Tumor BRCA testing can reveal a high tumor mutational burden related to POLE pathogenic variants.

OBJECTIVE: Tumors harboring a POLE pathogenic variant, associated with high tumor mutational burden, are good candidates for immunotherapy. However, POLE pathogenic variants are not currently screened in routine clinical practice. Can these tumors be identified by means of an already available test? METHODS: We describe seven tumors harboring a POLE pathogenic variant, among eight patients with tumors harboring multiple BRCA1/2 variants (from 4 to 20). All patients were managed at Institut Curie, Paris. Five patients were selected because of unexpected tumor BRCA testing results with multiple variants and another three patients were selected because of a POLE pathogenic variant detected by large tumor testing. We looked for other tumor variants by Next-Generation Sequencing in tumors harboring multiple BRCA1/2 variants, and for multiple BRCA1/2 variants in tumors harboring a POLE pathogenic variant. RESULTS: Four of the five tumors selected because of multiple BRCA1/2 variants exhibited a POLE pathogenic variant, and all three tumors selected for POLE pathogenic variants exhibited multiple BRCA1/2 variants. CONCLUSIONS: Tumor BRCA testing could be a way to detect tumors harboring a highly mutagenic POLE pathogenic variant.

[Cesarean scar ectopic pregnancies: combined modality therapies with uterine artery embolization before surgical procedure]. / Grossesse sur cicatrice de césarienne : traitement combiné avec embolisation des artères utérines avant procédure chirurgicale.

OBJECTIVES: To offer a therapeutic management of cesarean scar pregnancies (GSC) in the first trimester of pregnancy with a first approach by uterine artery embolization (UAE) PATIENTS AND METHODS: This study describes seven cases of GSC diagnosed between 2009 and 2013 in the clinic of the University Hospital of the Hospital of Croix-Rousse. We present the symptoms and how imagery has led to the diagnosis and the therapeutic management conducted. RESULTS: The mean gestational age at diagnosis was 9 weeks gestation. There were ongoing pregnancies with cardiac activity present for each patient. An additional MRI was performed in five patients. Five patients were treated with methotrexate injection, two patients received the Mifegyne. All patients then received a selective uterine artery embolization. Finally within 48hours, suction curettage was performed in 6 patients. A patient at 13 WA+1 required a subtotal hysterectomy for placenta accreta. Intra-operative complications were represented by a bladder injury, two bleeding of 1000mL in patients at 13 WA+1 and 12 WA. For the 6 cases of GSC with a gestational age less than 10 WA, average blood loss was less than 500mL. Three patients underwent resection of scar isthmocele confirmed by EVAC. An intrauterine pregnancy was carried to term after care. DISCUSSION AND CONCLUSION: Cesarean scar pregnancies is a diagnostic and therapeutic challenge, which should be diagnosed as early as soon as possible with care in a medical facility with a uterine artery embolization technical platform. Our protocol combining Mifegyne and methotrexate for termination of pregnancy and uterine artery embolization (UAE) followed by curettage for evacuation of pregnancy allows conservative treatment while minimizing the risk of bleeding (for GSC diagnosed before 10 WA).

The pharmacokinetics and safety of twice daily i.v. BU during conditioning in pediatric allo-SCT recipients.

Intravenous BU divided four times daily (q6 h) has been shown to be safe and effective in pediatric allo-SCT recipients. Though less frequent dosing is desirable, pharmacokinetic (PK) data on twice daily (q12 h) i.v. BU administration in pediatric allo-SCT recipients is limited. We prospectively examined the PK results in a cohort of pediatric allo-SCT recipients receiving i.v. BU q12 h as part of conditioning before allo-SCT. BU levels were obtained after the first dose of conditioning. PK parameter analysis (n=49) yielded the following 95% confidence intervals (CI95): weight-normalized volume of distribution: 0.65-0.73 L/kg; t(1/2): 122-147 min; weight-normalized clearance (CL(n)): 3.4-4.3 mL/min/kg; and area under the curve: 1835-2180 mmol × min/L. From these results, a steady state concentration was calculated with CI95 between 628-746 ng/mL. Comparison between recipients ≤4 vs >4 years old revealed significant differences in t(1/2) (mean: 115 vs 146 min, P=0.008) and CL(n) (mean: 4.4 vs 3.5 mL/min/kg, P=0.038). Intravenous BU q12 h had a comparable PK to i.v. BU q6 h PK seen in the literature, and in pediatric allo-SCT recipients, is a feasible, attractive alternative to i.v. q6h dosing.

