5-Year survival of pediatric anterior cruciate ligament reconstruction with living donor hamstring tendon grafts

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

Selected Toll-like Receptor Ligands and Viruses Promote Helper-Independent Cytotoxic T Cell Priming by Upregulating CD40L on Dendritic Cells

SummaryCD40L (CD154) on CD4+ T cells has been shown to license dendritic cells (DCs) via CD40 to prime cytotoxic T lymphocyte (CTL) responses. We found that the converse (CD40L on DCs) was also important. Anti-CD40L treatment decreased endogenous CTL responses to both ovalbumin and influenza infection even in the absence of CD4+ T cells. DCs expressed CD40L upon stimulation with agonists to Toll-like receptor 3 (TLR3) and TLR9. Moreover, influenza infection, which stimulates CTLs without help, upregulated CD40L on DCs, but herpes simplex infection, which elicits CTLs through help, did not. CD40L-deficient (Cd40lg−/−) DCs are suboptimal both in vivo in bone marrow chimera experiments and in vitro in mixed lymphocyte reactions. In contrast, Cd40lg−/− CD8+ T cells killed as effectively as wild-type cells. Thus, CD40L upregulation on DCs promoted optimal priming of CD8+ T cells without CD4+ T cells, providing a mechanism by which pathogens may elicit helper-independent CTL immunity

A large-scale genome-wide association study meta-analysis of cannabis use disorder

BACKGROUND: Variation in liability to cannabis use disorder has a strong genetic component (estimated twin and family heritability about 50-70%) and is associated with negative outcomes, including increased risk of psychopathology. The aim of the study was to conduct a large genome-wide association study (GWAS) to identify novel genetic variants associated with cannabis use disorder. METHODS: To conduct this GWAS meta-analysis of cannabis use disorder and identify associations with genetic loci, we used samples from the Psychiatric Genomics Consortium Substance Use Disorders working group, iPSYCH, and deCODE (20 916 case samples, 363 116 control samples in total), contrasting cannabis use disorder cases with controls. To examine the genetic overlap between cannabis use disorder and 22 traits of interest (chosen because of previously published phenotypic correlations [eg, psychiatric disorders] or hypothesised associations [eg, chronotype] with cannabis use disorder), we used linkage disequilibrium score regression to calculate genetic correlations. FINDINGS: We identified two genome-wide significant loci: a novel chromosome 7 locus (FOXP2, lead single-nucleotide polymorphism [SNP] rs7783012; odds ratio [OR] 1·11, 95% CI 1·07-1·15, p=1·84 × 10 INTERPRETATION: These findings support the theory that cannabis use disorder has shared genetic liability with other psychopathology, and there is a distinction between genetic liability to cannabis use and cannabis use disorder. FUNDING: National Institute of Mental Health; National Institute on Alcohol Abuse and Alcoholism; National Institute on Drug Abuse; Center for Genomics and Personalized Medicine and the Centre for Integrative Sequencing; The European Commission, Horizon 2020; National Institute of Child Health and Human Development; Health Research Council of New Zealand; National Institute on Aging; Wellcome Trust Case Control Consortium; UK Research and Innovation Medical Research Council (UKRI MRC); The Brain & Behavior Research Foundation; National Institute on Deafness and Other Communication Disorders; Substance Abuse and Mental Health Services Administration (SAMHSA); National Institute of Biomedical Imaging and Bioengineering; National Health and Medical Research Council (NHMRC) Australia; Tobacco-Related Disease Research Program of the University of California; Families for Borderline Personality Disorder Research (Beth and Rob Elliott) 2018 NARSAD Young Investigator Grant; The National Child Health Research Foundation (Cure Kids); The Canterbury Medical Research Foundation; The New Zealand Lottery Grants Board; The University of Otago; The Carney Centre for Pharmacogenomics; The James Hume Bequest Fund; National Institutes of Health: Genes, Environment and Health Initiative; National Institutes of Health; National Cancer Institute; The William T Grant Foundation; Australian Research Council; The Virginia Tobacco Settlement Foundation; The VISN 1 and VISN 4 Mental Illness Research, Education, and Clinical Centers of the US Department of Veterans Affairs; The 5th Framework Programme (FP-5) GenomEUtwin Project; The Lundbeck Foundation; NIH-funded Shared Instrumentation Grant S10RR025141; Clinical Translational Sciences Award grants; National Institute of Neurological Disorders and Stroke; National Heart, Lung, and Blood Institute; National Institute of General Medical Sciences

