Increased Uptake of HCV Testing through a Community-Based Educational Intervention in Difficult-to-Reach People Who Inject Drugs: Results from the ANRS-AERLI Study.

AIMS: The community-based AERLI intervention provided training and education to people who inject drugs (PWID) about HIV and HCV transmission risk reduction, with a focus on drug injecting practices, other injection-related complications, and access to HIV and HCV testing and care. We hypothesized that in such a population where HCV prevalence is very high and where few know their HCV serostatus, AERLI would lead to increased HCV testing. METHODS: The national multisite intervention study ANRS-AERLI consisted in assessing the impact of an injection-centered face-to-face educational session offered in volunteer harm reduction (HR) centers ("with intervention") compared with standard HR centers ("without intervention"). The study included 271 PWID interviewed on three occasions: enrolment, 6 and 12 months. Participants in the intervention group received at least one face-to-face educational session during the first 6 months. MEASUREMENTS: The primary outcome of this analysis was reporting to have been tested for HCV during the previous 6 months. Statistical analyses used a two-step Heckman approach to account for bias arising from the non-randomized clustering design. This approach identified factors associated with HCV testing during the previous 6 months. FINDINGS: Of the 271 participants, 127 and 144 were enrolled in the control and intervention groups, respectively. Of the latter, 113 received at least one educational session. For the present analysis, we selected 114 and 88 participants eligible for HCV testing in the control and intervention groups, respectively. In the intervention group, 44% of participants reported having being tested for HCV during the previous 6 months at enrolment and 85% at 6 months or 12 months. In the control group, these percentages were 51% at enrolment and 78% at 12 months. Multivariable analyses showed that participants who received at least one educational session during follow-up were more likely to report HCV testing, compared with those who did not receive any intervention (95%[CI] = 4.13[1.03;16.60]). CONCLUSION: The educational intervention AERLI had already shown efficiency in reducing HCV at-risk practices and associated cutaneous complications and also seems to have a positive impact in increasing HCV testing in PWID.

Comparing the Information and Support Needs of Different Population Groups in Preparation for 2015 Government Approval for HIV Self-testing in France.

CONTEXT: HIV self-tests are currently being introduced in France with the aim of promoting screening both for the general population and for high-risk populations. OBJECTIVE: The current study aimed to identify and compare the information and support needs of the different target population groups. METHODS: The Delphi process was used to synthesize expert opinions for each population group. Experts were chosen for their experience and expertise in the area of HIV and HIV screening for each population. Each group developed recommendations for a specific population: six high HIV prevalence populations (men who have sex with men; transgender people; substance users; migrants from sub-Saharan Africa; French West Indies; French Guiana) and two low prevalence populations (the general population; people under 25). Each group included expertise from four areas: research, screening and care, policy-making, and community groups. RESULTS: A final total of 263 recommendations were grouped into eight main themes: Communicating at both national and community levels about self-test arrival (24% of all recommendations); Providing information adapted to the different community groups' needs (23%); Providing counselling on self-test use and access to care (15%); Making self-tests available to all in terms of accessibility and cost (13%); Preparing community healthcare and screening systems for the arrival of the self-test (11%); Approving only high quality self-tests (6%); Defending self-test users' legal rights (5%); Evaluating self-test use (3%). Although a large number of recommendations were common to several groups of experts, the study highlighted a certain number of recommendations specific to each different population group, particularly with regard to information content and access both to information and to the self-tests themselves. CONCLUSION: Results from the current study should make a significant contribution to policy decisions concerning catering for the specific access, information and support needs of different potential HIV self-test user groups in France.

Innovative community-based educational face-to-face intervention to reduce HIV, hepatitis C virus and other blood-borne infectious risks in difficult-to-reach people who inject drugs: results from the ANRS-AERLI intervention study.