The "Swiss Statement": who knows about it? How do they know? What are its effects on people living with HIV/AIDS?

The publication of the "Swiss Statement" in 2008 shook the international HIV prevention and advocacy scene. HIV behavioral research has provided us with some studies focusing on the potential changes that new prevention strategies can produce, but results are not conclusive. Besides, there is a lack of data concerning awareness of these kinds of prevention strategies on real-life settings, studying mainly the behavior of people recruited in different types of trials (e.g., circumcision, pre and post-exposure prophylaxis). The present study aims to (1) identify the factors associated with awareness of the "Swiss Statement" among PLWHA, (2) determine in which setting they became aware of it, and (3) look for potential, behavioral, and/or emotional changes as a consequence of this awareness. In order to achieve these three objectives, we used the data collected by a community-based survey called "HIV, Hepatitis and you." In order to determine the factors associated with the awareness of the Swiss Statement, univariate and multivariate logistic regression were performed. Main results show that among the 997 HIV-positive people answering the questionnaire, 57% knew about the Swiss Statement, and that their main source of information was the associative setting, while 30% declared having found out about it from their doctor. As for the factors associated with the awareness of the Swiss Statement, we found that the following variables were significantly associated with such awareness: living in stable housing, having a CD4 count above 350 cell/mm(3), having an undetectable viral load, being in contact with a HIV-solidarity network, feeling of belonging to the LGBT community, and filling out the questionnaire online. The results of this study point out that interventions addressed to improve access to health-related information for PLWHA facing socioeconomical difficulties and isolation are strongly needed.

Barebacking and sexual health in the French setting: "NoKondom Zone" workshops.

Barebacking has been, since its emergence in the 1990s, a very controversial issue, and has as many definitions as authors writing about it. In France, sexual risk reduction strategies have been very contentious, and the advent of the bareback phenomenon increased this conflictual situation. This state of affairs has prevented the identification of needs and development of adequate programs for people not using condoms. In December 2008, a peer sexual health workshop, organized on a monthly basis and taking place over 1 year was launched and facilitated by a group of people who declared not using condoms (n approximate = 15). These workshops were hosted and organized by AIDES, the largest French HIV/AIDS community-based organization. The main objective was to create a safe place for exchanging about sexuality and health concerns. Most of the participants, who were mainly HIV positive, referred to being discriminated against in healthcare settings and in the gay community because of prevention policies and stereotypes about barebacking. This experience was extremely challenging for group members, for the facilitator and for the organisation. Main results show that taking part in the groups allowed participants to break their feelings of isolation, to discuss risk reduction strategies and, in some cases, to improve communication with medical staff. Besides, a political dimension related to implementing this kind of intervention was discussed. Participants declared that, in one way or another, they were more in need of this support than people not taking risks. Further interventions are needed in order to compare and contrast the present results.

Procedure volume is one determinant of centre effect in mechanically ventilated patients.

