Public health and economic benefits of seasonal influenza vaccination in risk groups in France, Italy, Spain and the UK: state of play and perspectives.

BACKGROUND: Seasonal influenza epidemics have a substantial public health and economic burden, which can be alleviated through vaccination. The World Health Organization (WHO) recommends a 75% vaccination coverage rate (VCR) in: older adults (aged ≥ 65 years), individuals with chronic conditions, pregnant women, children aged 6-24 months and healthcare workers. However, no European country achieves this target in all risk groups. In this study, potential public health and economic benefits achieved by reaching 75% influenza VCR was estimated in risk groups across four European countries: France, Italy, Spain, and the UK. METHODS: A static epidemiological model was used to estimate the averted public health and economic burden of increasing the 2021/2022 season VCR to 75%, using the efficacy data of standard-dose quadrivalent influenza vaccine. For each country and risk group, the most recent data on population size, VCR, pre-pandemic influenza epidemiology, direct medical costs and absenteeism were identified through a systematic literature review, supplemented by manual searching. Outcomes were: averted influenza cases, general practitioner (GP) visits, hospitalisations, case fatalities, number of days of work lost, direct medical costs and absenteeism-related costs. RESULTS: As of the 2021/2022 season, the UK achieved the highest weighted VCR across risk groups (65%), followed by Spain (47%), France (44%) and Italy (44%). Based on modelling, the 2021/2022 VCR prevented an estimated 1.9 million influenza cases, avoiding 375,200 GP visits, 73,200 hospitalisations and 38,400 deaths. To achieve the WHO 75% VCR target, an additional 24 million at-risk individuals would need to be vaccinated, most of which being older adults and patients with chronic conditions. It was estimated that this could avoid a further 918,200 influenza cases, 332,000 GP visits, 16,300 hospitalisations and 6,300 deaths across the four countries, with older adults accounting for 52% of hospitalisations and 80% of deaths. An additional €84 million in direct medical costs and €79 million in absenteeism costs would be saved in total, with most economic benefits delivered in France. CONCLUSIONS: Older adults represent most vaccine-preventable influenza cases and deaths, followed by individuals with chronic conditions. Health authorities should prioritise vaccinating these populations for maximum public health and economic benefits.

Cost of illness of the vaccine-preventable diseases influenza, herpes zoster and pneumococcal disease in France.

BACKGROUND: The incidence of certain vaccine-preventative diseases, such as influenza, herpes zoster and pneumococcal infection, continues to be high despite the availability of vaccines, resulting in a substantial health and economic burden on society, particularly among older adults aged ≥65 years. METHODS: A cost calculator was developed to assess the cost of illness of influenza, herpes zoster and pneumococcal disease in France. Direct medical costs related to diagnosis and treatment in the older adult population in both inpatient and outpatient settings were modelled over a 1-year time horizon. Scenario analyses were conducted to determine the impact of hospitalizations on the results by considering only influenza-attributed diagnoses. RESULTS: In France, influenza has the highest incidence, followed by herpes zoster and pneumococcal disease. Similarly, influenza poses the greatest cost burden among all older adults, while pneumococcal disease poses the greatest cost burden among those aged 65-74 years. When considering only influenza-attributed diagnoses, the number of inpatient visits and associated costs was reduced by 63% in the overall older adult population. In the low-incidence season, the number of inpatient visits and associated costs were reduced by 69%, while in the high-incidence season, the number of inpatient visits and associated costs increased by 63%. CONCLUSION: Influenza remains a leading vaccine-preventable disease among older adults in France, resulting in a substantial economic burden that could be prevented by increasing vaccine uptake.

Hospital admissions with influenza and impact of age and comorbidities on severe clinical outcomes in Brazil and Mexico.

