Invasive meningococcal disease epidemiology and control measures: a framework for evaluation

<p>Abstract</p> <p>Background</p> <p>Meningococcal disease can have devastating consequences. As new vaccines emerge, it is necessary to assess their impact on public health. In the absence of long-term real world data, modeling the effects of different vaccination strategies is required. Discrete event simulation provides a flexible platform with which to conduct such evaluations.</p> <p>Methods</p> <p>A discrete event simulation of the epidemiology of invasive meningococcal disease was developed to quantify the potential impact of implementing routine vaccination of adolescents in the United States with a quadrivalent conjugate vaccine protecting against serogroups A, C, Y, and W-135. The impact of vaccination is assessed including both the direct effects on individuals vaccinated and the indirect effects resulting from herd immunity. The simulation integrates a variety of epidemiologic and demographic data, with core information on the incidence of invasive meningococcal disease and outbreak frequency derived from data available through the Centers for Disease Control and Prevention. Simulation of the potential indirect benefits of vaccination resulting from herd immunity draw on data from the United Kingdom, where routine vaccination with a conjugate vaccine has been in place for a number of years. Cases of disease are modeled along with their health consequences, as are the occurrence of disease outbreaks.</p> <p>Results</p> <p>When run without a strategy of routine immunization, the simulation accurately predicts the age-specific incidence of invasive meningococcal disease and the site-specific frequency of outbreaks in the Unite States. 2,807 cases are predicted annually, resulting in over 14,000 potential life years lost due to invasive disease. In base case analyses of routine vaccination, life years lost due to infection are reduced by over 45% (to 7,600) when routinely vaccinating adolescents 12 years of age at 70% coverage. Sensitivity analyses indicate that herd immunity plays an important role when this population is targeted for vaccination. While 1,100 cases are avoided annually when herd immunity effects are included, in the absence of any herd immunity, the number of cases avoided with routine vaccination falls to 380 annually. The duration of vaccine protection also strongly influences results.</p> <p>Conclusion</p> <p>In the absence of appropriate real world data on outcomes associated with large-scale vaccination programs, decisions on optimal immunization strategies can be aided by discrete events simulations such as the one described here. Given the importance of herd immunity on outcomes associated with routine vaccination, published estimates of the economic efficiency of routine vaccination with a quadrivalent conjugate vaccine in the United States may have considerably underestimated the benefits associated with a policy of routine immunization of adolescents.</p

CD14 C-159T and Toll-Like Receptor 4 Asp299Gly Polymorphisms in Surviving Meningococcal Disease Patients

BACKGROUND: Carriage of Neisseria meningitidis occurs approximately in 10% of the population, onset of invasive meningococcal disease (IMD) cannot be predicted and differs between ages. It remains unclear, which host factors determine invasion of the bloodstream by the bacteria. Innate immunity has a very important role in the first recognition of invading pathogens. The functional single nucleotide polymorphisms (SNPs) CD14 C-159T and toll-like receptor 4 (TLR4) Asp299Gly have been associated with the risk of gram-negative infections. However, their role in development of IMD still remains unclear. Our aim was to investigate the influence of CD14 C-159T and TLR4 Asp299Gly polymorphisms on the risk of IMD. METHODOLOGY/PRINCIPAL FINDINGS: It was a retrospective case control study. Surviving Austrian meningococcal disease patients were enrolled by sending buccal swabs for DNA analysis. 185 cases with a proven meningococcal infection and 770 healthy controls were enrolled. In surviving meningococcal disease patients DNA analysis of CD14 C-159T and TLR 4 Asp299Gly polymorphisms was performed, as they are part of the innate immune response to bacterial determinants. CD14 C-159T and TLR4 Asp299Gly SNPs were not significantly associated with the presence of IMD when compared to healthy controls. The odds ratio for CD14 C-159T SNP was 1.14 (95% confidence interval (CI) 0.91-1.43; p = 0.266). In TLR4 Asp 299 Gly SNP the odds ratio was 0.78 (CI 0.47-1.43; p = 0.359). CONCLUSION/SIGNIFICANCE: We could not observe a significant influence of CD14 C-159T and TLR4 Asp299Gly polymorphisms on the risk of developing IMD in surviving meningococcal disease patients. To our knowledge, this is the first study investigating the influence of the CD14 C-159T SNP on the susceptibility to IMD