Survival rates vary significantly between intensive care units, most notably in patients requiring mechanical ventilation (MV). The present study sought to estimate the effect of hospital MV volume on hospital mortality. We included 179,197 consecutive patients who received mechanical ventilation in 294 hospitals. Multivariate logistic regression models with random intercepts were used to estimate the effect of annual MV volume in each hospital, adjusting for differences in severity of illness and case mix. Median annual MV volume was 162 patients (interquartile range 99-282). Hospital mortality in MV patients was 31.4% overall, 40.8% in the lowest annual volume quartile and 28.2% in the highest quartile. After adjustment for severity of illness, age, diagnosis and organ failure, higher MV volume was associated with significantly lower hospital mortality among MV patients (OR 0.9985 per 10 additional patients, 95% CI 0.9978-0.9992; p = 0.0001). A significant centre effect on hospital mortality persisted after adjustment for volume effect (p < 0.0001). Our study demonstrated higher hospital MV volume to be independently associated with increased survival among MV patients. Significant differences in outcomes persisted between centres after adjustment for hospital MV volume, supporting a role for other significant determinants of the centre effect.

Stigma, discrimination, and sexual (dis)satisfaction among people living with HIV: results from the "AIDES et toi" survey.

The effects of HIV-related stigma and discrimination have been studied in several areas, such as access to testing, quality of care quality, and access to work. Nevertheless, the effects of stigma and discrimination on the sexual life of people living with HIV/AIDS (PLWHA) have not been studied enough. AIDES, a French community-based organization, has developed a biannual survey which assesses several socioeconomical and psychosocial dimensions of the people in contact with this organization. A focus on the results concerning sexual (dis)satisfaction and the factors associated are presented here. A convenience sample of 521 HIV-positive men having sex with men, heterosexual men and women was analyzed. A logistic regression was performed to examine which factors were significantly associated with sexual dissatisfaction. Results showed that being older, not having a full-time job, not having a steady sexual partner, lower frequency of sexual intercourse, discrimination in the sexual relationship setting, and the perception of loneliness were independently associated with sexual dissatisfaction. A quality health approach must include the aspects linked to sexual life and sexual satisfaction. Given the potentially harmful effects that HIV-related stigma and discrimination have on PLWHA's well-being, more specific actions and advocacy in this direction should be developed and implemented.

[Mass neonatal screening using biological testing]. / Le dépistage néonatal généralisé par des tests d'analyse biologique.

Implementation of a generalized screening program for neonatal diseases obeys precise guidelines. The disease must be severe, recognizable at an early stage, accessible to an effective treatment, detected with a non expansive and widely applicable test and it must represent an important health problem. In case of positive results, treatment or prevention shall be offered immediately and any screening program has to be regularly evaluated. There is in France since 1978 a national screening program that depends on a private association ("Association française pour le dépistage et la prévention des handicaps de l'enfant") and is supervised by the "Caisse nationale d'assurance maladie" and the "Direction Générale de la Sante". Presently, five diseases are included in the screening program: phenylketonuria, hypothyroidism, congenital adrenal hyperplasia, cystic fibrosis and sickle cell disease, the latter only in at risk newborns. Toxoplasmosis represents a particular problem because screening takes place only in children of mothers that have not been controlled during their pregnancy or in case of seroconversion. Neonatal screening of phenylketonuria and hypothyrodism is unanimously recommended. That of congenital adrenal hyperplasia is approved in most countries. The cases of sickle cell disease and cystic fibrosis are more complex because: 1) all the children that carry the mutations are not affected with a severe disease; 2) there is no curative treatment; 3) parents given information are made anxious, sometimes wrongly if the disease is mild or asymptomatic. The supporters of the screening insist on the interest of an early diagnosis which makes longer the life time of these children, the possibility for the parents to utilize prenatal screening in case of a future pregnancy, and the information given to the heterozygous carriers following a familial screening. The question is raised of the extension of neonatal screening to other diseases. This is now possible due to technical progresses such as the tandem mass spectrometry that can detect about 50 diseases in an only testing. In addition of its cost and of the difficulty to ensure an efficient organization, increasing the number of the screened diseases will raise ethical problems including how the parents will be informed of an incurable disease or a late-onset disease or an entirely asymptomatic disease. It is unanimously admitted that only mendelian diseases should be detected excluding genetic polymorphisms. Analysis of the present situation suggests the following developments: 1) to actualize the guidelines for deciding of a new neonatal screening; 2) to experiment on a local scale any new screening before its extension to the whole country; 3) to create an evaluation committee including paediatricians and epidemiologists and to evaluate on the long term the future of the children; 4) to precisely define the conditions in which the heterozygous carriers will be informed following a familial investigation; 5) to store in a resource biological centre the blood samples in order to utilize this bank for epidemiology studies.