BACKGROUND: The risk of hospitalization or death after influenza infection is higher at the extremes of age and in individuals with comorbidities. We estimated the number of hospitalizations with influenza and characterized the cumulative risk of comorbidities and age on severe outcomes in Mexico and Brazil. METHODS: We used national hospital discharge data from Brazil (SIH/SUS) from 2010-2018 and Mexico (SAEH) from 2010-2017 to estimate the number of influenza admissions using ICD-10 discharge codes, stratified by age (0-4, 5-17, 18-49, 50-64, and ≥65 years). Duration of hospital stay, admission to the intensive care unit (ICU), and in-hospital case fatality rates (CFRs) defined the severe outcomes. Rates were compared between patients with or without pre-specified comorbidities and by age. RESULTS: A total of 327,572 admissions with influenza were recorded in Brazil and 20,613 in Mexico, with peaks period most years. In Brazil, the median hospital stay duration was 3.0 days (interquartile range, 2.0-5.0), ICU admission rate was 3.3% (95% CI, 3.2-3.3%), and in-hospital CFR was 4.6% (95% CI, 4.5-4.7). In Mexico, the median duration of stay was 5.0 days (interquartile range, 3.0-7.0), ICU admission rate was 1.8% (95% CI, 1.6-2.0%), and in-hospital CFR was 6.9% (95% CI, 6.5-7.2). In Brazil, ICU admission and in-hospital CFR were higher in adults aged ≥50 years and increased in the presence of comorbidities, especially cardiovascular disease. In Mexico, comorbidities increased the risk of ICU admission by 1.9 (95% CI, 1.0-3.5) and in-hospital CFR by 13.9 (95% CI, 8.4-22.9) in children 0-4 years. CONCLUSION: The SIH/SUS and SAEH databases can be used to estimate hospital admissions with influenza, and the disease severity. Age and comorbidities, especially cardiovascular disease, are cumulatively associated with more severe outcomes, with differences between countries. This association should be further analyzed in prospective surveillance studies designed to support influenza vaccination strategy decisions.

Public health and budget impacts of switching from a trivalent to a quadrivalent inactivated influenza vaccine in Paraguay.

This study aimed to investigate the public health and economic benefit of using a quadrivalent influenza vaccine (QIV) instead of a trivalent influenza vaccine (TIV) in past seasons in Paraguay. The budget impact of switching from TIV to QIV in the Immunization Program was also evaluated. The adapted model includes two modules. The first compared retrospectively Health and Economic outcomes resulting from the use of QIV instead of TIV. The second forecast the spending and savings that would be associated with the switch from TIV to QIV. Our findings estimate that the switch from TIV to QIV during the seasons 2012 to 2017 could have prevented around 2,600 influenza cases, 67 hospitalizations and 10 deaths. An alternative scenario using standardized estimates of the burden of influenza showed that 234 influenza-related hospitalizations and 29 deaths could have been prevented. The estimated annual budget impact of a full switch from TIV to QIV was around USD1,6 million both from the payer and societal perspectives. Those results are mainly driven by vaccine prices and coverage rate. In sum, this manuscript describes how the use of QIV instead of TIV could have prevented influenza cases and subsequent complications that led to hospitalizations and deaths. This could have generated savings for the health system and society, offsetting part of the additional investment needed to switch from TIV to QIV.

Switching from trivalent to quadrivalent inactivated influenza vaccines in Uruguay: a cost-effectiveness analysis.

We evaluated the cost-utility of replacing trivalent influenza vaccine (TIV) with quadrivalent influenza vaccine (QIV) in the current target populations in Uruguay. An existing decision-analytic static cost-effectiveness model was adapted for Uruguay. The population was stratified into age groups. Costs and outcomes were estimated for an average influenza season, based on observed rates from 2013 to 2019 inclusive. Introducing QIV instead of TIV in Uruguay would avoid around 740 additional influenza cases, 500 GP consultations, 15 hospitalizations, and three deaths, and save around 300 workdays, for the same vaccination coverage during an average influenza season. Most of the influenza-related consultations and hospitalizations would be avoided among children ≤4 and adults ≥65 years of age. Using QIV rather than TIV would cost an additional ~US$729,000, but this would be partially offset by savings in consultations and hospitalization costs. The incremental cost per quality-adjusted life-year (QALY) gained with QIV would be in the order of US$18,000 for both the payor and societal perspectives, for all age groups, and around US$12,000 for adults ≥65 years of age. The main drivers influencing the incremental cost-effectiveness ratio were the vaccine efficacy against the B strains and the percentage of match each season with the B strain included in TIV. Probabilistic sensitivity analysis showed that switching to QIV would provide a favorable cost-utility ratio for 50% of simulations at a willingness-to-pay per QALY of US$20,000. A switch to QIV is expected to be cost-effective for the current target populations in Uruguay, particularly for older adults.

