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).

Azimuthal reorientation of pentacene upon 2D condensation.

We report a novel two-dimensional gas-solid phase transition of pentacene molecules on the Cu(110)-(2 × 1)O surface where the 2D condensation is accompanied by a reversible azimuthal rotation of the pentacene molecules. The change of the optical anisotropy associated with this reorientation allows us to explore the 2D condensation as a function of coverage and temperature by reflectance difference spectroscopy. As a result, the 2D heat of condensation of pentacene on Cu(110)-(2 × 1)O is determined to be 84 meV, which is more than one order of magnitude smaller than the respective value for 3D crystallization.

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.

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.

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.

Glucose and its metabolites have distinct effects on the calcium-induced mitochondrial permeability transition.

Mitochondrial production of reactive oxygen species (ROS) due to up-regulated glucose oxidation is thought to play a crucial, unifying role in the pathogenesis of chronic complications associated with diabetes mellitus. Mitochondrial permeability transition (MPT) is an interesting phenomenon involved in calcium signalling and cell death. We investigated the effects of glucose and several of its metabolites on calcium-induced MPT (measured as mitochondrial swelling) in isolated rat liver mitochondria. The presence of glucose, glucose 1-phosphate (both at 30 mM) or methylglyoxal (6 mM) significantly slowed calcium-induced mitochondrial swelling. Thirty mM glucose also resulted in a significant delay of MPT onset. In contrast, 30 mM fructose 6-phosphate accelerated swelling, whereas glucose 6-phosphate did not influence the MPT. The calcium binding potentials of the three hexose phosphates were tested and found similar. In vitro hydrogen peroxide production by mitochondria respiring on succinate in the presence of rotenone was independent of mitochondrial membrane potential and increased transiently during calcium-induced MPT. Inhibition of MPT with cyclosporine A resulted in decreased mitochondrial ROS production in response to calcium. In contrast, inhibition of MPT by methylglyoxal was accompanied by increased ROS production in response to calcium. In conclusion, we confirm that methylglyoxal is a potent inhibitor of MPT. In addition, high levels of glucose, glucose 1-phosphate and fructose 6-phosphate can also affect MPT. Methylglyoxal simultaneously inhibits MPT and increases mitochondrial ROS production in response to calcium. Our findings provide a novel context for the role of MPT in glucose sensing and the cellular toxicity caused by methylglyoxal.

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.

Cajal bodies and histone locus bodies in Drosophila and Xenopus.

The organization of the cell nucleus into specialized compartments is important for nuclear function. We address the significance of compartmentalization by studying the Cajal body, an evolutionarily conserved nuclear organelle proposed to be involved in such diverse functions as assembly of the spliceosome, assembly of the transcription machinery, and modification of spliceosomal small nuclear RNAs. The Cajal body is typically identified by the presence of coilin, a protein of poorly defined function. Here, we demonstrate that coilin is not a unique Cajal body marker but also occurs in a related yet distinct nuclear organelle known as the histone locus body in both Drosophila and Xenopus. We stress the importance of multiple markers not only for identification of nuclear bodies but also for assessing their functional significance.

A flow cytometry-based assay to assess RSV-specific neutralizing antibody is reproducible, efficient and accurate.

Respiratory syncytial virus (RSV) is an important cause of respiratory infection in people of all ages, and is the leading cause of hospitalization in infants. Although commercially available monoclonal antibody is available for passive prophylaxis of neonates at risk of severe disease, there is no available vaccine to prevent RSV. Measurement of neutralizing activity will be a key endpoint for vaccine evaluation. Assessment of neutralizing antibody against RSV has been limited to traditional plaque reduction, which is time-consuming and inherently operator dependent and highly variable. Here, we describe a flow cytometry-based RSV-specific neutralization assay which is more rapid than traditional methods, highly sensitive and highly reproducible.

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.

Effect of Production System and Pruning on Temporal Development of Cercospora depazeoides and on Berry Yield in Black Elderberry Orchards.