[ICU performance: results of a French study involving 80,000 ICU stays]. / Performance en réanimation: résultats du PHRC Sfar-SRLF.

OBJECTIVE: The Standard Mortality Ratio (SMR), comparing the observed in-hospital mortality to the predicted, may measure the intensive care units (ICU) performance. STUDY DESIGN: Multicentric retrospective national study. METHODS: A probability model using a severity score such SAPS II calculated the predicted mortality rate. A national French study has been undertaken to compare the SMR of ICUs and looked for explanation. RESULTS: One hundred six units, 34 were medical (32%), 18 surgical (17%) and 57 medical/surgical (51%) participated to the study. Forty-six ICUs (43%) were located in teaching hospitals. The SMR of the 87,099 stays was 0.84 (0.82-0.85). The SMR of ICUs varied from 0.41 to 1.55. Ten units had a SMR>0.85, which suggested a low performance. They had more stays for cardiovascular failures, as compared with others. The best units (SMR<0.82) had more stays for drug overdose. The SMR increased with the number of organ failures, from 0.47 with zero failure to 1.11 with 4 or more organ failures. The stays with cardiovascular failure, either unique or associated, had a higher SMR. The 7935 stays with a drug overdose had a SMR of 0.12 (0.10-0.14), which suggested a bad calibration of the model in theses cases. CONCLUSION: The case mix must be taken in account when comparing the ICUs performance by the mean of SMR, particularly when the units admitted a lot of drug overdoses.

[Completeness of ICU activity reports sent to French healthcare authorities]. / Exhaustivité des résumés d'unité médicale adressés aux départements d'information médicale.

INTRODUCTION: Hospital units report on their inpatient care activity by writing yearly activity reports, which are used by their Medical Information Department (MID) to develop standardized summaries for communication to healthcare authorities. The data are categorized by uniform patient groups and used to describe inpatient care activity and to guide resource allocation. The objective of this study was to evaluate the completeness of activity reports from intensive care units (ICUs) in France. METHODS: Activity reports sent in 1998 and 1999 by French ICUs participating in the study were collected using dedicated abstracting software supplied to the relevant MIDs. Completeness of data in the activity reports was evaluated, with special attention to the SAPSII score, Omega rating of ICU procedures according to the Classification of Medical Procedures, and primary and secondary diagnoses. RESULTS: The 106 ICUs that volunteered for the study reported data on 107,652-hospital stays. Mean age and SAPSII were 55 +/- 21 years and 35 +/- 21 years, respectively. Mean ICU and hospital lengths of stay were 6.2 +/- 12.4 and 16.1 +/- 21.6 days, respectively. Mean ICU and hospital mortality rates were 15% and 19%. The SAPSII and Omega procedures were reported for 81% and 80% of stays, respectively. The SAPSII and Omega procedures were calculated or coded in 94% (100/106) and 96% (102/106) of ICUs, respectively. Mean number of Omega procedures was 4.3+/-3.9. However, only 5% (5/106) of ICUs entered the SAPSII for every stay, and 21% (22/106) of ICUs failed to enter the SAPSII for over 20% of stays. Similarly, 53% (56/106) of ICUs rated no more than five Omega procedures on average per stay. The primary diagnosis was reported for all stays, and the mean number of secondary diagnoses was 3.5 +/- 3.8. In 80% (86/106) of ICUs, no more than five secondary diagnoses were coded on average per stay. CONCLUSION: The analysis of this national database shows that data communicated to the MIDs and therefore to the healthcare authorities, are incomplete regarding SAPSII, ICU procedures, treatment intensity, and diagnoses. This may lead to the underestimation of ICU activity and resource needs, particularly if the SAPSII and selected procedures identified as markers for high-intensity critical care are used in the future.