Cost-effectiveness analysis of switching from a trivalent to a quadrivalent inactivated influenza vaccine in the Peruvian immunisation programme.

BACKGROUND: Seasonal influenza is an acute respiratory infection mostly caused by type A and B influenza viruses. The severe form of the infection can be life-threatening and lead to a significant burden. Vaccination is the most efficient way of preventing influenza infections and limit this burden. OBJECTIVES: To assess the cost-effectiveness of switching from a trivalent influenza vaccine (TIV) to a quadrivalent influenza vaccine (QIV) in the vaccination programme in Peru, and to evaluate the health and economic impact of reaching the vaccination coverage rate targeted by the Ministry of Health. METHODS: A decision-analytic static cost-effectiveness model, was adapted to the Peruvian setting under both payer and societal perspectives. RESULTS: A switch from TIV to QIV would prevent 29,126 additional cases (including 12,815 consultations), 54 hospitalisations, and 23 deaths related to influenza, mostly in the population <2 years-old and >60 years-old. This would lead to a saving of US $505,206 under the payer perspective, that would partially offset the investment necessary to introduce QIV into the immunisation programme. The resulting incremental cost-effectiveness ratio (ICER) is $16,649 per QALYs gained. The main drivers of the model results were vaccine efficacy against influenza B viruses, degree of match, vaccines prices and proportion of cases attributable to influenza B. The robustness of the results seems satisfactory as QIV has the probability of being a cost-effective strategy of 83.8% (considering a threshold of three GDP per capita). Reaching the coverage targeted by the Ministry of Health would result in health benefits and disease management savings, and lower ICERs. CONCLUSION: Introducing QIV instead of TIV in the Peruvian immunisation programme is expected to be a cost-effective strategy, especially in younger children and the elderly. The benefit of QIV would be even more important if the coverage targeted by the Ministry of Health would be reached in the most vulnerable groups.

Impact of quadrivalent influenza vaccines in Brazil: a cost-effectiveness analysis using an influenza transmission model.

BACKGROUND: Influenza epidemics significantly weight on the Brazilian healthcare system and its society. Public health authorities have progressively expanded recommendations for vaccination against influenza, particularly to the pediatric population. However, the potential mismatch between the trivalent influenza vaccine (TIV) strains and those circulating during the season remains an issue. Quadrivalent vaccines improves vaccines effectiveness by preventing any potential mismatch on influenza B lineages. METHODS: We evaluate the public health and economic benefits of the switch from TIV to QIV for the pediatric influenza recommendation (6mo-5yo) by using a dynamic epidemiological model able to consider the indirect impact of vaccination. Results of the epidemiological model are then imputed in a health-economic model adapted to the Brazilian context. We perform deterministic and probabilistic sensitivity analysis to account for both epidemiological and economical sources of uncertainty. RESULTS: Our results show that switching from TIV to QIV in the Brazilian pediatric population would prevent 406,600 symptomatic cases, 11,300 hospitalizations and almost 400 deaths by influenza season. This strategy would save 3400 life-years yearly for an incremental direct cost of R$169 million per year, down to R$86 million from a societal perspective. Incremental cost-effectiveness ratios for the switch would be R$49,700 per life-year saved and R$26,800 per quality-adjusted life-year gained from a public payer perspective, and even more cost-effective from a societal perspective. Our results are qualitatively similar in our sensitivity analysis. CONCLUSIONS: Our analysis shows that switching from TIV to QIV to protect children aged 6mo to 5yo in the Brazilian influenza epidemiological context could have a strong public health impact and represent a cost-effective strategy from a public payer perspective, and a highly cost-effective one from a societal perspective.

Cost-effectiveness of bevacizumab plus paclitaxel versus paclitaxel for the first-line treatment of HER2-negative metastatic breast cancer in specialist oncology centers in France.

