Given the importance of flexible use of different COVID-19 vaccines within the same schedule to facilitate rapid deployment, we studied mixed priming schedules incorporating an adenoviral-vectored ...vaccine (ChAdOx1 nCoV-19 ChAd, AstraZeneca), two mRNA vaccines (BNT162b2 BNT, Pfizer–BioNTech, and mRNA-1273 m1273, Moderna) and a nanoparticle vaccine containing SARS-CoV-2 spike glycoprotein and Matrix-M adjuvant (NVX-CoV2373 NVX, Novavax).
Com-COV2 is a single-blind, randomised, non-inferiority trial in which adults aged 50 years and older, previously immunised with a single dose of ChAd or BNT in the community, were randomly assigned (in random blocks of three and six) within these cohorts in a 1:1:1 ratio to receive a second dose intramuscularly (8–12 weeks after the first dose) with the homologous vaccine, m1273, or NVX. The primary endpoint was the geometric mean ratio (GMR) of serum SARS-CoV-2 anti-spike IgG concentrations measured by ELISA in heterologous versus homologous schedules at 28 days after the second dose, with a non-inferiority criterion of the GMR above 0·63 for the one-sided 98·75% CI. The primary analysis was on the per-protocol population, who were seronegative at baseline. Safety analyses were done for all participants who received a dose of study vaccine. The trial is registered with ISRCTN, number 27841311.
Between April 19 and May 14, 2021, 1072 participants were enrolled at a median of 9·4 weeks after receipt of a single dose of ChAd (n=540, 47% female) or BNT (n=532, 40% female). In ChAd-primed participants, geometric mean concentration (GMC) 28 days after a boost of SARS-CoV-2 anti-spike IgG in recipients of ChAd/m1273 (20 114 ELISA laboratory units ELU/mL 95% CI 18 160 to 22 279) and ChAd/NVX (5597 ELU/mL 4756 to 6586) was non-inferior to that of ChAd/ChAd recipients (1971 ELU/mL 1718 to 2262) with a GMR of 10·2 (one-sided 98·75% CI 8·4 to ∞) for ChAd/m1273 and 2·8 (2·2 to ∞) for ChAd/NVX, compared with ChAd/ChAd. In BNT-primed participants, non-inferiority was shown for BNT/m1273 (GMC 22 978 ELU/mL 95% CI 20 597 to 25 636) but not for BNT/NVX (8874 ELU/mL 7391 to 10 654), compared with BNT/BNT (16 929 ELU/mL 15 025 to 19 075) with a GMR of 1·3 (one-sided 98·75% CI 1·1 to ∞) for BNT/m1273 and 0·5 (0·4 to ∞) for BNT/NVX, compared with BNT/BNT; however, NVX still induced an 18-fold rise in GMC 28 days after vaccination. There were 15 serious adverse events, none considered related to immunisation.
Heterologous second dosing with m1273, but not NVX, increased transient systemic reactogenicity compared with homologous schedules. Multiple vaccines are appropriate to complete primary immunisation following priming with BNT or ChAd, facilitating rapid vaccine deployment globally and supporting recognition of such schedules for vaccine certification.
UK Vaccine Task Force, Coalition for Epidemic Preparedness Innovations (CEPI), and National Institute for Health Research. NVX vaccine was supplied for use in the trial by Novavax.
Pregnant women are vulnerable to COVID-19, with increased risk of more severe illness and pregnancy complications, particularly if infected during the third trimester.1 Based on prior experience with ...vaccines in pregnancy, and with no hypothesised mechanisms for fetal harm, similar efficacy and side-effects to the non-pregnant population were anticipated with vaccination against SARS-CoV-2 in pregnancy. ...recently, there was little consensus regarding routine vaccination in pregnancy, and vaccine hesitancy in pregnant women remains high.2 Informed health-care decision making requires balancing of benefits and risks. Real-life estimates of NNV for pregnant women are likely to be lower (ie, better) than those estimated here based on rising cumulative rates of SARS-CoV-2 infection over time, particularly among unvaccinated individuals, and prevalence of SARS-CoV-2 variants of concern.
Background:
Bioabsorbable screws for anterior cruciate ligament reconstruction (ACLR) have been a popular choice, with theoretical advantages in imaging and surgery. Titanium and poly-L-lactic acid ...with hydroxyapatite (PLLA-HA) screws have been compared, but with less than a decade of follow-up.
Purpose/Hypothesis:
The purpose was to compare long-term outcomes of hamstring autograft ACLR using either PLLA-HA screws or titanium screws. We hypothesized there would be no difference at 13 years in clinical scores or tunnel widening between PLLA-HA and titanium screw types, along with high-grade resorption and ossification of PLLA-HA screws.