Serum paraoxonase activity and paraoxonase gene polymorphism in type 2 diabetic patients with or without vascular complications.

BACKGROUND: Serum paraoxonase (PON) activity and the relevance of PON gene polymorphism in vascular complications of type 2 diabetic patients were investigated in a case-control study. METHODS: The population included 105 control subjects, 96 diabetic patients without vascular complications and 71 diabetics with vascular complications. RESULTS: Serum PON activity was significantly decreased (p<0.001) in diabetic patients without vascular complications: 207 IU (25-817) compared with the controls: 259 IU (24-950). Although serum PON activity was also decreased: 232 IU (34-797) in the population with vascular complications, the difference was not statistically significant (p=0.11). The Q192 allele frequency is significantly higher (p<0.005) in diabetics without vascular complications (77%), and with vascular complications (73%) than in the controls (63%). No significant association was found between either PON(1)55 L/M and PON(2)311 C/S gene polymorphisms and vascular complications. CONCLUSIONS: The difference in allele frequency for the PON(1) Q/R 192 gene polymorphism may be the cause of the low paraoxonase activity observed in type 2 diabetes mellitus. Further studies need to be conducted to elucidate the role of the enzyme in the development of vascular complications in diabetes.

Identification of 96 single nucleotide polymorphisms in eight genes involved in iron metabolism: efficiency of bioinformatic extraction compared with a systematic sequencing approach.

Single nucleotide polymorphisms (SNPs) can significantly contribute to the characterization of the genes predisposing to iron overloads or deficiencies. We report an SNP survey of coding and non-coding regions of eight genes involved in iron metabolism, by two successive methods. First, we made use of the public domain sequence data, by using assembled expressed sequence tags, non-redundant sequences, and SNP database screening. We extracted 77 potential SNPs of which only 31 could be further validated by sequencing DNA from 44 unrelated multi-ethnic individuals. Our results indicate that a bioinformatic approach may be effective only in those cases where candidate SNPs are extracted from two different data sources or in cases of experimentally confirmed SNPs. Second, additional systematic sequencing of DNA from 24 unrelated Breton subjects increased the number of SNPs over a total length of 86 kb to 96. The average distance between the SNPs and minor allele frequencies were higher than reported by others authors; this discrepancy may reflect the nature of the genes studied and the ethnic homogeneity of our test population.

Compliance with triage to intensive care recommendations.

DESIGN: Recommendations for triage to intensive care units (ICUs) have been issued but not evaluated. SETTING: In this prospective, multicenter study, all patients granted or refused admission to 26 ICUs affiliated with the French Society for Critical Care were included during a 1-month period. Characteristics of participating ICUs and patients, circumstances of triage, and description of the triage decision with particular attention to compliance with published recommendations were recorded. RESULTS: During the study period, 1,009 patients were and 283 were not admitted to the participating ICUs. Refused patients were more likely to be older than 65 yrs (odds ratio [OR], 3.53; confidence interval [CI], 1.98-5.32) and to have a poor chronic health status (OR, 3.09; CI, 2.05-4.67). An admission diagnosis of acute respiratory or renal failure, shock, or coma was associated with admission, whereas chronic severe respiratory and heart failure or metastatic disease without hope of remission were associated with refusal (OR, 2.24; CI, 1.38-3.64). Only four (range, 0-8) of the 20 recommendations for triage to ICU were observed; a full unit and triage over the phone were associated with significantly poorer compliance with recommendations (0 [0-2] vs. 6 [2-9], p =.0003; and 1 [0-6] vs. 6 [1-9], p <.0001; respectively). CONCLUSION: Recommendations for triage to intensive care are rarely observed, particularly when the unit is full or triage is done over the phone. These recommendations may need to be redesigned to improve their practicability under real-life conditions, with special attention to phone triage and triaging to a full unit.

