Abstract Background and aims Annexin-A2 (AnxA2) is an endogenous inhibitor of proprotein convertase subtilisin/kexin type-9 (PCSK9). The repeat-one (R1) domain of AnxA2 binds to PCSK9, blocking its ...ability to promote degradation of low-density lipoprotein cholesterol-receptors (LDL-R) and thereby regulate low-density lipoprotein cholesterol (LDL-C) levels. Here we identify variants in ANXA2 influencing LDL-C levels and we determine the molecular mechanisms of their effects. Results The ANXA2 single nucleotide polymorphism (SNP) genotype-phenotype association was examined using the Second-Northwick-Park Heart Study (NPHSII) (n∼2700) and the UCL-LSHTM-Edinburgh-Bristol (UCLEB) consortium (n∼14,600). The ANXA2 -R1 domain coding-SNP rs17845226 (V98L) associated with LDL-C, homozygotes for the minor allele having ≈18.8% higher levels of LDL-C ( p = 0.004), and higher risk of coronary heart disease (CHD) ( p = 0.04). The SNP is in modest linkage disequilibrium (r2 > 0.5) with two intergenic SNPs, rs17191344 and rs11633032. Both SNPs showed allele-specific protein binding, and the minor alleles caused significant reduction in reporter gene expression (≈18%, p < 0.001). In the expression quantitative trait loci (eQTL) study, minor allele homozygotes have significantly lower levels of ANXA2 -mRNA expression ( p = 1.36 × 10−05 ). Conclusions Both rs11633032 and rs17191344 SNPs are functional variants, where the minor alleles create repressor-binding protein sites for transcription factors that contribute to reduced ANXA2 gene expression. Lower AnxA2 levels could increase plasma levels of PCSK9 and thus increase LDL-C levels and risk of CHD. This supports, for the first time in humans, previous observations in mouse models that changes in the levels of AnxA2 directly influence plasma LDL-C levels, and thus implicate this protein as a potential therapeutic target for LDL-C lowering.
We have demonstrated that recombinant hepatitis E vaccine suitable for clinical evaluation was highly immunogenic and efficacious in preventing hepatitis E and even infection in rhesus macaques ...following intravenous challenge with three different genotypes of hepatitis E virus (HEV). Two doses of vaccine were essential for optimal protection; the two-dose regimen was more important than the formulation of the vaccine for achieving efficacy. The titers of anti-HEV that were protective in this study were quantified against a World Health Organization (WHO) standard. This permits direct comparison of the results with other studies. The results of this pre-clinical trial of a candidate hepatitis E vaccine strongly suggest that it will be highly efficacious for preventing hepatitis E in the field trial of this vaccine that is currently in progress in Nepal.
Hepatitis C virus (HCV) is the most important etiologic agent of non-A, non-B hepatitis and is a major cause of chronic liver disease and hepatocellular carcinoma. Development of an effective vaccine ...would be the most practical method for prevention of the infection, but whether infection with HCV elicits protective immunity in the host is unclear. Neutralization of HCV in vitro was attempted with plasma of a chronically infected patient, and the residual infectivity was evaluated by inoculation of eight seronegative chimpanzees. The source of HCV was plasma obtained from a patient during the acute phase of posttransfusion non-A, non-B hepatitis, which had previously been titered for infectivity in chimpanzees. Neutralization was achieved with plasma obtained from the same patient 2 yr after the onset of primary infection but not with plasma obtained 11 yr later, although both plasmas contained antibodies against nonstructural and structural (including envelope) HCV proteins. Analysis of sequential viral isolates from the same patient revealed significant genetic divergence as early as 2 yr after infection. However, the HCV recovered from the patient 2 yr after the infection had a striking sequence similarity with the HCV recovered from one of the chimpanzees inoculated with the acute-phase virus, suggesting that the progenitor of the new strain was already present 2 yr earlier. This evidence, together with the different sequences of HCV recovered from the chimpanzees that received the same inoculum, confirms that HCV is present in vivo as a quasispecies. These results provide experimental evidence in vivo that HCV infection elicits a neutralizing antibody response in humans but suggest that such antibodies are isolate-specific. This result raises concerns for the development of a broadly reactive vaccine against HCV.
Purpose: Liver transplantation (LT) is the definite curative treatment for hepatocellular carcinoma (HCC), but recurrence can occur even under stringent criteria. “Delayed” HCC recurrence (> 3 years ...after LT) is not common. Here, we present the clinical features of patients who developed delayed HCC recurrence after LT. Patients and Methods: We reviewed the data of eligible patients from February 1999 to December 2020 from medical records. Results: From among 195 (17%) HCC patients who received LT, 34 experienced HCC recurrence, with 5 (15%) delayed recurrence. These five explant tumors were staged T1b–T2, graded II–III, with two vascular invasion and four beyond the Milan criteria. The median time to recurrence was 6.1 years, with the longest interval being nearly 18 years. Recurrence patterns included two extrahepatic, one intrahepatic, and two mixed extrahepatic and intrahepatic recurrences. A drastic increase in serum alpha-fetoprotein levels was observed in four cases 1 year before recurrence. Management of recurrence included locoregional (surgssical resection in three, radiotherapy in three, transarterial chemoembolization in one, radiofrequency ablation in one) and systemic sorafenib use in three. Two patients died within 12– 18 months, one died within 18– 24 months, and two are still alive until the end of the study, with respective 13.5- and 16.5-month survival. Conclusion: Delayed HCC recurrence could occur over 10 years. Therefore, continual surveillance for recurrence is justified, but biomarkers and intervals or intensities specific for delayed recurrence are not validated, which warrants further validation to facilitate personalized medical care.
