Cinematic reflectometry using QIKR, the quite intense kinetics reflectometer.

The Quite Intense Kinetics Reflectometer (QIKR) will be a general-purpose, horizontal-sample-surface neutron reflectometer. Reflectometers measure the proportion of an incident probe beam reflected from a surface as a function of wavevector (momentum) transfer to infer the distribution and composition of matter near an interface. The unique scattering properties of neutrons make this technique especially useful in the study of soft matter, biomaterials, and materials used in energy storage. Exploiting the increased brilliance of the Spallation Neutron Source Second Target Station, QIKR will collect specular and off-specular reflectivity data faster than the best existing such machines. It will often be possible to collect complete specular reflectivity curves using a single instrument setting, enabling "cinematic" operation, wherein the user turns on the instrument and "films" the sample. Samples in time-dependent environments (e.g., temperature, electrochemical, or undergoing chemical alteration) will be observed in real time, in favorable cases with frame rates as fast as 1 Hz. Cinematic data acquisition promises to make time-dependent measurements routine, with time resolution specified during post-experiment data analysis. This capability will be deployed to observe such processes as in situ polymer diffusion, battery electrode charge-discharge cycles, hysteresis loops, and membrane protein insertion into lipid layers.

Automatically Identifying Financial Stress Information from Clinical Notes for Patients with Prostate Cancer.

Background: Financial stress, one of the social determinants, is common among cancer patients because of high out-ofpocket costs for treatment, as well as indirect costs. The National Academy of Medicine (NAM) has advised providers to recognize and discuss cost concerns with patients in order to enhance shared decision-making for treatment and exploration of financial assistant programs. However, financial stress is rarely assessed in clinical practice or research, thus, under-coded and under-documented in clinical practice. Natural language processing (NLP) offers great potential that can automatically extract and process data on financial stress from clinical free text existing in the patient electronic health record (EHR). Methods: We developed and evaluated an NLP approach to identify financial stress from clinical narratives for patients with prostate cancer. Of 4,195 eligible prostate cancer patients, we randomly sampled 3,138 patients (75%) as a training dataset (150,990 documents) to develop a financial stress lexicon and NLP algorithms iteratively. The remaining 1,057 patients (25%) were used as a test dataset (55,516 documents) to evaluate the NLP algorithm performance. The common terms representing financial stress were "financial concerns," "unable to afford," "insurance issue," "unemployed," and "financial assistance." Negations were used to exclude false mentions of financial stress. Results: Applying both pre- and post-negation, the NLP algorithm identified 209 patients (6.0%) from the training sample and 66 patients (6.2%) with 161 notes from the test sample as having documented financial stress. Two independent domain experts manually reviewed all 161 notes with NLP identified positives and randomly selected 161 notes with NLP-identified negatives, the NLP algorithm yielded 0.86 for precision, 1 for recall, and 0.9.2 for F-score. Conclusions: Financial stress information is not commonly documented in the EHR, neither in structured format nor in clinical narratives. However, natural language processing can accurately extract financial stress information from clinical notes when such narrative information is available.

Social Networks Across Common Cancer Types: The Evidence, Gaps, and Areas of Potential Impact.

Although the association between social context and health has been demonstrated previously, much less is known about network interactions by gender, race/ethnicity, and sociodemographic characteristics. Given the variability in cancer outcomes among groups, research on these relationships may have important implications for addressing cancer health disparities. We examined the literature on social networks and cancer across the cancer continuum among adults. Relevant studies (N=16) were identified using two common databases: PubMed and Google Scholar. Most studies used a prospective cohort study design (n=9), included women only (n=11), and were located in the United States (n=14). Seventy-five percent of the studies reviewed used a validated scale or validated items to measure social networks (n=12). Only one study examined social network differences by race, 57.1% (n=8) focused on breast cancer alone, 14.3% (n=2) explored colorectal cancer or multiple cancers simultaneously, and 7.1% (n=1) only prostate cancer. More than half of the studies included multiple ethnicities in the sample, while one study included only low-income subjects. Despite findings of associations between social networks and cancer survival, risk, and screening, none of the studies utilized social networks as a mechanism for reducing health disparities; however, such an approach has been utilized for infectious disease control. Social networks and the support provided within these networks have important implications for health behaviors and ultimately cancer disparities. This review serves as the first step toward dialog on social networks as a missing component in the social determinants of cancer disparities literature that could move the needle upstream to target adverse cancer outcomes among vulnerable populations.