AIMS: To study the effectiveness of an educational intervention on risks associated with drug injection, comparing primary [unsafe HIV-hepatitis C virus (HCV) practices] and secondary (local complications at injecting site) end-points in harm reduction (HR) programmes offering this intervention versus HR programmes not offering it. DESIGN: This non-random clustered intervention study was conducted in nine intervention groups (programmes offering the intervention) and eight control groups (programmes not offering it). Each participant was followed-up through a telephone interview at enrolment and at 6 and 12 months. SETTING: The study took place in 17 cities throughout France. PARTICIPANTS: Of the 271 participants, 144 were enrolled into the intervention group and 127 in the control group. Of the latter, 113 received at least one educational session. INTERVENTION: A series of participant-centred face-to-face educational sessions. Each session included direct observation by trained non-governmental organization (NGO) staff or volunteers of participants' self-injecting the psychoactive product they used habitually; analysis by the trained NGO staff or volunteers of the participant's injecting practices, identification of injection-related risks and explanation of safer injecting practices; and an educational exchange on the individual participant's injection practices and the questions he or she asked. MEASUREMENTS: Primary and secondary outcomes were 'at least one unsafe HIV-HCV practice' and at least one injection-related complication (derived from a checklist). FINDINGS: The proportion of participants with at least one unsafe HIV-HCV practice in the intervention group decreased significantly, from 44% at M0 to 25% at M6, as well as complications at the injection site (from 66 to 39% at M12), while in the control group it remained mainly stable. Multivariate probit analyses showed that the intervention group experienced a significant reduction in unsafe HIV-HCV practices at M6 [coefficient, 95% confidence interval (CI) = -0.73 (-1.47 to 0.01)] and in injection-related complications at M12 [coefficient, 95% CI = -1.01 (-1.77 to -0.24)], compared with the control group. CONCLUSIONS: An inexpensive and easily implemented educational intervention on risks associated with drug injection reduces significantly unsafe HIV-HCV transmission practices and injection-related complications.

On-Demand Preexposure Prophylaxis in Men at High Risk for HIV-1 Infection.

BACKGROUND: Antiretroviral preexposure prophylaxis has been shown to reduce the risk of human immunodeficiency virus type 1 (HIV-1) infection in some studies, but conflicting results have been reported among studies, probably due to challenges of adherence to a daily regimen. METHODS: We conducted a double-blind, randomized trial of antiretroviral therapy for preexposure HIV-1 prophylaxis among men who have unprotected anal sex with men. Participants were randomly assigned to take a combination of tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) or placebo before and after sexual activity. All participants received risk-reduction counseling and condoms and were regularly tested for HIV-1 and HIV-2 and other sexually transmitted infections. RESULTS: Of the 414 participants who underwent randomization, 400 who did not have HIV infection were enrolled (199 in the TDF-FTC group and 201 in the placebo group). All participants were followed for a median of 9.3 months (interquartile range, 4.9 to 20.6). A total of 16 HIV-1 infections occurred during follow-up, 2 in the TDF-FTC group (incidence, 0.91 per 100 person-years) and 14 in the placebo group (incidence, 6.60 per 100 person-years), a relative reduction in the TDF-FTC group of 86% (95% confidence interval, 40 to 98; P=0.002). Participants took a median of 15 pills of TDF-FTC or placebo per month (P=0.57). The rates of serious adverse events were similar in the two study groups. In the TDF-FTC group, as compared with the placebo group, there were higher rates of gastrointestinal adverse events (14% vs. 5%, P=0.002) and renal adverse events (18% vs. 10%, P=0.03). CONCLUSIONS: The use of TDF-FTC before and after sexual activity provided protection against HIV-1 infection in men who have sex with men. The treatment was associated with increased rates of gastrointestinal and renal adverse events. (Funded by the National Agency of Research on AIDS and Viral Hepatitis [ANRS] and others; ClinicalTrials.gov number, NCT01473472.).

[Critical care of Onco-hematology patients: new therapeutic targets, new complications and new admission policies]. / Réanimation des patients d'onco-hématologie: nouvelles thérapeutiques, nouvelles complications, nouveaux contrats d'admission.

Overall prognosis of cancer or haematological has dramatically decreased over the last decades. Thus advances regarding cancer or haematological treatment, improved knowledge of usual complications and of their pathophysiology and changes in ICU admission policy and management are among factors which participated to the overall prognostic changes. Tyrosine-Kinase inhibitors in patients with chronic myeloid leukemia and anti-CD20 antibodies in patients with non-hodgkin's lymphoma were among the first success of targeted therapies. These success stories have been followed by others and no less than 13 targeted therapies were available for cancer patients in December 2013. Additionally, pathophysiology of complication is better understood and prognostic impact of organ failure better apprehended. Standardized diagnostic criteria of tumor lysis syndrome along with improved understanding of short-term and long term influence of acute kidney injury (AK) in this setting have led to specific management strategiesfocusing on prevention. In non-malignant haematological diseases, pathophysiological processes leading to thrombotic thrombocytopenic purpura or atypical haemolytic and uremic syndrome are now better understood leading to additional therapeutic options. Last, diversification of ICU admission policies may help in taking into account uncertainties, therapeutic advances and patients' autonomy. This review will give an overview of these recent advances.