BACKGROUND: Evidence from clinical trials suggests that the addition of bevacizumab to chemotherapy in the first-line treatment of patients with HER2-negative metastatic breast cancer improves progression-free survival (PFS) but not overall survival (OS). However, a retrospective analysis of real-world data from the French Comprehensive Cancer Centers (FCCC) through the Epidemiological Strategy and Medical Economics (ESME) Research Program, suggested that in this setting, the addition of bevacizumab may confer a significant benefit in terms of both PFS and OS. A cost-effectiveness analysis was performed to determine the cost-effectiveness of bevacizumab plus paclitaxel versus paclitaxel alone in the first-line treatment of HER2-negative metastatic breast cancer at specialist oncology centers in France. METHODS: The analysis was performed using a three-state Markov model and clinical input data from N = 3426 HER2-negative metastatic breast cancer patients treated with bevacizumab plus paclitaxel or paclitaxel alone. The analysis was performed from a third party payer perspective over a 10-year time horizon; future costs and clinical outcomes were discounted at 4% per annum. RESULTS: In the overall population, the addition of bevacizumab to paclitaxel led to incremental gain of 0.72 life years and 0.48 quality-adjusted life years (QALYs) relative to paclitaxel alone. The incremental lifetime cost of the addition of bevacizumab was EUR 27,390, resulting in an incremental cost-effectiveness ratio (ICER) of EUR 56,721 per QALY gained for bevacizumab plus paclitaxel versus paclitaxel alone. In a subgroup of triple negative patients the ICER was EUR 66,874 per QALY gained. CONCLUSIONS: The analysis indicated that the combination of bevacizumab plus paclitaxel is likely to be cost-effective compared with paclitaxel alone for the first-line treatment of HER2-negative metastatic breast cancer in specialized oncology centers in France.

Comparison of the Thorax Dynamic Responses of Small Female and Midsize Male Post Mortem Human Subjects in Side and Forward Oblique Impact Tests.

Despite the increasing knowledge of the thorax mechanics in impact loadings, the effects of inter-individual differences on the mechanical response are difficult to take into account. For example, the biofidelity corridors for the small female or large male are extrapolated from the midsize male corridors. The present study reports on the results of new tests performed on small female Post Mortem Human Subjects (PMHS), and compares them with test results on midsize male PMHS. Three tests in pure side impact and three tests in forward oblique impact were performed on the thorax of small female specimens. The average weight and stature were 43 kg and 1.58 m for the small female specimens. The initial speed of the impactor was 4.3 m/s. The mass and the diameter of the impactor face were respectively 23.4 kg and 130 mm. The instrumentation and methodology was the same as for the tests published in 2008 by Trosseille et al. on midsize male specimens. The rib cages were instrumented with accelerometers on the T1, T4 and T12 vertebrae, upper and lower sternum, and the ribs were instrumented with up to 110 strain gauges. A force transducer and an accelerometer were mounted on the impactor in order to record the force applied onto the thorax. Targets fixed on vertebrae were tracked using high speed cameras in order to estimate the thoracic deflection. For the six midsize males, the test conditions were exactly the same as for the small female specimens, except for the diameter of the impactor face which was 152 mm. The average weight and stature were 70.3 kg and 1.70 m for the midsize male specimens. The force and thoracic deflection time-histories and the injury assessments are given for each specimen. The thorax force magnitude varied from 1.05 to 1.45 kN and from 1.63 to 2.34 kN, respectively for the small female and midsize male groups. The maximum deflection varied from 51 to 117 mm and from 59 to 81 mm, respectively for the small female and midsize male groups. The maximum forces appeared to be a function of the total body mass for each loading angle.

Injury risk curves for the WorldSID 50th male dummy.