[Multicentric study of medical care and practices in spinal muscular atrophy type 1 over two 10-year periods]. / Amyotrophie spinale type 1 : enquête multicentrique des pratiques de soins et d'accompagnement palliatif sur deux périodes successives de 10ans.

AIM: Questions about care practices and the role of palliative care in pediatric neurodegenerative diseases have led the Neuromuscular Committee of the French Society of Neurology to conduct a retrospective study in spinal muscular atrophy type 1, a genetic disease most often leading to death before the age of 1 year. MATERIAL AND METHODS: A retrospective multicenter study from pediatricians included in the reference centers of pediatric neuromuscular diseases was carried out on two 10-year periods (1989-1998 and 1999-2009). RESULTS: The 1989-1998 period included 12 centers with 106 patients, the 1999-2009 period 13 centers with 116 children. The mean age of onset of clinical signs was 2.1 months (range, 0-5.5 months), the median age at diagnosis was 4 months (range, 0-9 months) vs 3 months. The median age of death was 7.5 months (range, 0-24 months) vs 6 months. The care modalities included physiotherapy (90 %), motor support (61 % vs 26 % for the previous period), enteral nutrition by nasogastric tube (52 % vs 24 %), and 3.4 % of children had a gastrostomy (vs 1.8 %). At home, pharyngeal aspiration was used in 64 % (vs 41 %), oxygen therapy in 8 %, noninvasive ventilatory support in 7 %. The mean age at death was 8.1 months (range, 0-24 months) vs 7 months, the time from diagnosis to death was 4 months vs 3 months. Death occurred at home in 23 % vs 17 %, in a pediatric unit in 62 % vs 41 %. The use of analgesics and sedative drugs was reported in 60 % of cases: 40 % morphine (vs 18 %) and benzodiazepines in 48 % (vs 29 %). Respiratory support was limited mostly to oxygen by nasal tube (55 % vs 54 %), noninvasive ventilation in 9 % of the cases, and intubation and assisted mechanical ventilation (2 %). DISCUSSION AND CONCLUSION: These results confirm a change in practices and the development of palliative care in children with a French consensus of practices quite different from the standard care in North-America and closer to the thinking of English medical teams. A prospective study within the 2011 national hospital clinical research program (PHRC 2011) is beginning in order to evaluate practices and the role of families and caregivers.

Elimination of contaminating cap genes in AAV vector virions reduces immune responses and improves transgene expression in a canine gene therapy model.

Animal and human gene therapy studies utilizing AAV vectors have shown that immune responses to AAV capsid proteins can severely limit transgene expression. The main source of capsid antigen is that associated with the AAV vectors, which can be reduced by stringent vector purification. A second source of AAV capsid proteins is that expressed from cap genes aberrantly packaged into AAV virions during vector production. This antigen source can be eliminated by the use of a cap gene that is too large to be incorporated into an AAV capsid, such as a cap gene containing a large intron (captron gene). Here, we investigated the effects of elimination of cap gene transfer and of vector purification by CsCl gradient centrifugation on AAV vector immunogenicity and expression following intramuscular injection in dogs. We found that both approaches reduced vector immunogenicity and that combining the two produced the lowest immune responses and highest transgene expression. This combined approach enabled the use of a relatively mild immunosuppressive regimen to promote robust micro-dystrophin gene expression in Duchenne muscular dystrophy-affected dogs. Our study shows the importance of minimizing AAV cap gene impurities and indicates that this improvement in AAV vector production may benefit human applications.