HIV-Related discrimination in European health care settings.

This cross-sectional European study assessed self-reported HIV-related discrimination and its associated factors in health care settings. Socio-demographics, health status, support needs relating to sexual and reproductive health (SRH), and self-reported HIV-related discrimination were measured using an anonymous survey in a sample of 1549 people living with HIV from 14 countries. Thirty-two per cent of the participants had experienced HIV-related discrimination during the previous 3 years; almost half of them felt discriminated against by health care providers. For this type of discrimination, logistic regression analysis revealed significant associations with not being a migrant (OR: 2.0; IC 1.0-3.7; p<0.05), having been forced into sexual activities (OR: 1.6; IC 1.2-2.2; p<0.001), reporting lack of time to discuss SRH during service provision (OR: 1.7; IC 1.0-2.7; p<0.05), and insufficient openness among service providers to discuss SRH (OR: 2.0; IC 1.1-3.4; p<0.05). Other significant associations related to unmet support needs on safer sex practices (OR: 1.8; IC 1.0-3.2; p<0.05), partner communication about sexuality (OR: 2.0; IC 1.1-3.4; p<0.05), and prevention of sexually transmitted infections (OR: 1.7; IC 1.0-3.0; p<0.05). Female gender had a protective effect (OR: 0.2; IC 0.0-0.9; p<0.05). Being denied the opportunity to discuss SRH may translate in feelings of discrimination. Improving health care providers' communication skills, and fostering openness about SRH topics in HIV care could contribute to destigmatization of PLHIV.

[Genome sequencing and personalized medicine: perspectives and limitations]. / Séquençage des génomes et médecine personnalisée: perspectives et limites.

DNA sequencing technologies have advanced at an exponential rate in recent years: the first human genome was sequenced in 2001 after many years of effort by dozens of international laboratories at a cost of tens of millions of dollars, while in 2013 a genome can be sequenced within 24 hours for a few hundred dollars (exome sequencing takes only a few hours). More and more hospital laboratories are acquiring new high-throughput sequencing devices ("next-generation sequencers", NGS), allowing them to analyze tens or hundreds of genes, or even the entire exome. This is having a major impact on medical concepts and practices, especially with respect to genetics and oncology. This ability to search for mutations simultaneously in a large number of genes is finding applications in the diagnosis of Mendelian diseases (including at birth), routine screening for heterozygotes, and pre-conception diagnosis. NGS is now sufficiently sensitive to analyze circulating fetal DNA in maternal blood (cell-free fetal DNA, cffDNA), enabling applications such as non invasive diagnosis of fetal sex (and X-linked diseases), fetal rhesus among rhesus-negative women, trisomy and, in the near future, Mendelian mutations. Data on multifactorial diseases are still preliminary, but it should soon be possible to identify "strong" factors of genetic predisposition that have so far been beyond the scope of genome-wide association studies (GWAS). In the field of constitutional oncogenetics, NGS can also be used for simultaneous analysis of genes involved in " hereditary " cancers (21 breast cancer genes, 6 colon cancer genes, etc.). More generally, NGS can identify all genomic abnormalities (deletions, translocations, mutations) in a given malignant tissue (hemopathy or solid tumor), and has the potential to distinguish between important mutations (those that drive tumor progression) from " bystander " or accessory mutations, and also to identify "druggable" mutations amenable to targeted therapies (e.g. imatinib and Bcr/Abl rearrangement; verumafemib and the BRAF V600E mutation). Systematic sequencing of all the genes involved in drug metabolism and responsiveness will lead to individualized pharmacogenetics. Finally, sequencing of the tumoral and constitutional genomes, identfication of somatic mutations, and detection of pharmacogenetic variants will open up the era of personalized medicine. The first results of these targeted therapeutic indications show a gain in the duration of remission and survival, although the cost-effectiveness of these approaches remains to be determined. Finally, this huge capacity for genome sequencing raises a number of regulatory and ethical issues.

