyses of EVMP data collected from 2008–2018, the last year comprehensive measurements were made. The EVMP was developed with a focus on the primary elk winter range in the upper montane zone on the east side of RMNP. The plan distinguishes core elk winter range, where elk concentrate during winter, and noncore winter range areas that typically have less elk use. Data were also collected in the Kawuneeche Valley in the headwaters of the Colorado River on the west side of the park, an area supporting extensive wet meadows and areas once dominated by willow. Data were also collected to investigate the effects of wildland fires that burned through the winter range in 2012 to determine the potential for using fire as a management tool to achieve EVMP goals. The overwintering elk population in the park has declined, from its peak of 1,500 animals in 2001, and over the course of EVMP implementation, from 614 animals in 2009 to 124 animals in 2019. Declines in the overwintering elk population may be best explained by increased cow elk harvest outside of the park, and, most notably, by a change in seasonal migration patterns and habitat use that have elk moving to lower elevation wintering areas following the fall rut. In sites in aspen communities, stand structure was changed little or declined across sampling periods in unfenced plots with continued patterns of little regeneration and recruitment and steady progression toward stands dominated by large-diameter trees. However, there was a progression towards taller sapling heights inside fenced plots and recruitment of small diameter tree-sized stems. Fencing had large and positive effects on aspen stand structure, with different patterns observed in fenced and unfenced core winter range and noncore winter range. Increased recruitment was observed across the winter range but occurred mainly inside fenced plots. Aspen stem counts varied between time periods and in relation to wildfire, with fenced and burned plots on the core winter range having higher stem counts by 2018 than unfenced and unburned plots. Willow height and cover increased over time in sampled sites, but positive trends were generally restricted to sites in fenced areas. Willow height also increased on noncore (all unfenced) winter range sites. Willow in unfenced core winter range sites had only minor increase in height from baseline (2008 for most sites) to 2018, but willow in fenced plots had greater height increases over the same time period. Noncore winter range willow sites had modest height increases over the 10-yr period. Mean willow cover increased nearly 5-fold compared to baseline conditions within the core winter range fenced areas and roughly 1.5-fold in noncore winter range. Willow cover was greater in unfenced than fenced plots at baseline, but the pattern was reversed in 2013 and 2018. The highest cover occurred in 2018 in fenced core winter range plots (mean = 70.8%) and unfenced noncore winter range plots (mean = 68.6%). Mean cover increased from 14.6% at baseline to 25.3% in 2013 and 70.8% in 2018 in fenced core winter range plots. Mean willow cover changed little in unfenced core winter range plots between baseline and 2018, although the range of cover values increased over time, and willow cover increases were modest in the noncore winter range. Fencing reduced or eliminated browsing from plots located inside fences, but offtake varied widely among unfenced plots. Patterns of willow browse intensity differed management subgroups (e.g., core and noncore winter range), and generally showed a downward trend between baseline and 2018 measurements. Herbaceous offtake in upland communities was measured in the first sample period (baseline–2013) to assess levels of grazing on herbaceous vegetation, however it was determined that the associated EVMP objectives had been achieved so measurements were discontinued after 2013. Continued monitoring of upland shrubs indicated no shift from herbaceous dominated to shrub dominated communities after 2013. Noncore upland plots had higher shrub cover than core winter range plots across all time periods, but most differences between year and core/noncore had low probability of effect. Cover for individual species varied over time and winter range plots. Moose presence has increased in winter range aspen and willow sites over the past decade, while beaver presence at our monitoring sites has decreased. Results indicate that RMNP is making progress toward the vegetation objectives set out in the EVMP, however positive trends were most pronounced in plots protected from ungulate herbivory through fencing. Aspen recruitment was greatest in fenced plots. Likewise, trajectories of willow height and cover were positive in fenced winter range plots. Results demonstrate that fencing is an effective means of improving condition in aspen and willow habitats. Changes outside the fences were slower and less pronounced than inside the fences, however, the positive (if small) increases in willow height and cover and aspen regeneration as well as decreases in upland herbaceous offtake, indicate that decreased wintering elk populations are also contributing to improvement of habitat conditions on the elk winter range. In the Kawuneeche Valley, which has not traditionally been heavily used by overwintering elk but does experience summer elk and moose use, poor and declining habitat condition were recorded in unfenced willow and aspen sites.