In a 2-year study, the temporal development of Cercospora leaf spot (Cercospora depazeoides) and berry yield were evaluated in two production systems (integrated and organic) and in two winter pruning treatments (trees pruned to four and eight scaffolds) in two black elderberry (Sambucus nigra) orchards in Hungary. Under organic production, leaf spot onset occurred 2 to 4 weeks earlier (mid- and late July) in both years and both orchards compared with the integrated program. Disease then continuously progressed until the final assessment date (late September) in both years, reaching a maximum final disease incidence of 15.9% in the integrated system and of 38.2% in the organic system. In general, disease progress after late August was greater on trees pruned to eight scaffolds than on trees pruned to four scaffolds in both production systems. Both final disease incidence and area under the disease progress curves (AUDPC) were significantly lower (P < 0.001) in the integrated treatments compared with organic ones. Across all treatments, both disease measures were significantly (P < 0.05) lower on trees pruned to four scaffolds compared with trees pruned to eight scaffolds. However, when the effect of pruning on final disease incidence and AUDPC was analyzed separately for integrated and organic systems, pruning caused uniformly significant differences in disease development only for the organic system. Berry yield was significantly higher (P < 0.05) in the integrated system compared with the organic system, but pruning showed no significant effect on yield. Overall, pruning to four scaffolds resulted in consistently lower disease development in organic production compared to integrated. Thus, winter pruning may be useful as a Cercospora leaf spot management practice in organic elderberry orchards.

[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.

Wet-chemical templateless assembly of metal nanowires from nanoparticles.

We describe a new, simple, room-temperature wet-chemical approach for assembling Au and Ag nanoparticles into nanowire networks, without the use of lithographic templates. Five to 35 nm-diameter nanowires passivated with a thin organic layer were synthesized by mechanically agitating a biphasic liquid mixture of an aqueous hydrosol containing the nanoparticles, and toluene. Nanowire structure and surface chemistry are discussed based on electron microscopy, UV-visible spectroscopy and thermogravimetric analyses.

Analysis of summer epidemic progress of apple scab at different apple production systems in the Netherlands and hungary.

ABSTRACT Two, 4-year studies on summer epidemic progress of apple scab were conducted at Randwijk, the Netherlands, from 1998 until 2001 and at Eperjeske, Hungary, from 2000 until 2003. Disease assessments were made on scab-susceptible cv. Jonagold. A range of nonlinear growth functions were fitted to a total of 96 disease progress curves (3 treatment classes x 2 plant parts x 2 disease measures x 4 years x 2 locations) of apple scab incidence and severity. The three-parameter logistic model gave the most consistent fit across three treatment classes in the experiment (integrated, organic-sprayed, and organic-unsprayed). Parameters estimated or calculated from the three-parameter logistic function were used to analyze disease progress. These were disease incidence and severity on the day of the first assessment (Y(s)); final disease incidence or upper asymptote for incidence (Y(if)) or severity (Y(sf)); fruit incidence and severity on day 40, after which no new lesions on fruits appeared (Y(40)); leaf incidence and severity on day 75, at which shoot growth stopped (Y (75)); relative (beta) and "absolute" (theta) rates of disease progress; inflection point (M); and area under the disease progress curve (AUDPC(S)) standardized by the duration of the total epidemic. Comparisons among disease progress curves were made by correlation and factor analysis followed by Varimax rotation. There were large differences but high positive correlations among the parameters Y(s), Y(f), theta, and AUDPC(S) across the three treatment classes. In the factor analysis, two factors accounted for more than 85% of the total variance for both incidence and severity. Factor 1 gave an overall description of epidemic progress of both scab incidence and severity and included the parameters Y(f), Y(40), Y(75), theta, and AUDPC(S). Factor 2 identified a relationship between the relative rate parameter (beta) and the inflection point (M) for severity and a relationship between disease incidence and severity. For an integrated or an organic orchard, theta, AUDPC(S), and one of Y(f) or Y(75) (because of the link with host phenology) can characterize apple scab epidemics during summer. Based on these findings, improved scab management approaches were provided for integrated and organic apple production systems.

[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.

Templateless room-temperature assembly of nanowire networks from nanoparticles.

We demonstrate a new, room-temperature approach to assemble two-dimensional and three-dimensional networks of gold nanowires by agitating nanoparticles in a toluene-aqueous mixture, without the use of templates. The nanowires have a uniform diameter of about 5 nm and consist of coalesced face-centered cubic nanocrystals. Toluene molecules passivate the gold surfaces during nanoparticle coalescence, rendering the nanowires hydrophobic and enabling their transfer into the toluene layer. Such templateless low-temperature assembly of mesostructures from nanoscale building blocks open up new possibilities for creating porous self-supporting nanocatalysts, nanowires for device interconnection, and low-density high-strength nanofillers for composites.