[Phenotypic heterogeneity and phenotype-genotype correlations in dystrophinopathies: Contribution of genetic and clinical databases]. / Variabilité phénotypique et corrélations génotype-phénotype des dystrophinopathies : contribution des banques de données.

The objective of this work was to study the natural history of dystrophinopathies and the genotype-phenotype correlations made possible by the development of the clinical part of the French DMD database. The collection of 70,000 clinical data for 600 patients with an average longitudinal follow-up of 12years enabled clarification of the natural history of Duchenne and Becker muscular dystrophies and clinical presentations in symptomatic females. We were able to specify the phenotypic heterogeneity of motor, orthopedic and respiratory involvements (severe, standard and intermediary form), of the cardiac disorder (severe, standard or absent cardiomyopathy, absence of correlation between motor and cardiac involvements), and of brain function (mental deficiency in the patients with Becker muscular dystrophy, psychopathological disorders in dystrophinopathies). Phenotypic variability did not correlate with a specific mutational spectrum. We propose a model of phenotypic analysis based on the presence or not of muscular and cardiac involvements (described by age at onset and rate of progression) and brain involvement (described by the type and the severity of the cognitive impairment and of the psychological disorders). The methodology developed for the DMD gene can be generalized and used for other databases dedicated to genetic diseases. Application of this model of phenotypic analysis for each patient and further development of the database should contribute substantially to clinical research providing useful tools for future clinical trials.

[Neuromyelitis optica in children. Two case reports]. / Neuromyélite optique chez l'enfant. À propos de deux cas.

Devic neuromyelitis optica (NMO) is an inflammatory demyelinating disease of the central nervous system associating acute transverse myelitis and optic neuritis. This is a different disease from multiple sclerosis for which the presence of the NMO antibody directed against aquaporin 4 is a specific marker. Brain damage on MRI does not exclude the diagnosis; the location is superposable in the brain zones rich in aquaporin 4 channels. We report 2 cases of NMO with anti-aquaporin 4. One patient was not symptomatic of brain damage. In this patient, the affinity of anti-NMO for aquaporin 4, studied by flow cytometry, was particularly high. Both patients were treated with immunosuppressive agents (rituximab) due to the failure of or dependence on high-dose corticosteroids.

[Epilepsy and mitochondrial diseases: retrospective study on 53 epileptic children]. / Épilepsie et cytopathies mitochondriales : étude rétrospective de 53 enfants épileptiques.

AIM: Mitochondrial disease is a heterogeneous disorder entity induced by defects in the mitochondrial respiratory chain complex. Neurological symptoms, including epilepsy, are common in children. The aim of this study was to research the clinical signs indicating mitochondrial disease. METHODS: We retrospectively studied epileptic children who underwent a muscle and/or hepatic biopsy between 1995 and 2010 searching for a mitochondrial disease. Patients were separated into 2 groups depending on the biopsy result: group 1 (presence of mitochondrial disease) and group 2 (absence of mitochondrial disease). Epileptic phenotypes were compared between these 2 groups. In group 1, we specified the clinical phenotype and characterized mitochondrial disease. RESULTS: Fifty-three children were included: 29 in group 1 and 24 in group 2. The average age at onset of epilepsy was 39.6 months in group 1 versus 11.8 months in group 2. In the 1st group, epilepsy was less refractory and associated with other clinical symptoms. CONCLUSIONS: In this study, epilepsy did not appear to be a unique sign of mitochondrial disease. It most often appeared during the 2nd year of life and is correlated with multiorgan involvement, notably ophthalmologic, such as oculomotor apraxia, optic atrophy, and retinitis pigmentosa, as well as auditory (deafness) and hepatic (hepatic failure, hepatomegaly). On the other hand, in children who did not have mitochondrial disease, epilepsy often began earlier (before 3 months of age), it was refractory, isolated without multiorgan involvement, and seems to be due to genetic anomalies in developmental genes, a finding that requires further research.

[Subdural empyema complicating meningococcal meningitis: a pediatric observation]. / Empyème sous-dural compliquant une méningite à méningocoque : une observation pédiatrique.