The development of the WorldSID 50th percentile male dummy was initiated in 1997 by the International Organisation for Standardisation (ISO/TC22/SC12/WG5) with the objective of developing a more biofidelic side impact dummy and supporting the adoption of a harmonised dummy into regulations. The dummy is currently under evaluation at the Working Party on Passive Safety (GRSP) in order to be included in the pole side impact global technical regulation (GTR). Injury risk curves dedicated to this dummy and built on behalf of ISO/TC22/SC12/WG6 were proposed in order to assess the occupant safety performance (Petitjean et al. 2009). At that time, there was no recommendation yet on the injury criteria and no consensus on the most accurate statistical method to be used. Since 2009, ISO/TC22/SC12/WG6 reached a consensus on the definition of guidelines to build injury risk curves, including the use of the survival analysis, the distribution assessment and quality checks. These guidelines were applied to the WorldSID 50th results published in 2009 in order to be able to provide a final set of injury risk curves recommended by ISO/TC22/SC12/WG6. The paper presents the different steps of the guidelines as well as the recommended injury risk curves dedicated to the WorldSID 50th for lateral shoulder load, thoracic rib deflection, abdomen rib deflection and pubic force.

Statistical simulations to evaluate the methods of the construction of injury risk curves.

Several statistical methods are currently used to build injury risk curves in the biomechanical field. These methods include the certainty method (Mertz et al. 1996), Mertz/Weber method (Mertz and Weber 1982), logistic regression (Kuppa et al. 2003, Hosmer and Lemeshow 2000), survival analysis with Weibull distribution (Kent et al. 2004, Hosmer and Lemeshow 2000), and the consistent threshold estimate (CTE) (Nusholtz et al. 1999, Di Domenico and Nusholtz 2005). There is currently no consensus on the most accurate method to be used and no guidelines to help the user to choose the more appropriate one. Injury risk curves built for the WorldSID 50th side impact dummy with these different methods could vary significantly, depending on the sample considered (Petitjean et al. 2009). As a consequence, further investigations were needed to determine the fields of application of the different methods and to recommend the best statistical method depending on the biomechanical sample considered. This study used statistical simulations on theoretical samples to address these questions. Two different theoretical distributions of injury thresholds were utilized to assess the five different methods of constructing injury risk curves. A normal distribution and a Weibull distribution, whose shape was not similar to a normal distribution, were selected. One hundred sets of "test subjects" were randomly chosen from each theoretical distribution, with sample sizes ranging from 10 to 50. A "stimulus value" was chosen for each "test subject." The stimulus values were equally spaced, distributed tightly or loosely about the theoretical mean injury threshold, concentrated below the mean value, or concentrated above the mean value. An adaptive method was also used to assign stimulus values, based on the proportion of uninjured and injured in an early subset of the test subjects. The influences of 10%, 25%, and 50% exact data were compared to stimulus values that were either right or left censored. The test subject was considered to be uninjured if the stimulus was less than the subject's threshold or injured if the stimulus was equal to or greater than the subject's threshold. In all, 12,800 simulated data sets with both normal and Weibull distributions were used to construct injury risk curves by each of the five statistical methods. Cumulative errors of the constructed injury risk curves, compared to the theoretical curves, were calculated across the whole curve, as well as the portion of the theoretical curve up to 25% risk of injury. P-values were used to assess the significance of the differences in the errors. The CTE and the survival analysis take into account the exact data whatever the theoretical distribution of injury threshold, while the logistic regression, the Mertz/Weber and the certainty methods do not. For left and right censored data, the logistic regression and/or the survival analysis lead to the lowest error. The survival analysis leads to the lowest error whatever the sample size, the level of censoring and the theoretical distribution evaluated. Increasing the sample size generally decreased the error. However, the benefit from increasing the sample size decreased when the sample size was already high. For the survival analysis, increasing the proportion of exact data decreased the error. The same way, the benefit from increasing the proportion of exact data decreased when the proportion of exact data was already high. Survival analysis may not converge for small sample size with left and right censored data. The number of simulations for which the survival analysis did not converge highly decreases with the increase of proportion of exact data and the increase of the sample size. Therefore, it is recommended to use survival analysis with Weibull distribution to build risk curves compared to the four other statistical methods evaluated. The accuracy of survival analysis with other distributions (log-normal, log-logistic, etc) was not studied. There is no recommendation for the method to be used when survival analysis does not converge. The balance between maximal acceptable error and the need for an injury risk curve, even for a small dataset of poor quality, is not addressed.