A study to explore specific stressors and coping strategies in primary dental care practice

Background and Aims: It is widely acknowledged that dentists experience occupational stress. This qualitative study aimed to explore previously identified specific stressors in more detail in order to inform the development of a future stress management programme. Method: Two focus groups of dentists (N: 7 & 6) were conducted to explore, in more detail, nine specific stressors and concepts; being out of one’s comfort zone, zoning out from the patient, celebrating the positive aspects of work, thinking aloud, the effect of hurting patients, the impact of perfectionism, responsibility for patient’s self-care, the emotional impact of difficult situations as a foundation dentist. Participants were also asked for their views on the structure and contents of the proposed stress management package. Verbatim transcripts were subjected to thematic analysis. Results and Discussion: Dentists described the impact of these stressors and their current coping methods; thematic analysis revealed 9 themes which covered the above concepts and a further overall theme of need for control. The findings are elaborated in connection to their relevant stress, coping and emotion psychological theory. Their implications for personal well-being and clinical outcomes are discussed. Conclusion: Dentists’ stressful and coping experiences are complex and it is essential that any stress management programme reflects this and that the skills are easily accessible and sustainable within the context of a busy dental practice

Utilisation of an operative difficulty grading scale for laparoscopic cholecystectomy

Background A reliable system for grading operative difficulty of laparoscopic cholecystectomy would standardise description of findings and reporting of outcomes. The aim of this study was to validate a difficulty grading system (Nassar scale), testing its applicability and consistency in two large prospective datasets. Methods Patient and disease-related variables and 30-day outcomes were identified in two prospective cholecystectomy databases: the multi-centre prospective cohort of 8820 patients from the recent CholeS Study and the single-surgeon series containing 4089 patients. Operative data and patient outcomes were correlated with Nassar operative difficultly scale, using Kendall’s tau for dichotomous variables, or Jonckheere–Terpstra tests for continuous variables. A ROC curve analysis was performed, to quantify the predictive accuracy of the scale for each outcome, with continuous outcomes dichotomised, prior to analysis. Results A higher operative difficulty grade was consistently associated with worse outcomes for the patients in both the reference and CholeS cohorts. The median length of stay increased from 0 to 4 days, and the 30-day complication rate from 7.6 to 24.4% as the difficulty grade increased from 1 to 4/5 (both p < 0.001). In the CholeS cohort, a higher difficulty grade was found to be most strongly associated with conversion to open and 30-day mortality (AUROC = 0.903, 0.822, respectively). On multivariable analysis, the Nassar operative difficultly scale was found to be a significant independent predictor of operative duration, conversion to open surgery, 30-day complications and 30-day reintervention (all p < 0.001). Conclusion We have shown that an operative difficulty scale can standardise the description of operative findings by multiple grades of surgeons to facilitate audit, training assessment and research. It provides a tool for reporting operative findings, disease severity and technical difficulty and can be utilised in future research to reliably compare outcomes according to case mix and intra-operative difficulty

Assessment of Blood Hemodynamics by USPIO-Induced R1 Changes in MRI of Murine Colon Carcinoma