Postmeningitis subdural empyema is rare in infants. It can have a severe clinical course with possible serious long-term consequences and 10% mortality. Diagnosis is often difficult. Postmeningitis subdural empyema must be discussed in cases of atypical progression of well-treated meningitis. We report the case of an 18-month-old infant presenting subdural empyema with an insidious course following Neisseria meningitidis group C meningitis.

[Serious pulmonary barotrauma in a child after first-time scuba dive]. / Accident barotraumatique grave chez un enfant lors d'un baptême de plongée.

Scuba diving is increasingly popular for children. However, this activity, including in shallow water, can be responsible for severe accidents. We report the case of a 13-year-old boy who dove for the first time in the Mediterranean Sea and suffered pulmonary barotraumas, complicated by arterial gas embolism with pneumomediastinum, cerebral, and coronary injuries. Any symptoms occurring after a dive, even in shallow water, must be considered a diving accident. Emergency medical personnel should contact a hyperbaric center for advice. In case of coronary or cerebral gaseous embolism, specific management requiring therapeutic recompression is urgently required.

[Association of type 1 diabetes mellitus and epilepsy in children. A cohort of 10 cases]. / Association diabète de type 1et épilepsie chez l'enfant. À propos d'une série de 10 cas.

UNLABELLED: The association of type 1 diabetes mellitus (DM) and epilepsy has been previously reported. However, the physiopathology of this association remains misunderstood. OBJECTIVE: To describe epilepsy combined with type 1 DM in children. METHODS: Retrospective monocentric study of all the epileptic and type 1 diabetic children consulting at the Timone University Hospital, Marseille, France. For each patient, the type of epilepsy and its electroclinical and radiographic characteristics were studied as well as the type of diabetes (biological characteristics, glycemic control), and the onset of these 2 diseases. RESULTS: Ten patients are reported. Five suffered from generalized epilepsy (4 idiopathic, 1 nonidiopathic) and 5 from focal epilepsy (4 non-idiopathic, 1 idiopathic). For most of these cases, presence of GAD (glutamic acid decarboxylase) autoantibodies were confirmed and epilepsy followed diabetes. CONCLUSIONS: The 2 most common types of epilepsy in this association are idiopathic generalized epilepsy and non-idiopathic temporal epilepsy. Several mechanisms could be involved (immune, glycemia, and genetic disorders).

Capsid-expressing DNA in AAV vectors and its elimination by use of an oversize capsid gene for vector production.

Adeno-associated virus (AAV) vectors have been shown to mediate persistent transduction in animal models of gene therapy. However, clinical trials with AAV vectors have shown that an immune response to AAV capsid protein can result in clearance of transduced cells. One source of capsid antigen is from the delivered vector virions, but expression of cap DNA impurities in AAV vector preparations might provide an alternative and persistent source of capsid antigen. Here we show that DNA without any AAV sequences can be packaged in AAV virions, and that both cap and rep DNA are packaged into AAV vectors produced by standard methods. Using a sensitive complementation assay, we also observed significant expression of capsid in cultured cells transduced with AAV vectors. In an attempt to solve this problem, we inserted a large intron into the cap gene to generate a capsid expression cassette (captron) that is too large for packaging into AAV virions. Both complementation assays and quantitative reverse-transcription PCR analysis showed that cultured cells infected with AAV vectors made with the captron plasmid expressed no detectable capsid. Elimination of transfer of capsid-expressing DNA may reduce immune responses to AAV vector-transduced cells and promote long-term expression of therapeutic proteins.

Effect of genetic counseling and testing for BRCA1 and BRCA2 mutations in African American women: a randomized trial.