Sensitivity of the WorldSID 50th and ES-2re Thoraces to Loading Configuration.

An ideal injury criterion should be predictive of the risk of injury across the range of loading conditions where it may be applied. The injury risk curve associated with this criterion should be applicable to all loading conditions. With respect to side impact, the injury risk curve should apply to pure lateral or oblique loading by rigid and padded walls, as well as airbags. Trosseille et al. (2009) reported that the number of fractured ribs was higher in pure lateral impact than in forward oblique interaction with an airbag. A good dummy criterion should be able to account for this difference. To evaluate various injury criteria with the WorldSID 50 th and ES-2re dummies, the dummies were exposed to the same airbag loadings as the PMHS. The criteria measured in the dummy tests were paired with the rib fractures from the PMHS tests. Regarding the effect of configuration, results of sled tests with the 50 th percentile WorldSID (Petitjean, 2009) and ES-2re (Kuppa, 2003) have been paired with injuries found in the PMHS tested in the same conditions. The relationships obtained were compared with the relationships established in the same way for the subjects loaded in the airbag tests. Comparing the lateral and oblique lateral loading conditions, both the WorldSID and the ES-2re exhibited differences in peak lateral deflection of their ribs that were consistent with the different number of rib fractures for PMHS subjected to these loading conditions. For each dummy, the risk of rib fractures could be assessed from one injury risk curve, regardless of the loading angle. Furthermore, the same injury risk curve can be used to assess the risk of rib fractures from sled tests and airbag loading. However, because the WorldSID deflection measurements differed in the rigid and padded sled tests, it is recommended that the dummy's sensitivity to padding be further assessed prior to adopting injury risk curves for WorldSID. Rib deflections of the ES- 2re were not sensitive to padding. Finally, VC should not be considered as a valid criterion to assess the risk of rib fractures.

The effect of angle on the chest injury outcome in side loading.

Thoracic injury criteria and injury risk curves in side impact are based on impactor or sled tests, with rigid or padded surfaces while airbags are very common on current cars. Besides, the loading is generally pure lateral while real crashes or regulations can generate oblique loadings. Oblique tests were found in the literature, but no conclusion was drawn with regard to the effect of the direction on the injury outcome. In order to address these two limitations, a series of 17 side airbag tests were performed on Post Mortem Human Subjects (PMHS) at different severities and angles. The subjects were instrumented with accelerometers on the spine and strain gauges on the ribs. They were loaded by an unfolded airbag at different distances in pure lateral or 30 degrees forward. The airbag forces ranged from 1680 N to 6300 N, the injuries being up to 9 separated fractured ribs. This paper provides the test results in terms of physical parameters and injury outcome of the 17 subjects. Geometrical and physical characteristics of the subjects are described as well as the distribution of injuries as a function of test conditions. Then a statistical analysis is presented which gives the effect of the loading angle on the injury outcome. The results of this study provide useful data for the validation of finite element models in terms of injury prediction, as well as for the development of injury risk curves for side impact dummies.

Injury risk curves for the WorldSID 50th male dummy.

The development of the WorldSID 50th percentile male dummy was initiated in 1997 by the International Organisation for Standardisation (ISO/SC12/TC22/WG5) with the objective of developing a more biofidelic side impact dummy and supporting the adoption of a harmonised dummy into regulations. More than 45 organizations from all around the world have contributed to this effort including governmental agencies, research institutes, car manufacturers and dummy manufacturers. The first production version of the WorldSID 50th male dummy was released in March 2004 and demonstrated an improved biofidelity over existing side impact dummies. Full scale vehicle tests covering a wide range of side impact test procedures were performed worldwide with the WorldSID dummy. However, the vehicle safety performance could not be assessed due to lack of injury risk curves for this dummy. The development of these curves was initiated in 2004 within the framework of ISO/SC12/TC22/WG6 (Injury criteria). In 2008, the ACEA- Dummy Task Force (TFD) decided to contribute to this work and offered resources for a project manager to coordinate of the effort of a group of volunteer biomechanical experts from international institutions (ISO, EEVC, VRTC/NHTSA, JARI, Transport Canada), car manufacturers (ACEA, Ford, General Motors, Honda, Toyota, Chrysler) and universities (Wayne State University, Ohio State University, John Hopkins University, Medical College of Wisconsin) to develop harmonized injury risk curves. An in-depth literature review was conducted. All the available PMHS datasets were identified, the test configurations and the quality of the results were checked. Criteria were developed for inclusion or exclusion of PMHS tests in the development of the injury risk curves. Data were processed to account for differences in mass and age of the subjects. Finally, injury risk curves were developed using the following statistical techniques, the certainty method, the Mertz/Weber method, the logistic regression, the survival analysis and the Consistent Threshold Estimate. The paper presents the methods used to check and process the data, select the PMHS tests, and construct the injury risk curves. The PMHS dataset as well as the injury risk curves are provided.