Routine exploratory thoracentesis in ICU patients with pleural effusions: results of a French questionnaire study.

PURPOSE: The purpose of this study was to report the opinions of intensivists regarding pleural effusions in patients in the intensive care unit (ICU). MATERIALS AND METHODS: Questionnaires were sent to 1,032 intensivists, who were members of the French Society of Critical Care. RESULTS: Four hundred thirty-one questionnaires (41.7%) were returned. Overall, the respondents' estimated the incidence of pleural effusion in ICU patients to be 22.19 +/- 17%, whereas 37 +/- 27% considered that exploratory thoracentesis was likely to determine the cause of the effusion, and 17.36 +/- 16% considered that its results were likely to result in a change in their therapeutic attitude. Sixty-five (15%) physicians, chiefly pulmonologists, performed exploratory thoracentesis routinely (Group 1). Compared with those who did not perform routine thoracentesis (Group 2), they ascribed a higher proportion of pleural effusions to infection (31.3% vs. 13.5%) and were more likely to consider that exploratory thoracentesis had a diagnostic and therapeutic contribution (51.2% vs. 34% and 23% vs. 16%, respectively). In addition to the respiratory medicine subspecialty, the practice of routine exploratory thoracentesis was significantly related to seniority, to the frequency of the suspicion of an infectious cause in the physician's practice, and to his or her appreciation of the risks associated with exploratory thoracentesis. Physicians from Group 1 were also more likely to describe exploratory thoracentesis as a noninvasive procedure. CONCLUSIONS: The beliefs and attitudes of intensivists regarding pleural effusions and exploratory thoracentesis are divergent. This may be due to the lack of precise guidelines on the topic and prompt the design of further studies to establish precisely the epidemiology and causes of pleural effusions in ICU patients.

Symptoms of anxiety and depression in family members of intensive care unit patients: ethical hypothesis regarding decision-making capacity.

OBJECTIVE: Anxiety and depression may have a major impact on a person's ability to make decisions. Characterization of symptoms that reflect anxiety and depression in family members visiting intensive care patients should be of major relevance to the ethics of involving family members in decision-making, particularly about end-of-life issues. DESIGN: Prospective multicenter study. SETTING: Forty-three French intensive care units (37 adult and six pediatric); each unit included 15 patients admitted for longer than 2 days. PATIENTS: Six hundred thirty-seven patients and 920 family members. INTERVENTIONS: Intensive care unit characteristics and data on the patient and family members were collected. Family members completed the Hospital Anxiety and Depression Scale to allow evaluation of the prevalence and potential factors associated with symptoms of anxiety and depression. MEASUREMENTS AND MAIN RESULTS: Of 920 Hospital Anxiety and Depression Scale questionnaires that were completed by family members, all items were completed in 836 questionnaires, which formed the basis for this study. The prevalence of symptoms of anxiety and depression in family members was 69.1% and 35.4%, respectively. Symptoms of anxiety or depression were present in 72.7% of family members and 84% of spouses. Factors associated with symptoms of anxiety in a multivariate model included patient-related factors (absence of chronic disease), family-related factors (spouse, female gender, desire for professional psychological help, help being received by general practitioner), and caregiver-related factors (absence of regular physician and nurse meetings, absence of a room used only for meetings with family members). The multivariate model also identified three groups of factors associated with symptoms of depression: patient-related (age), family-related (spouse, female gender, not of French descent), and caregiver-related (no waiting room, perceived contradictions in the information provided by caregivers). CONCLUSIONS: More than two-thirds of family members visiting patients in the intensive care unit suffer from symptoms of anxiety or depression. Involvement of anxious or depressed family members in end-of-life decisions should be carefully discussed.

Identification of an endogenous RNA transcribed from the antisense strand of the HFE gene.