The objective of this study is to assess whether ultrasmall superparamagnetic iron oxide (USPIO)-induced changes of the water proton longitudinal relaxation rate (R1) provide a means to assess blood hemodynamics of tumors. Two types of murine colon tumors (C26a and C38) were investigated prior to and following administration of USPIO blood-pool contrast agent with fast R1 measurements. In a subpopulation of mice, R1 was measured following administration of hydralazine, a well-known blood hemodynamic modifier. USPIO-induced R1 increase in C38 tumors (ΔR1 = 0.072 ± 0.0081 s−1) was significantly larger than in C26a tumors (ΔR1 = 0.032 ± 0.0018 s−1, N = 9, t test, P < 0.001). This was in agreement with the immunohistochemical data that showed higher values of relative vascular area (RVA) in C38 tumors than in C26a tumors (RVA = 0.059 ± 0.015 vs. 0.020 ± 0.011; P < 0.05). Following administration of hydralazine, a decrease in R1 value was observed. This was consistent with the vasoconstriction induced by the steal effect mechanism. In conclusion, R1 changes induced by USPIO are sensitive to tumor vascular morphology and to blood hemodynamics. Thus, R1 measurements following USPIO administration can give novel insight into the effects of blood hemodynamic modifiers, non-invasively and with a high temporal resolution

Understanding emotionally relevant situations in primary care dental practice: 1. Clinical situations and emotional responses

Background and aims. The stressful nature of dental practice is well established. Much less information is available on the coping strategies used by dentists and the emotions which underlie the stressful experience. Previous research has been almost exclusively questionnaire-based, limiting the range of emotions explored. This study used qualitative methods to explore the full extent of emotions and coping strategies associated with stressful events in primary dental practice. Method. Semi-structured interviews were conducted with 20 dentists in Lincoln and the surrounding area. Verbatim transcriptions were analysed using thematic analysis. Results. Participants reported a wide variety of stressful situations, consistent with the existing literature, which were associated with a diverse range of negative emotional responses including anxiety, anger and sadness. Dentists tended to have more difficulty identifying positive events and emotions. The designation of a situation as stressful or otherwise was dependent on the dentist's personal interpretation of the event. Data relating to the effects of stressors and the coping strategies used by dentists will be presented in subsequent papers. Conclusion. The situations which dentists find difficult are accompanied by a diverse set of emotions, rather than omnipresent 'stress.' This has implications for stress management programmes for those in dental practic

Meningococcal Factor H Binding Proteins in Epidemic Strains from Africa: Implications for Vaccine Development

Epidemics of meningococcal meningitis are common in sub-Saharan Africa. Most are caused by encapsulated serogroup A strains, which rarely cause disease in industrialized countries. A serogroup A polysaccharide protein conjugate vaccine recently was introduced in some countries in sub-Saharan Africa. The antibodies induced, however, may allow replacement of serogroup A strains with serogroup W-135 or X strains, which also cause epidemics in this region. Protein antigens, such as factor H binding protein (fHbp), are promising for prevention of meningococcal serogroup B disease. These proteins also are present in strains with other capsular serogroups. Here we report investigation of the potential of fHbp vaccines for prevention of disease caused by serogroup A, W-135 and X strains from Africa. Four fHbp amino acid sequence variants accounted for 81% of the 106 African isolates studied. While there was little cross-protective activity by antibodies elicited in mice by recombinant fHbp vaccines from each of the four sequence variants, a prototype native outer membrane vesicle (NOMV) vaccine from a mutant with over-expressed fHbp elicited antibodies with broad protective activity. A NOMV vaccine has the potential to supplement coverage by the group A conjugate vaccine and help prevent emergence of disease caused by non-serogroup A strains