[Intestinal microbiota]. / Le microbiote intestinal.

The human body normally lives in symbiosis with a considerable microscopic environment present on all interfaces with the external environment; it hosts ten times more microbes (microbiota) that it has somatic or germ cells, representing a gene diversity (microbiome) 100-150 times higher than the human genome. These germs are located mainly in the gut, where they represent a mass of about one kilogram. The primary colonization of the gastrointestinal tract depends on the delivery route, the bacterial flora rewarding then depending on the environment, food hygiene, medical treatments. The intestinal microbiota plays an important role in the maturation of the immune system and in different physiological functions: digestion of polysaccharides, glycosaminoglycans and glycoproteins, vitamins biosynthesis, bile salt metabolism of some amino acids and xenobiotics. Quantitative and qualitative changes in the microbiota are observed in a wide range of diseases: obesity, colorectal cancer, liver cancer, inflammatory bowel disease, autoimmune diseases, allergies... pharmacobiotics aim to modify the intestinal microbiota in a therapeutic goal and this by various means: prebiotics, probiotics, antibiotics or fecal transplants. Intestinal flora also plays a direct role in the metabolism of certain drugs and the microbiota should be considered as a predictive parameter of response to some chemotherapies.

Expanding access to non-medicalized community-based rapid testing to men who have sex with men: an urgent HIV prevention intervention (the ANRS-DRAG study).

BACKGROUND: Little is known about the public health benefits of community-based, non-medicalized rapid HIV testing offers (CBOffer) specifically targeting men who have sex with men (MSM), compared with the standard medicalized HIV testing offer (SMOffer) in France. This study aimed to verify whether such a CBOffer, implemented in voluntary counselling and testing centres, could improve access to less recently HIV-tested MSM who present a risk behaviour profile similar to or higher than MSM tested with the SMOffer. METHOD: This multisite study enrolled MSM attending voluntary counselling and testing centres' during opening hours in the SMOffer. CBOffer enrolees voluntarily came to the centres outside of opening hours, following a communication campaign in gay venues. A self-administered questionnaire was used to investigate HIV testing history and sexual behaviours including inconsistent condom use and risk reduction behaviours (in particular, a score of "intentional avoidance" for various at-risk situations was calculated). A mixed logistic regression identified factors associated with access to the CBOffer. RESULTS: Among the 330 participants, 64% attended the CBOffer. Percentages of inconsistent condom use in both offers were similar (51% CBOffer, 50% SMOffer). In multivariate analyses, those attending the CBOffer had only one or no test in the previous two years, had a lower intentional avoidance score, and met more casual partners in saunas and backrooms than SMOffer enrolees. CONCLUSION: This specific rapid CBOffer attracted MSM less recently HIV-tested, who presented similar inconsistent condom use rates to SMOffer enrolees but who exposed themselves more to HIV-associated risks. Increasing entry points for HIV testing using community and non-medicalized tests is a priority to reach MSM who are still excluded.

[Genetic control of infectious diseases: from Mendel's laws to exome sequencing]. / Le contrôle génétique des maladies infectieuses: des lois de Mendel au séquençage de l'exome.

About one-quarter of deaths worldwide (nearly 13 million per year) are still directly related to infectious diseases. Many new infections have emerged since the end of the 20th century and others will continue to do so. Human beings, like other animals, are not all equal with respect to their susceptibility to infection. Since the 1930s, numerous epidemiological studies have shown that host genetic factors play a major role in susceptibility and resistance to infections. Studies of Mendelian genetics and genetic epidemiology based on association studies, now using high-speed typing of anonymous polymorphic markers, can detect genes or loci that influence an individual's response to a particular germ. Different cases of susceptibility or resistance to viral, bacterial, fungal and parasitic infections will be used to illustrate the importance of genetic factors in the diagnosis of clinical manifestations and their prevention, characterization of host immune responses, and their influence on evolutionary biology. With different phenotypes associated with genetic polymorphisms, and new genomic techniques, the genetics of infectious diseases is entering a new era, raising questions of medical practice, ethics, and public and industrial policies.