Study Design:
Randomized controlled trial; Level of evidence, 1.
Methods:
Forty patients undergoing ACLR were randomized to receive either a PLLA-HA screw or a titanium screw for ACL hamstring autograft fixation. Blinded evaluation was performed at 2, 5, and 13 years using the International Knee Documentation Committee score, Lysholm knee score, and KT-1000 arthrometer. Magnetic resonance imaging (MRI) was performed at 2 or 5 years and 13 years to evaluate tunnel volumes, ossification around the screw, graft integration, and cyst formation. Computed tomography (CT) of patients with PLLA-HA was performed at 13 years to evaluate tunnel volumes and intratunnel ossification.
Results:
No differences were seen in clinical outcomes at 2, 5, or 13 years between the 2 groups. At 13 years, tibial tunnel volumes were smaller for the PLLA-HA group (2.17 cm3) compared with the titanium group (3.33 cm3; P = .004). By 13 years, the PLLA-HA group had complete or nearly complete resorption on MRI or CT scan.
Conclusion:
Equivalent clinical results were found between PLLA-HA and titanium groups at 2, 5, and 13 years. Although PLLA-HA screws had complete or nearly complete resorption by 13 years, tunnel volumes remained largely unchanged, with minimal ossification.
Regulator of calcineurin 1 (RCAN1) is an endogenous inhibitor of the calcineurin pathway in cells. It is expressed as two isoforms in vertebrates: RCAN1.1 is constitutively expressed in most tissues, ...whereas transcription of RCAN1.4 is induced by several stimuli that activate the calcineurin-NFAT pathway. RCAN1.4 is highly upregulated in response to VEGF in human endothelial cells in contrast to RCAN1.1 and is essential for efficient endothelial cell migration and tubular morphogenesis. Here, we show that RCAN1.4 has a role in the regulation of agonist-stimulated VEGFR-2 internalisation and establishment of endothelial cell polarity. siRNA-mediated gene silencing revealed that RCAN1 plays a vital role in regulating VEGF-mediated cytoskeletal reorganisation and directed cell migration and sprouting angiogenesis. Adenoviral-mediated overexpression of RCAN1.4 resulted in increased endothelial cell migration. Antisense-mediated morpholino silencing of the zebrafish RCAN1.4 orthologue revealed a disrupted vascular development further confirming a role for the RCAN1.4 isoform in regulating vascular endothelial cell physiology. Our data suggest that RCAN1.4 plays a novel role in regulating endothelial cell migration by establishing endothelial cell polarity in response to VEGF.
Background:
It is well accepted that there is a higher incidence of repeat anterior cruciate ligament (ACL) injuries in the pediatric population after ACL reconstruction (ACLR) with autograft tissue ...compared with adults. Hamstring autograft harvest may contribute to the risk for repeat ACL injuries in this high functional demand group. A novel method is the use of a living donor hamstring tendon (LDHT) graft from a parent; however, there is currently limited research on the outcomes of this technique, particularly beyond the short term.
Purpose/Hypothesis:
The purpose was to determine the medium-term survival of the ACL graft and the contralateral ACL (CACL) after primary ACLR with the use of an LDHT graft from a parent in those aged less than 18 years and to identify factors associated with subsequent ACL injuries. It was hypothesized that ACLR with the use of an LDHT provides acceptable midterm outcomes in pediatric patients.
Study Design:
Case series; Level of evidence, 4.
Methods:
Between 2005 and 2014, 247 (of 265 eligible) consecutive patients in a prospective database, having undergone primary ACLR with the use of an LDHT graft and aged less than 18 years, were included. Outcomes were assessed at a minimum of 2 years after surgery including data on ACL reinjuries, International Knee Documentation Committee (IKDC) scores, and current symptoms, as well as factors associated with the ACL reinjury risk were investigated.
Results:
Patients were reviewed at a mean of 4.5 years (range, 24-127 months 10.6 years) after ACLR with an LDHT graft. Fifty-one patients (20.6%) sustained an ACL graft rupture, 28 patients (11.3%) sustained a CACL rupture, and 2 patients sustained both an ACL graft rupture and a CACL rupture (0.8%). Survival of the ACL graft was 89%, 82%, and 76% at 1, 2, and 5 years, respectively. Survival of the CACL was 99%, 94%, and 86% at 1, 2, and 5 years, respectively. Survival of the ACL graft was favorable in patients with Tanner stage 1-2 at the time of surgery versus those with Tanner stage 3-5 at 5 years (87% vs 69%, respectively; hazard ratio, 3.7; P = .01). The mean IKDC score was 91.7. A return to preinjury levels of activity was reported by 59.1%.