Impact of mutant p53 functional properties on TP53 mutation patterns and tumor phenotype: lessons from recent developments in the IARC TP53 database.

The tumor suppressor gene TP53 is frequently mutated in human cancers. More than 75% of all mutations are missense substitutions that have been extensively analyzed in various yeast and human cell assays. The International Agency for Research on Cancer (IARC) TP53 database (www-p53.iarc.fr) compiles all genetic variations that have been reported in TP53. Here, we present recent database developments that include new annotations on the functional properties of mutant proteins, and we perform a systematic analysis of the database to determine the functional properties that contribute to the occurrence of mutational "hotspots" in different cancer types and to the phenotype of tumors. This analysis showed that loss of transactivation capacity is a key factor for the selection of missense mutations, and that difference in mutation frequencies is closely related to nucleotide substitution rates along TP53 coding sequence. An interesting new finding is that in patients with an inherited missense mutation, the age at onset of tumors was related to the functional severity of the mutation, mutations with total loss of transactivation activity being associated with earlier cancer onset compared to mutations that retain partial transactivation capacity. Furthermore, 80% of the most common mutants show a capacity to exert dominant-negative effect (DNE) over wild-type p53, compared to only 45% of the less frequent mutants studied, suggesting that DNE may play a role in shaping mutation patterns. These results provide new insights into the factors that shape mutation patterns and influence mutation phenotype, which may have clinical interest.

TP63 gene in stress response and carcinogenesis: a broader role than expected.

The TP63 gene is a member of the TP53 gene family. In contrast with TP53, this gene is not frequently inactivated by mutation in cancer. Initial experiments with disrupted TP63 have allowed specifying p63 protein a role in the regulation of differentiation and morphogenesis in epithelial and mesenchymal tissues. Nevertheless, there is growing evidence that p63 is also involved in oncogenesis through several mechanisms. Indeed, amplification of TP63 is detected in about 25% of squamous cell carcinomas of lung, head and neck and oesophagus. This results in overexpression of a truncated form of p63 (DeltaNp63) that may counteract growth suppression induced by full length p63 (TAp63), as well as by the other family members, p53 and TAp73. Moreover, mice heterozygous for TP63 develop spontaneous tumours. Whereas p53 plays a major role in response to numerous DNA-damaging agents, the involvement of p63 in this process is not well documented. Nevertheless, several groups recently reported that TAp63 can induce cell cycle arrest and apoptosis in DNA-damaged cells, alone or in synergy with chemotherapeutic agents, and thus appears as a chemosensitivity factor. Overall, in addition to non-redundant, specific functions in differentiation and morphogenesis, p63 appears to exert biological functions similar to those of p53 and to take a growing place in oncogenesis and modulation of responses to anti-cancer therapy.

The expression of TA and DeltaNp63 are regulated by different mechanisms in liver cells.