Investigating Recent Testing among MSM: Results from Community-Based HIV Rapid Testing Attendees in France.

Background. We aimed to identify factors associated with recent HIV testing in MSM who attended two experimental community-based and nonmedicalized voluntary counselling and testing programmes (CB-VCT) targeting MSM in France. Methods. This analysis was based on data collected in 2009-2011 through a self-administered pretesting questionnaire. An index measuring the level of participants' sexual orientation disclosure was built: the higher the index, the greater the disclosure. Factors associated with recent HIV testing (last test ≤ 1 year) were identified using a multivariate logistic regression model adjusted for the CB-VCT programme of enrolment. Results. 716 MSM provided data on testing history. Overall, 49% were recently tested for HIV and 51% were not. Recently tested MSM had a higher homosexuality disclosure index (adjusted OR [95% confidence interval]: aOR = 1.2 [1.1-1.4]), reported more inconsistent condom use during anal sex with men (aOR = 1.6 [1.2-2.1]), and were less likely to have sex under the influence of club drugs (aOR = 0.6 [0.4-1.0]). Conclusion. New testing strategies should focus on those who live their homosexuality relatively secretly and those who use club drugs before sex. Governments should develop policies which encourage improved social acceptance of homosexuality as concealment of sexual orientation represents a major barrier to testing.

ANRS-COM'TEST: description of a community-based HIV testing intervention in non-medical settings for men who have sex with men.

OBJECTIVE: To describe a community-based HIV testing programme. DESIGN AND SETTING: An intervention of HIV voluntary testing conducted in non-medical settings in four French cities. PARTICIPANTS: Men who have sex with men (MSM). INTERVENTION: Counselling and rapid HIV testing staffed by trained personnel from an HIV/AIDS community-based organisation. PRIMARY AND SECONDARY OUTCOME MEASURES: The population that has taken hold of the intervention and the satisfaction of participants. Data were collected on demographics, HIV testing history, sexual practices and satisfaction with the testing programme. RESULTS: 532 MSM were tested between February 2009 and June 2010, of whom 49 (9%) were tested two or more times. 468 MSM (88%) had casual male partners in the previous 6 months, and 152 (35%) reported having unprotected anal intercourse with risky casual partners (HIV infected or HIV serostatus unknown). 159 men (30%) had not been tested in the previous 2 years, and 50 (31%) of whom had unprotected anal intercourse with risky casual partners. Among the 15 patients who tested positive (2.8%), 12 (80%) received confirmation and were linked to care (median CD4 cell count =550/mm(3)). Satisfaction was high: 92% reported being 'very satisfied' with their experience. Steps of counselling and testing procedure were respected by testers and difficulties in handling tests were rare. CONCLUSIONS: This community-based HIV testing programme reached high-risk MSM, of whom a substantial proportion had not been tested lately. This novel service supplements pre-existing HIV testing services and increases access to HIV testing in high-risk groups.

Empowering HIV testing as a prevention tool: targeting interventions for high-risk men who have sex with men.

In France, HIV testing can be easily performed in free and anonymous voluntary counselling testing (VCT) centres. The recent national study among French men who have sex with men (MSM) showed that 73% of those already tested for HIV had been tested in the previous two years. Nothing is known about the risk behaviours of MSM attending VCT centres. This study aimed to characterize sexual risk behaviours of MSM tested for HIV in such centres and identify factors associated with inconsistent condom use (ICU). A cross-sectional study was conducted from March to December 2009 in four VCT centres where a self-administered questionnaire was proposed to all MSM about to have a HIV test. ICU was defined as reporting non-systematic condom use during anal intercourse with casual male partners. Among the 287 MSM who fully completed their questionnaire, 44% reported ICU in the previous six months. Among those who had been already tested, 63% had had their test in the previous two years. Factors independently associated with ICU included: never avoiding one-night stands, not having been recently HIV tested, experiencing difficulty in using condoms when with a HIV negative partner or when under the influence of drugs or alcohol and finally, reporting to have had a large number of casual male partners in the previous six months. The rate of recently tested MSM was high in our study. Nevertheless, this rate was lower than that found in the last national study. Furthermore those not recently tested were significantly more likely to report high risk behaviours. We therefore recommend that further efforts be made to adapt the offer of both HIV testing and counselling to meet the specific needs of hard-to-reach MSM. Accordingly, an additional community-based offer of HIV testing to reach most-at-risk MSM is forthcoming in France.