Conclusion:
After ACLR with an LDHT graft from a parent in those aged less than 18 years, a second ACL injury (ACL graft or CACL injury) occurred in 1 in 3 patients. The 5-year survival rate of the ACL graft was 76%, and the 5-year survival rate of the CACL was 86%. High IKDC scores and continued participation in sports were maintained over the medium term. Importantly, there was favorable survival of the ACL graft in patients with Tanner stage 1-2 compared with patients with Tanner stage 3-5 over 5 years. Patients with Tanner stage 1-2 also had a significantly lower incidence of second ACL injuries over 5 years compared with those with Tanner stage 3-5, occurring in 1 in 5 patients. Thus, an LDHT graft from a parent is an appropriate graft for physically immature children.
Background
Total hip replacement (THR) and total knee replacement (TKR) are cost‐effective interventions to reduce pain and disability associated with osteoarthritis, however there is no clear ...guidelines available to determine appropriate patient selection and the timing of surgery. This prospective cohort study aimed to evaluate the hospital‐ and surgeon‐level variation in the severity of patient‐reported symptoms prior to THR and TKR.
Methods
Patients undergoing primary THR (n = 4330) or TKR (n = 7054) for osteoarthritis who participated in a national registry‐led Patient Reported Outcome Measures (PROMs) pilot program were included in the analysis. Pre‐operative Oxford Hip Score (OHS) and Oxford Knee Score (OKS) (range 0–48; representing worst to best hip/knee pain and function) data were examined for variation between private and public hospitals and between surgeons using linear mixed models.
Results
Pre‐operative mean OHS was significantly higher (better) in patients whose surgery was performed in a private hospital compared to public hospitals; 21.39 versus 18.11 (mean difference 3.27, 95% CI 1.75, 4.79). For OKS, the difference between private hospital and public hospital scores was dependent on BMI and gender. Most of the variation in pre‐operative OHS and OKS was not at the individual hospital‐ or surgeon‐level, which explained only a negligible proportion of the model variance (⟨5%) for THR and TKR.
Conclusion
Apart from a difference between private and public hospitals, there was little between‐hospital or between‐surgeon symptom variation in joint‐specific pain and function prior to THR or TKR. The findings suggest consistency in the surgical thresholds for patients being offered hip and knee joint replacement procedures.
This study evaluated the hospital‐ and surgeon‐level variation in the severity of patient‐reported symptoms prior to total hip and total knee replacement surgery and found only negligible between‐surgeon variation in symptom severity, but significant differences between public and private hospital settings. These data indicate that surgeons are applying consistent surgical thresholds to hip and knee joint replacement patients. Threshold differences between public and private hospitals may reflect under‐ or over‐treatment and differences in access to care in these settings.
There is a global emphasis on expanding data collection for joint replacement procedures beyond implant attributes and progression to revision surgery. Patient-reported outcome measures (PROMs) are ...increasingly considered as an important measure of surgical outcomes from a patient's perspective. However, a major limitation preventing wider use of PROMs data in national data collection has been the inability to systematically collect and share electronic information with relevant stakeholders in a comprehensive and financially sustainable manner.
This study reports on the development of an electronic data capture and reporting system by a national registry for the collection of PROMs and the processes used to identify and overcome barriers to implementation and uptake. The study also aims to provide a cost breakdown of establishing and maintaining a nationwide electronic PROMs program.
Between 2018 and 2020, 3 governance and advisory committees were established to develop and implement a PROMs pilot program nested within a nationwide joint replacement registry. The program involved electronic collection of preoperative and 6-month postoperative data for hip, knee, or shoulder replacement surgery from 44 Australian hospitals. Resource requirements for the program included a project manager, software developers, data manager, and statistician. An online platform was tested, refined, and implemented for electronic PROMs collection with scalability considered for future expansion to all Australian hospitals and additional data fields. Technical capabilities included different access for multiple user types, patient registration, automatic reminders via SMS text messages and email, online consent, and patient outcome real-time dashboards accessible for different user groups (surgeons, patients, hospitals, and project stakeholders).
During the PROMs pilot period there were 19,699 primary procedures undertaken with 10,204 registered procedures in the electronic system. This equated to 51.80% of people who had a joint replacement at participating hospitals during this period. Patient registration and data collection were efficient (20-30 seconds and 10-12 minutes, respectively). Engagement with the reporting dashboards (as a proportion of those who viewed their dashboard) varied by user group: 197/277 (71.1%) hospital administrators, 68/129 (52.7%) project stakeholders, 177/391 (45.3%) surgeons, and 1138/8840 patients (12.9%). Cost analysis determined an overall cost per patient of Aus $7-15 (approximately US $5-12) for 2 PROMs collections per joint replacement procedure once the program was established.