One year of smokefree bars and restaurants in New Zealand: Impacts and responses

BACKGROUND: New Zealand introduced a smokefree bars and restaurants policy in December 2004. We reviewed the data available at December 2005 on the main public health, societal and political impacts and responses within New Zealand to the new law. METHODS: Data were collected from publicly available survey reports, and from government departments and interviews. This included data on smoking in bars, attitudes to smokefree bars, bar patronage, socially cued smoking, and perceived rights to smokefree workplaces. RESULTS: The proportion of surveyed bars with smoking occurring decreased from 95% to 3% during July 2004 – April 2005. Between 2004 and 2005, public support for smokefree bars rose from 56% to 69%. In the same period, support for the rights of bar workers to have smokefree workplaces rose from 81% to 91%. During the first ten months of the smokefree bars policy, there were only 196 complaints to officials about smoking in the over 9900 licensed premises. The proportion of smokers who reported that they smoked more than normal at bars, nightclubs, casinos and cafés halved between 2004 and 2005 (from 58% to 29%). Seasonally adjusted sales in bars and clubs changed little (0.6% increase) between the first three quarters of 2004 and of 2005, while café and restaurant sales increased by 9.3% in the same period. Both changes continued existing trends. Compared to the same period in 2004, average employment during the first three quarters of 2005 was up 24% for 'pubs, taverns and bars', up 9% for cafés/restaurants, and down 8% for clubs (though employment in 'pubs, taverns and bars' may have been affected by unusually high patronage around a major sports-series). The proportion of bar managers who approved of smokefree bars increased from 44% to 60% between November 2004 and May 2005. Bar managers also reported increased agreement with the rights of bar workers and patrons to smokefree environments. The main reported concerns of the national and regional Hospitality Associations, in 2005, were the perceived negative effects on rural and traditional pubs. CONCLUSION: As in other jurisdictions, the introduction of smokefree bars in New Zealand has had positive overall health protection, economic and social effects; in contrast to the predictions of opponents

Consequences of Cold-Ischemia Time on Primary Nonfunction and Patient and Graft Survival in Liver Transplantation: A Meta-Analysis

Introduction: The ability to preserve organs prior to transplant is essential to the organ allocation process. Objective: The purpose of this study is to describe the functional relationship between cold-ischemia time (CIT) and primary nonfunction (PNF), patient and graft survival in liver transplant. Methods: To identify relevant articles Medline, EMBASE and the Cochrane database, including the non-English literature identified in these databases, was searched from 1966 to April 2008. Two independent reviewers screened and extracted the data. CIT was analyzed both as a continuous variable and stratified by clinically relevant intervals. Nondichotomous variables were weighted by sample size. Percent variables were weighted by the inverse of the binomial variance. Results: Twenty-six studies met criteria. Functionally, PNF%=-6.678281+0.9134701*CIT Mean+0.1250879*(CIT Mean-9.89535) 2 - 0.0067663*(CIT Mean-9.89535) 3, r2=.625, p<.0001. Mean patient survival: 93 % (1 month), 88 % (3 months), 83 % (6 months) and 83 % (12 months). Mean graft survival: 85.9 % (1 month), 80.5 % (3 months), 78.1 % (6 months) and 76.8 % (12 months). Maximum patient and graft survival occurred with CITs between 7.5-12.5 hrs at each survival interval. PNF was also significantly correlated with ICU time, % first time grafts and % immunologic mismatches. Conclusion: The results of this work imply that CIT may be the most important pre-transplant information needed in the decision to accept an organ. © 2008 Stahl et al

The opposing transcriptional functions of Sin3a and c-Myc are required to maintain tissue homeostasis.

How the proto-oncogene c-Myc balances the processes of stem-cell self-renewal, proliferation and differentiation in adult tissues is largely unknown. We explored c-Myc's transcriptional roles at the epidermal differentiation complex, a locus essential for skin maturation. Binding of c-Myc can simultaneously recruit (Klf4, Ovol-1) and displace (Cebpa, Mxi1 and Sin3a) specific sets of differentiation-specific transcriptional regulators to epidermal differentiation complex genes. We found that Sin3a causes deacetylation of c-Myc protein to directly repress c-Myc activity. In the absence of Sin3a, genomic recruitment of c-Myc to the epidermal differentiation complex is enhanced, and re-activation of c-Myc-target genes drives aberrant epidermal proliferation and differentiation. Simultaneous deletion of c-Myc and Sin3a reverts the skin phenotype to normal. Our results identify how the balance of two transcriptional key regulators can maintain tissue homeostasis through a negative feedback loop