Acceptability of an "on-demand" pre-exposure HIV prophylaxis trial among men who have sex with men living in France.

Although predictors of willingness to take daily, self-administered pre-exposure HIV prophylaxis (PrEP) for men who have sex with men (MSM) have been studied in the context of several PrEP trials internationally, little is known about MSM interested in participating in a trial on the use of PrEP on an "on -demand" basis, i.e., taking a first dose of combined tenofovir/emtricitabine a few hours before possible HIV sexual exposure and a second dose a few hours afterwards. A double-blind placebo randomized PrEP trial will soon begin in France to evaluate the effectiveness of PrEP in terms of reducing HIV infection rates, among MSM self-administering "on-demand" PrEP. To assess potential participants' characteristics associated with willingness to participate in the trial and identify barriers and facilitators to implementation, MSM completed a self-administered questionnaire, distributed via gay venues and community websites. Among the 443 respondents who reported being HIV-negative, 40% reported being interested in participating. Factors independently associated with interest included: reporting lower educational level, more than 20 male sexual partners in the previous year, reporting unprotected anal sex with casual partners and preferring PrEP follow-up visits in a devoted area within a hospital. There is great interest in participating in a future "on-demand" PrEP trial among HIV-negative MSM and particularly in those at potentially high risk of HIV exposure. Providing confidentiality and tailored counseling during PrEP follow-up are important issues.

[Burn out syndrome among critical care workers]. / Epuisement professionnel en réanimation.

Burnout syndrome (BOS) is a psychological state resulting from prolonged exposure to job stressors. Because intensive care units (ICUs) are characterized by a high level of work-related stress, we reviewed the available literature on BOS among ICU-healthcare workers. Recent studies suggest that severe BOS (measured with the Maslach Burnout Inventory) is present in about half of all critical care physicians and one-third of critical care nurses. Interestingly, the determinants of BOS difer between the two groups of caregivers. Intensivists with severe BOS tend to be those with a large number of working hours (number of night shifts, and time since last vacation), whereas severe BOS among ICU nurses is mainly related to ICU organization and end-of-life care policy. ICU conflicts were independent predictors of severe BOS in both groups. Recent studies also identify potential preventive measures, such as ICU working groups, better communication during end-of-life care, and prevention and management of ICU conflicts.

[Not Available]. / Améliorer la santé des personnes séropositives au VIH : SERONET, un nouvel outil de l'approche communautaire.

In developed countries, the lives of HIV seropositive patients have not been unaffected by the technological revolution initiated by internet. HIV seropositive patients use the Web as a tool for searching information, meeting other Web users and developing social networks. In July 2008, taking advantage of the advent of Web technology 2.0, AIDES, a non-profit organization dedicated to fighting AIDS, launched Seronet, a website premised on a communitarian objective that aims to improve access to knowledge, provide a forum for sharing individual experience of the disease and break the cycle of isolation. Despite certain limitations, a relatively wide support network has gradually developed around Seronet. The long-term impact of this network on isolation, the development of autonomy, and the encouragement of a communitarian involvement of HIV-positive patients in terms of healthcare will need to be assessed.

[The biology of aging]. / Biologie du vieillissement.