The case for the therapeutic use of mechanistic/mammalian target of rapamycin (mTOR) inhibitors in xenotransplantation

Abstract: The mechanistic/mammalian target of rapamycin (mTOR) is one of the systems that are necessary to maintain cell homeostasis, such as survival, proliferation, and differentiation. mTOR inhibitors (mTOR‐Is) are utilized as immunosuppressants and anti‐cancer drugs. In organ allotransplantation, current regimens infrequently include an mTOR‐I, which are positioned more commonly as alternative immunosuppressants. In clinical allotransplantation, long‐term efficacy has been established, but there is a significant incidence of adverse events, for example, inhibition of wound healing, buccal ulceration, anemia, hyperglycemia, dyslipidemia, and thrombocytopenia, some of which are dose‐dependent. mTOR‐Is have properties that may be especially beneficial in xenotransplantation. These include suppression of T cell proliferation, increases in the number of T regulatory cells, inhibition of pig graft growth, and anti‐inflammatory, anti‐viral, and anti‐cancer effects. We here review the potential benefits and risks of mTOR‐Is in xenotransplantation and suggest that the benefits exceed the adverse effects.

Efficacy of a 4-Antigen Staphylococcus aureus Vaccine in Spinal Surgery: The STRIVE Randomized Clinical Trial.

Abstract: BACKGROUND Staphylococcus aureus is a global pathogen frequently responsible for healthcare-associated infections, including surgical site infections (SSIs). Current infection prevention and control approaches may be limited, with S aureus antibiotic resistance remaining problematic. Thus, a vaccine to prevent or reduce S aureus infection is critically needed. This study evaluated efficacy and safety of an investigational 4-antigen S aureus vaccine (SA4Ag) in adults undergoing elective open posterior spinal fusion procedures with multilevel instrumentation. METHODS In this multicenter, site-level, randomized, double-blind trial, subjects 18-85 years old received a single dose of SA4Ag or placebo 10-60 days before surgery. SA4Ag efficacy in preventing postoperative S aureus bloodstream infection and/or deep incisional or organ/space SSI was the primary endpoint. Safety evaluations included local reactions, systemic events, and adverse events (AEs). Immunogenicity and colonization were assessed. RESULTS Study enrollment was halted when a prespecified interim efficacy analysis met predefined futility criteria. SA4Ag showed no efficacy (0.0%) in preventing postoperative S aureus infection (14 cases in each group through postoperative Day 90), despite inducing robust functional immune responses to each antigen compared with placebo. Colonization rates across groups were similar through postoperative Day 180. Local reactions and systemic events were mostly mild or moderate in severity, with AEs reported at similar frequencies across groups. CONCLUSIONS In patients undergoing elective spinal fusion surgical procedures, SA4Ag was safe, well tolerated, but despite eliciting substantial antibody responses that blocked key S aureus virulence mechanisms, was not efficacious in preventing S aureus infection. ClinicalTrials.gov: NCT02388165.

Reassessing the Composition of Hybrid Orbitals in Contemporary VB Calculations

Abstract: Large variations in the ratios between the p and s components of individual hybrid orbitals that have been observed in contemporary ab initio VB calculations are reassessed, and links are established to specific energy terms that drive bond formation. It is demonstrated that the ratios between the p and s components for individual hybrid orbitals are not indicative of the overall hybridization status of the relevant atom, which exhibits only relatively small variations with the level of theory, irrespective of whether or not non-dynamical and dynamical electron correlation effects are accounted for. An alternative orbital representation that turns out to be far more consistent with the overall hybridization of the relevant atom is examined. The chosen test cases, which can be compared with the classical sp3, sp2, and sp hybridization models for a central carbon atom, are CH4 (Td), trigonal CH3 (D3h), and triplet CH2 distorted from its ground state geometry so as to be linear (D∞h).