Successful implementation of an orthopedic PROMs program with planned scalability for a broader national rollout requires significant funding and staffing resources. However, this expenditure can be considered worthwhile, given that collection and reporting of PROMs can drive health care improvement processes. Further consideration of strategies to improve stakeholder engagement with electronic reporting dashboards (particularly for patients and surgeons) will be critical to the ongoing success of a national PROMs program.
Bridged flavinium organocatalysts have displayed efficacy in the diimide mediated reduction of enamides in aqueous conditions. This represents the first diimide reduction of an electron rich alkene ...and offers a clean alternative to the use of alkylating agents for N-alkylation.
This was the first study to investigate the reactogenicity and immunogenicity of heterologous or fractional second dose COVID-19 vaccine regimens in adolescents.
A phase II, single-blind, ...multi-centre, randomised-controlled trial recruited across seven UK sites from September to November 2021, with follow-up visits to August 2022. Healthy 12-to-16 years olds were randomised (1:1:1) to either 30 µg BNT162b2 (BNT-30), 10 µg BNT162b2 (BNT-10), or NVX-CoV2373 (NVX), 8 weeks after a first 30 µg dose of BNT162b2. The primary outcome was solicited systemic reactions in the week following vaccination. Secondary outcomes included immunogenicity and safety. ‘Breakthrough infection’ analyses were exploratory.
148 participants were recruited (median age 14 years old, 62% female, 26% anti-nucleocapsid IgG seropositive pre-second dose); 132 participants received a second dose. Reactions were mostly mild-to-moderate, with lower rates in BNT-10 recipients. No vaccine-related serious adverse events occurred. Compared to BNT-30, at 28 days post-second dose anti-spike antibody responses were similar for NVX (adjusted geometric mean ratio aGMR) 1.09 95% confidence interval (CI): 0.84, 1.42 and lower for BNT-10 (aGMR 0.78 95% CI: 0.61, 0.99). For Omicron BA.1 and BA.2, the neutralising antibody titres for BNT-30 at day 28 were similar for BNT-10 (aGMR 1.0 95% CI: 0.65, 1.54 and 1.02 95% CI: 0.71, 1.48, respectively), but higher for NVX (aGMR 1.7 95% CI: 1.07, 2.69 and 1.43 95% CI: 0.96, 2.12, respectively). Compared to BNT-30, cellular immune responses were greatest for NVX (aGMR 1.73 95% CI: 0.94, 3.18), and lowest for BNT-10 (aGMR 0.65 95% CI: 0.37, 1.15) at 14 days post-second dose. Cellular responses were similar across the study arms by day 236 post-second dose. Amongst SARS-CoV-2 infection naïve participants, NVX participants had an 89% reduction in risk of self-reported ‘breakthrough infection’ compared to BNT-30 (adjusted hazard ratio aHR 0.11 95% CI: 0.01, 0.86) up until day 132 after second dose. BNT-10 recipients were more likely to have a ‘breakthrough infection’ compared to BNT-30 (aHR 2.14 95% CI: 1.02, 4.51) up to day 132 and day 236 post-second dose. Antibody responses at 132 and 236 days after second dose were similar for all vaccine schedules.
Heterologous and fractional dose COVID-19 vaccine schedules in adolescents are safe, well-tolerated and immunogenic. The enhanced performance of the heterologous schedule using NVX-CoV2373 against the Omicron SARS-CoV-2 variant suggests this mRNA prime and protein-subunit boost schedule may provide a greater breadth of protection than the licensed homologous schedule.
National Institute for Health Research and Vaccine Task Force.
International Standard Randomised Controlled Trial Number registry: 12348322.
•Heterologous and fractional dose COVID-19 vaccine schedules in adolescents are safe, well-tolerated and immunogenic.•NVXCoV2373 following 30µg BNT162b2 as a first dose elicited the highest humoral and peak cellular immune responses.•Neutralising antibodies against Omicron BA.1 and BA.2 were higher after NVXCoV2373 than a two-dose 30µg BNT162b2 schedule.•The lowest rate of SARS-CoV-2 breakthrough infections occurred in participants who received NVXCoV2373 as their second dose.•Enhanced protection may be provided by heterologous vaccine schedules using NVXCoV2373 than the homologous BNT162b2 schedule.
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