Hereditary haemochromatosis is an autosomal recessive disease which results in iron overload, and it is the most frequently inherited disorder in Caucasian populations. The gene involved (HFE) has recently been identified, and it encodes an MHC class I-like molecule. A 2.7 kb cDNA has been isolated, whereas the HFE gene expression is characterized by an almost ubiquitous mRNA of 4.1 kb in size. The difference between this transcript and the isolated cDNA has not yet been explained. Thus, the 5' end of the HFE gene is still undefined and very little is known about the regulation of its expression. By searching this end, we isolated an antisense transcript originating from the same gene locus. Further investigations (rapid amplification of cDNA ends, RT-PCR experiments and dbEST screening) indicated that this RNA spans exon 1, exon 2, part of intron 1 of the HFE gene and approximately 1 kb upstream of it. This HFE antisense transcript is polyadenylated but displays no open reading frame. A ribonuclease A protection assay definitively demonstrated the biological existence of the HFE antisense RNA, which appears to be expressed in all of the tissues and cell lines tested. Furthermore, in vitro coupled transcription-translation experiments revealed that the HFE expression is decreased by this antisense RNA, indicating that it may play a critical role in the regulation of the HFE gene expression.

Evaluation of the logistic organ dysfunction system for the assessment of organ dysfunction and mortality in critically ill patients.

OBJECTIVES: To evaluate the performance of the logistic organ dysfunction (LOD) system for the assessment of morbidity and mortality in multiple organ dysfunction/failure (MOD/F) in an independent database and to evaluate the use of sequential LOD measurements for the prediction of outcome. DESIGN AND SETTING: Prospective, multicentric cohort study in 13 adult medical, surgical, and mixed intensive care units (ICUs) in Austria. PATIENTS: A total of 2,893 consecutive admissions to the ICUs. MEASUREMENTS AND MAIN RESULTS: Patient vital status at ICU and hospital discharge was recorded. Univariate analysis showed that the LOD was able to distinguish between survivors and nonsurvivors (2 vs. 6 median score). Within organ systems, higher levels of the severity of organ dysfunction were consistently associated with higher mortality. For the prediction of hospital mortality, the original prognostic LOD model did not perform well in our patients, as indicated by the goodness-of-fit C statistic. Using multiple logistic regression we developed a prognostic model with a satisfactory fit in our patients. The integration of further measurements during the ICU stay increased discrimination but not calibration. CONCLUSIONS: The LOD system is well correlated well with the numbers and levels of organ dysfunctions and discriminates well between survivors and nonsurvivors. It can thus be used to quantify the baseline severity of organ dysfunction. Moreover, after customization of the predictive equation the LOD predicted hospital mortality in our patients with high precision. It thus provides a combined measure of morbidity and mortality for critically ill patients with MOD/F.

Low penetrant hemochromatosis phenotype in eight families: no evidence of modifiers in the MHC region.

The gene responsible for hemochromatosis (HFE) has been identified on the short arm of chromosome 6, 4.5 Mb telomeric to HLA-A. A major mutation C282Y is closely correlated with the disease, as it accounts for 68 to 100\% of the cases of hemochromatosis. Nevertheless, some C282Y homozygotes subjects have no clinical or biological expression of the disease. Moreover, in Northern European populations a large discrepancy is observed between the number of C282Y homozygotes and the number of diagnosed hemochromatosis patients, suggesting incomplete penetrance of the mutation. To localize and identify the modifying genes, we investigated eight families including C282Y homozygous relatives showing no clinical signs of the disease, in addition to the hemochromatosis patients. Genomic DNA from 20 C282Y homozygotes (10 patients and 10 siblings presenting no or minor biological abnormalities) were studied. Five polymorphisms from the HFE gene were determined by PCR restriction. Extended haplotypes of the 6p21.3 region were constructed with 10 microsatellite markers. All the C282Y homozygotes shared the same HFE polymorphism. The haplotypes presented no significant difference between the probands and their unaffected relatives. These studies suggest that neither HFE polymorphism nor genes surrounding HFE are able to modulate HFE expression.