Aims: Tissue transglutaminase (tTG) is a major autoantigen recognised by IgA anti-endomysial antibodies (IgA EMA). Enzyme linked immunosorbent assays (ELISA) for IgA anti-tissue transglutaminase ...antibodies (IgA tTG) have therefore been developed as an alternative serological screening test to IgA EMA for coeliac disease (CD). The use of human tTG (h-tTG), as opposed to guinea pig liver tTG (gpl-tTG), in these assays has been reported to produce superior results. This study compared 13 commercial IgA tTG ELISA kits to ascertain their performance characteristics in the diagnosis of CD in patients with biopsy confirmed disease compared with controls. All patients and controls were adults aged 21 years or older. Methods: Sera from the following groups of patients were tested in each kit: (1) 49 patients with CD confirmed on small bowel biopsies (all IgA EMA positive); (2) 34 patients with small bowel biopsies that were not consistent with CD; and (3) 30 patients with biopsy confirmed inflammatory bowel disease. All controls were negative for IgA EMA and were not IgA deficient. Sensitivities and specificities were determined using both the manufacturers' recommended cut off points and receiver operating characteristic (ROC) analysis derived decision thresholds. The area under the curve (AUC) for each ROC plot was also calculated and compared between kits. Results: In general, the h-tTG based IgA tTG ELISA kits demonstrated superior performance (especially specificity) compared with the gpl-tTG based kits, although 100% sensitivity and specificity (comparable to the IgA EMA assay) was obtained in only one recombinant h-tTG based kit. Conclusions: The use of h-tTG in IgA tTG ELISA kits is generally, but not universally, associated with superior performance. Factors other than antigen source are important in determining kit performance.
Purpose
The purpose of this study is to examine the effects of managers’ authentic leadership, person–job match in the six areas of worklife (AWLs) and emotional exhaustion on long-term care ...registered nurses’ job satisfaction.
Design/methodology/approach
A secondary analysis of baseline data from a national survey of 1,410 Canadian registered nurses from various work settings was used in this study, which yielded a subsample of 78 nurses working in direct care roles in long-term care settings. Hayes’ PROCESS macro for mediation analysis in SPSS was used to test the hypothesized model.
Findings
Findings showed that authentic leadership significantly predicted job satisfaction directly and indirectly through AWLs and emotional exhaustion.
Practical implications
Authentic leadership may provide guidance to long-term care managers about promoting nurses’ job satisfaction, which is essential to recruiting and retaining nurses to meet the care needs of an aging population.
Originality/value
As demand for care of the aged is increasing and creating challenges to ensuring a sufficient and sustainable nursing workforce, it is important to understand factors that promote long-term care nurses’ job satisfaction. Findings contribute to knowledge of long-term care nurses by suggesting that managers’ authentic leadership can positively affect nurses’ job satisfaction directly and indirectly through positive perceptions of AWLs and lower emotional exhaustion.
IntroductionOlder adults prioritise surviving surgery, but also preservation of their functional status and quality of life. Current approaches to measure postoperative recovery, which focus on ...death, complications and length of hospitalisation, may miss key relevant domains. We propose that postoperative disability is an important patient-centred outcome to measure intermediate-to-long recovery after major surgery in older adults.Methods and analysisThe Functional Improvement Trajectories After Surgery (FIT After Surgery) study is a multicentre cohort study of 2000 older adults (≥65 years) having major non-cardiac surgery. Its objectives are to characterise the incidence, trajectories, risk factors and impact of new significant disability after non-cardiac surgery. Disability is assessed using WHO Disability Assessment Schedule (WHODAS) 2.0 instrument and participants’ level-of-care needs. Disability assessments occur before surgery, and at 1, 3, 6, 9 and 12 months after surgery. The primary outcome is significantly worse WHODAS score or death at 6 months after surgery. Secondary outcomes are (1) significantly worse WHODAS score or death at 1 year after surgery, (2) increased care needs or death at 6 months after surgery and (3) increased care needs or death at 1 year after surgery. We will use multivariable logistic regression models to determine the association of preoperative characteristics and surgery type with outcomes, joint modelling to characterise longitudinal time trends in WHODAS scores over 12 months after surgery, and longitudinal latent class mixture models to identify clusters following similar trajectories of disability.Ethics and disseminationThe FIT After Surgery study has received research ethics board approval at all sites. Recruitment began in December 2019 but was placed on hold in March 2020 because of the COVID-19 pandemic. Recruitment was gradually restarted in October 2020, with 1-year follow-up expected to finish in 2023. Publication of the primary results is anticipated to occur in 2024.
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