Although aging is unavoidable, its course can be influenced by various factors, as illustrated by the increase in life expectancy associated with improvements in hygiene and with the general reduction in morbidity. Longevity has also been altered experimentally in some animal species. Aging follows a period of growth and reproduction. Death may occur when the immortality of the germinal line has been ensured. In other cases it results from gradual cellular deterioration. Four principal molecular and cellular processes have been studied in experimental models (mainly mice, worms and fruit flies):--inhibition of the insulin/IGF-1 axis increases life expectancy by allowing a transcription factor (DAF-16 in C. elegans, FoXo in mice) to enter the nucleus, where it stimulates the expression of genes encoding survival-promoting proteins; one such inhibitor is Klotho protein;--the detrimental effects of highly toxic reactive oxygen species, mainly produced in the mitochondria, are partly controlled by scavenging molecules and enzymes. Their accumulation leads to DNA, lipid and protein changes, resulting in cell dysfunction;--the telomeres situated at the ends of each chromosome get shorter with time because of inadequate telomerase activity, and this appears to be associated with diminished longevity;--autophagia within lysosomes destroys altered proteins and thereby maintains cell homeostasis. However, this activity diminishes with time, resulting in the accumulation of toxic metabolites in the cell, dysfunction of the endoplasmic reticulum and mitochondria, and increased apoptosis. Studies of genetically mediated aging disorders have revealed the importance of lamins (intermediate nuclear filaments). For example, a mutation that prevents the protein lamin A from maturing is the cause of progeria, a disease associated with an acceleration of most aging processes and with premature death. There is no single biological marker of aging. In contrast, a combination of Nt-proBNP, troponin I, C-reactive protein and cystatin may be useful, as increased levels are a risk factor for atheroma and cardiovascular diseases, both of which are associated with aging. The different organs age in different ways: vessel walls become rigid due to protein glycation and develop atheroma; the heart is invaded by fibrosis; the brain suffers from neurofibrillar degeneration and senile plaques (responsible for Alzheimer's disease); the retina undergoes macular degeneration; renal function declines in parallel with the fall in the glomerular filtration rate due to a gradual decrease in the nephron pool; and immune defenses become less effective due to the functional degradation of B and T lymphocytes and thymus involution. Reproduction is a special case: despite the increase in human longevity, the chronology of the reproductive cycle and the age of menopause onset have not changed. The frequency of cancers increases with age, due to the increase in somatic mutations and the decline in immune defenses. Drug therapy must be adapted to age, owing to age-related changes in pharmacology. Physical exercise and dietary measures are currently the only known ways of slowing the aging process.

Austrian validation and customization of the SAPS 3 Admission Score.

OBJECTIVE: To test the prognostic performance of the SAPS 3 Admission Score in a regional cohort and to empirically test the need and feasibility of regional customization. DESIGN: Prospective multicenter cohort study. PATIENTS AND SETTING: Data on a total of 2,060 patients consecutively admitted to 22 intensive care units in Austria from October 2, 2006 to February 28, 2007. MEASUREMENTS AND RESULTS: The database includes basic variables, SAPS 3, length-of-stay and outcome data. The original SAPS 3 Admission Score overestimated hospital mortality in Austrian intensive care patients through all strata of the severity-of-illness. This was true for both available equations, the General and the Central and Western Europe equation. For this reason a customized country-specific model was developed, using cross-validation techniques. This model showed excellent calibration and discrimination in the whole cohort (Hosmer-Lemeshow goodness-of-fit: H = 4.50, P = 0.922; C = 5.61, P = 0.847, aROC, 0.82) as well as in the various tested subgroups. CONCLUSIONS: The SAPS 3 Admission Score's general equation can be seen as a framework for addressing the problem of outcome prediction in the general population of adult ICU patients. For benchmarking purposes, region-specific or country-specific equations seem to be necessary in order to compare ICUs on a similar level.

Outcome prediction in critical care: the Simplified Acute Physiology Score models.

PURPOSE OF REVIEW: Outcome prediction models measuring severity of illness of patients admitted to the intensive care unit should predict hospital mortality. This review describes the state-of-the-art of Simplified Acute Physiology Score models from the clinical and managerial perspectives. Methodological issues concerning the effects of differences between new samples and original databases in which the models were developed are considered. RECENT FINDINGS: The progressive lack of fit of the Simplified Acute Physiology Score II in independent intensive care unit populations induced investigators to propose customizations and expansions as potential evolutions for Simplified Acute Physiology Score II. We do not know whether those solutions did solve the issue because there are no demonstrations of consistent good fit in new databases. The recently developed Simplified Acute Physiology Score 3 Admission Score with customization for geographical areas is discussed. The points shared by the Simplified Acute Physiology Score models and the pros and cons for each of them are introduced. SUMMARY: Comparisons of intensive care unit performance should take into account not only the patient severity of illness, but also the effect of the 'intensive care unit variable', that is, differences in human resources, structure, equipment, management and organization of the intensive care unit. In the future, moving from patient and geographical area adjustment to resource use could allow the user to adjust for differences in healthcare provision.