The effect of recombinant erythropoietin on long-term outcome after moderate-to-severe traumatic brain injury

Abstract: Recombinant erythropoietin (EPO) administered for traumatic brain injury (TBI) may increase short-term survival, but the long-term effect is unknown.We conducted a pre-planned long-term follow-up of patients in the multicentre erythropoietin in TBI trial (2010-2015). We invited survivors to follow-up and evaluated survival and functional outcome with the Glasgow Outcome Scale-Extended (GOSE) (categories 5-8 = good outcome), and secondly, with good outcome determined relative to baseline function (sliding scale). We used survival analysis to assess time to death and absolute risk differences (ARD) to assess favorable outcomes. We categorized TBI severity with the International Mission for Prognosis and Analysis of Clinical Trials in TBI model. Heterogeneity of treatment effects were assessed with interaction p-values based on the following a priori defined subgroups, the severity of TBI, and the presence of an intracranial mass lesion and multi-trauma in addition to TBI.Of 603 patients in the original trial, 487 patients had survival data; 356 were included in the follow-up at a median of 6 years from injury. There was no difference between treatment groups for patient survival [EPO vs placebo hazard ratio (HR) (95% confidence interval (CI) 0.73 (0.47-1.14) p = 0.17]. Good outcome rates were 110/175 (63%) in the EPO group vs 100/181 (55%) in the placebo group (ARD 8%, 95% CI [Formula: see text] 3 to 18%, p = 0.14). When good outcome was determined relative to baseline risk, the EPO groups had better GOSE (sliding scale ARD 12%, 95% CI 2-22%, p = 0.02). When considering long-term patient survival, there was no evidence for heterogeneity of treatment effect (HTE) according to severity of TBI (p = 0.85), presence of an intracranial mass lesion (p = 0.48), or whether the patient had multi-trauma in addition to TBI (p = 0.08). Similarly, no evidence of treatment heterogeneity was seen for the effect of EPO on functional outcome.EPO neither decreased overall long-term mortality nor improved functional outcome in moderate or severe TBI patients treated in the intensive care unit (ICU). The limited sample size makes it difficult to make final conclusions about the use of EPO in TBI.

Plain language summary of Pfizer-BioNTech BNT162b2 vaccine protection against COVID-19 and its safety in participants 12- to 15-years-old

Abstract: This is a summary of an article about part of a clinical study for the BNT162b2 COVID-19 vaccine, also called the Pfizer-BioNTech vaccine. The article was published in the New England Journal of Medicine in May 2021. This summary describes how the vaccine worked in participants 12- to 15-years old. The part of the study described in the article is ongoing and expected to finish March 2023. This means that the final results may be different from the results included in this summary. The part of the study described in this summary included participants 12- to 15-years old who had no serious health issues. The BNT162b2 vaccine had already been studied in participants 16 years of age or older. In this part of the study, the researchers wanted to find out: How effective and safe the vaccine was in participants 12- to 15-years old. What the immune response to the vaccine and the vaccine safety were like in 12- to 15-year-olds compared with 16- to 25-year-olds. How well the vaccine prevented SARS-CoV-2 infections in participants who received the vaccine compared to those who did not. This is also called efficacy of the BNT162b2 vaccine Half of the participants in this study received 2 injections of the BNT162b2 vaccine and half received 2 injections of a placebo in a muscle of the upper arm. The placebo looked like the BNT162b2 vaccine but did not have any active vaccine in it. BNT162b2 had a favorable safety profile. The most common reactions were pain at the injection site, fatigue, and headache. None of the participants had serious reactions to the vaccine. The 12- to 15-year-old participants' immune system responses to the BNT162b2 vaccine were as good as or stronger than the 16- to 25-year-old participants' immune responses. The participants who received the BNT162b2 vaccine were less likely to get COVID-19 compared with the participants who got the placebo. Clinical Trial Registration: NCT04368728 ( ClinicalTrials.gov )

Immunogenicity and Safety of a Third COVID-19 BNT162b2 mRNA Vaccine Dose in 5- to 11-Year Olds

Abstract: Abstract In this ongoing study, substantially increased ancestral SARS-CoV-2 neutralizing responses were observed 1 month after a third 10-µg BNT162b2 dose given to 5 to 11-year olds versus neutralizing responses post-dose 2. After dose 3, increased neutralizing responses against Omicron BA.1 and BA.4/BA.5 strains were also observed. The safety/tolerability profile was acceptable. (NCT04816643)