Risk factors for adverse perinatal outcomes in imprisoned pregnant women: a systematic review

BACKGROUND: Imprisoned pregnant women constitute an important obstetric group about whom relatively little is known. This systematic review was conducted to identify the risk factors associated with adverse pregnancy outcome present in this group of women. METHODS: The review was conducted according to a prespecified protocol. Studies of any design were included if they described information on any of the pre-specified risk factors. We calculated the results as summary percentages or odds ratios where data was available on both cases and population controls. RESULTS: The search strategy identified 27 relevant papers of which 13 met the inclusion criteria, involving 1504 imprisoned pregnant women and 4571 population control women. Imprisoned women are more likely to be single, from an ethnic minority, and not to have completed high school. They are more likely to have a medical problem which could affect the pregnancy outcome and yet less likely to receive adequate antenatal care. They are also more likely to smoke, drink alcohol to excess and take illegal drugs. CONCLUSION: Imprisoned women are clearly a high risk obstetric group. These findings have important implications for the provision of care to this important group of women

Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis.

Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis

The predictive role of symptoms in COVID-19 diagnostic models : A longitudinal insight

Acknowledgements 2019nCoV-302 Study Group Members: The NVX-CoV2373-2019nCoV-302 clinical trial was a collective group effort across multiple institutions and locations. Below is a list of sites and staff that significantly contributed to the implementation and conduct of the NVX-CoV2373-2019nCoV-302 clinical trial.Peer reviewe

Safety and efficacy of the NVX-CoV2373 coronavirus disease 2019 vaccine at completion of the placebo-controlled phase of a randomized controlled trial

Background: The recombinant protein-based vaccine, NVX-CoV2373, demonstrated 89.7% efficacy against coronavirus disease 2019 (COVID-19) in a phase 3, randomized, observer-blinded, placebo-controlled trial in the United Kingdom. The protocol was amended to include a blinded crossover. Data to the end of the placebo-controlled phase are reported. Methods: Adults aged 18–84 years received 2 doses of NVX-CoV2373 or placebo (1:1) and were monitored for virologically confirmed mild, moderate, or severe COVID-19 (onset from 7 days after second vaccination). Participants who developed immunoglobulin G (IgG) against nucleocapsid protein but did not show symptomatic COVID-19 were considered asymptomatic. Secondary outcomes included anti-spike (S) IgG responses, wild-type virus neutralization, and T-cell responses. Results: Of 15 185 participants, 13 989 remained in the per-protocol efficacy population (6989 NVX-CoV2373, 7000 placebo). At a maximum of 7.5 months (median, 4.5) postvaccination, there were 24 cases of COVID-19 among NVX-CoV2373 recipients and 134 cases among placebo recipients, a vaccine efficacy of 82.7% (95% confidence interval [CI], 73.3%–88.8%). Vaccine efficacy was 100% (95% CI, 17.9%–100.0%) against severe disease and 76.3% (95% CI, 57.4%–86.8%) against asymptomatic disease. High anti-S and neutralization responses to vaccination were evident, together with S-protein–specific induction of interferon-γ secretion in peripheral blood T cells. Incidence of serious adverse events and adverse events of special interest were similar between groups. Conclusions: A 2-dose regimen of NVX-CoV2373 conferred a high level of ongoing protection against asymptomatic, symptomatic, and severe COVID-19 through >6 months postvaccination. A gradual decrease of protection suggests that a booster may be indicated. Clinical Trials Registration: EudraCT, 2020-004123-16

Safety and Efficacy of the NVX-CoV2373 Coronavirus Disease 2019 Vaccine at Completion of the Placebo-Controlled Phase of a Randomized Controlled Trial

Acknowledgements The study and article were funded by Novavax. We would like to thank all the study participants for their commitment to this study. We also acknowledge the investigators and their study teams for their hard work and dedication. In addition, we would like to thank the National Institute for Health Research, representatives from the Department of Health and Social Care laboratories and NHS Digital and the members of the UK Vaccine Task Force. Editorial support was provided by Kelly Cameron of Ashfield MedComms, an Inizio company Funding This work was funded by Novavax, and the sponsor had primary responsibility for study design, study vaccines, protocol development, study monitoring, data management, and statistical analyses. All authors reviewed and approved the manuscript before submission. LF reports a position as a prior full-time employee, now contractor to Novavax re-imbursed hourly for work performed on this study and in analyses and drafting this report. IC reports providing medical writing support for this work as an employee of NovavaxPeer reviewedPublisher PD