The TP63 gene, a member of the TP53 gene family, encodes several isoforms with (TAp63) or without (DeltaNp63) transactivating properties. Whereas the role of p63 in the normal development of squamous epithelia is well established, its function in other cell types remains to be elucidated. Here, we have analysed the expression of TA and DeltaNp63 isoforms in liver cells, by using both primary hepatocytes from wild type and p53-null mice and three human hepatocellular carcinoma (HCC) cell lines, according to the transformation state and the TP53 status of the cells. We observed the expression of DeltaNp63 isoforms only in a p53-null context. On the other hand, the expression of TAp63 isoforms was restricted to the HCC cell lines, whatever the TP53 status. We then studied the expression of TP63 upon genotoxic treatment. When treated with UVB or H(2)O(2), hepatocytes did not exhibit any change in p63 mRNA level. At the opposite, upon treatment with topoisomerase II inhibitors (doxorubicin or etoposide), the expression of TAp63 isoforms was clearly induced, independently of the TP53 status of cells. The same treatment did not induce any variation in the expression of DeltaNp63 isoforms, both at mRNA and protein levels. In HCC cell lines, doxorubicin or etoposide treatment also resulted in an increase of TAp63 transcripts only. This increase was accompanied by an increase in the intracellular level of TAp63 alpha protein. In parallel, we observed an upregulation of some p53-target genes related to cell cycle regulation, such as WAF1/CIP1, PIG3, 14-3-3sigma or GADD45, independently of the TP53 status of cells. In conclusion, we report for the first time that TA and DeltaNp63 alpha proteins are present in liver cells. Furthermore, our results suggest that p63 may partially substitute for wild-type p53, in counteracting uncontrolled liver cell proliferation in response to certain forms of DNA-damage.

Thoracic injury criterion for frontal crash applicable to all restraint systems.

For several years now, car manufacturers have made significant efforts in the field of thoracic protection. After first limiting the forces in the shoulder belt to 6 kN, these forces are now usually limited to 4 kN, with airbags intentionally designed to absorb the surplus of energy. If this technology is rewarded by a considerable improvement in safety on the road, it remains penalized by the usual biomechanical criteria, when calculated on the Hybrid III and if applied to all restraint systems. To remedy this problem, a new criterion, valid in all the current restraint configurations (belt, airbag only or airbag and belt) is proposed. It is based on the measurement of the shoulder belt forces and of the central deflection and consequently is directly applicable to the current dummy model (Hybrid III). The use of shoulder belt forces allows the separation of the belt and airbag contributions to the deflection. A weighted criterion is calculated from these deflections, taking into account the different risks associated with a belt and an airbag for the same deflection. This new criterion was developed using 65 simulations on the LAB human model and validated by means of 48 sled tests from the literature, consisting of Hybrid III dummy and PMHS tests performed in similar configurations. This paper describes the logic behind the development of the criterion and gives all the parameters used as well as the elements of validation.

Laboratory Reconstructions of Real World Frontal Crash Configurations using the Hybrid III and THOR Dummies and PMHS.

Load-limiting belt restraints have been present in French cars since 1995. An accident study showed the greater effectiveness in thorax injury prevention using a 4 kN load limiter belt with an airbag than using a 6 kN load limiter belt without airbag. The criteria for thoracic tolerance used in regulatory testing is the sternal deflection for all restraint types, belt and/or airbag restraint. This criterion does not assess the effectiveness of the restraint 4 kN load limiter belt with airbag observed in accidentology. To improve the understanding of thoracic tolerance, frontal sled crashes were performed using the Hybrid III and THOR dummies and PMHS. The sled configuration and the deceleration law correspond to those observed in the accident study. Restraint conditions evaluated are the 6 kN load-limiting belt and the 4 kN load-limiting belt with an airbag. Loads between the occupant and the sled environment were recorded. Various measurements (including thoracic deflections and head, thorax and pelvis accelerations and angular velocities on the dummies) characterize the dummy and PMHS behavior. PMHS anthropometry and injuries were noted. This study presents the test methodology and the results used to evaluate dummy ability to discriminate both restraint types and dummy measurement ability to be representative of thoracic injury risk for all restraint types. The injury results of the PMHS tests showed the same tendency as the accident study. Some of the criteria proposed in the literature did not show a better protection of the 4 kN load limiter belt with airbag restraint, in particular thoracic deflection maxima for both dummies. The four thoracic deflections measured on the THOR and Hybrid III dummies may allow more accurate analysis of the loading pattern and therefore of injury risk.