BACKGROUND: Limited empirical data are available on the effects of genetic counseling and testing among African American women. OBJECTIVE: To evaluate the effects of genetic counseling and testing in African American women based on different levels of exposure: (a) women who were randomized to culturally tailored (CTGC) and standard genetic counseling (SGC) to women who declined randomization (non-randomized group), (b) participants and non-participants in genetic counseling, and (c) BRCA1 and BRCA2 (BRCA1/2) test result acceptors and decliners. DESIGN: Randomized trial of genetic counseling conducted from February 2003 to November 2006. MEASURES: We evaluated changes in perceived risk of developing breast cancer and cancer worry. RESULTS: Women randomized to CTGC and SGC did not differ in terms of changes in risk perception and cancer worry compared to decliners. However, counseling participants had a significantly greater likelihood of reporting reductions in perceived risk compared to non-participants (p = 0.03). Test result acceptors also had a significantly greater likelihood of reporting decreases in cancer worry (p = 0.03). However, having a cancer history (p = 0.03) and a BRCA1/2 prior probability (p = 0.04) were associated with increases in cancer worry. CONCLUSIONS: Although CTGC did not lead to significant improvements in perceived risk or psychological functioning, African American women may benefit from genetic counseling and testing. Continued efforts should be made to increase access to genetic counseling and testing among African American women at increased risk for hereditary disease. But, follow-up support may be needed for women who have a personal history of cancer and those with a greater prior probability of having a BRCA1/2 mutation.

[Spontaneous pneumomediastinum in a 4-month-old boy]. / Pneumomédiastin spontané chez un nourrisson de 4 mois.

Spontaneous pneumomediastinum is a rare entity in children, especially in young infants. We report the case of a 4-month-old infant with a massive spontaneous pneumomediastinum caused by acute viral bronchiolitis. Treatment including bed rest, codeine for its antitussive action, and nitrogen washout resolved the pneumomediastinum within 3 days. In the literature, cases of pneumomediastinum in very young infants are exceptional. To our knowledge, codeine has never been used in this situation. Nitrogen washout is also rarely used because of poorly demonstrated efficacy.

Decisions and outcomes of genetic testing for inherited breast cancer risk.

Since the discovery of breast cancer susceptibility genes and the availability of genetic testing, a substantial amount of research has been conducted to evaluate rates of genetic test acceptance and to understand the psychological and behavioral impact of BRCA1 and BRCA2 (BRCA1/2) genetic test results. This article explores findings related to genetic test acceptance for inherited breast cancer risk and the impact of genetic test results on psychological functioning, cancer prevention and control behaviors, and family communication about genetic testing. Overall, rates of genetic test acceptance were lower than anticipated based on interest in genetic testing reported in early research. While there is limited evidence that genetic testing generates adverse psychological effects, receiving positive BRCA1/2 test results may cause emotional reactions and concerns that are specific to such results. Although early reports suggested that receiving positive BRCA1/2 test results may have a limited impact on cancer screening or prevention behaviors, recent studies have shown that genetic testing for inherited breast cancer risk may increase screening behaviors among mutation carriers. However, utilization of some screening tests remains low among mutation carriers. Additional studies are needed to identify subgroups of participants in genetic testing who may be vulnerable to experiencing testing-specific concerns, and to evaluate the effects of interventions designed to promote behavioral change and address other concerns that may be generated by receiving positive BRCA1/2 test results.

Adeno-associated virus type 6 (AAV6) vectors mediate efficient transduction of airway epithelial cells in mouse lungs compared to that of AAV2 vectors.

Although vectors derived from adeno-associated virus type 2 (AAV2) promote gene transfer and expression in many somatic tissues, studies with animal models and cultured cells show that the apical surface of airway epithelia is resistant to transduction by AAV2 vectors. Approaches to increase transduction rates include increasing the amount of vector and perturbing the integrity of the epithelia. In this study, we explored the use of vectors based on AAV6 to increase transduction rates in airways. AAV vectors were made using combinations of rep, cap, and packaged genomes from AAV2 or AAV6. The packaged genomes encoded human placental alkaline phosphatase and contained terminal repeat sequences from AAV2 or AAV6. We found that transduction efficiency was primarily dependent on the source of Cap protein, defined here as the vector pseudotype. The AAV6 and AAV2 pseudotype vectors exhibited different tropisms in tissue-cultured cells, and cell transduction by AAV6 vectors was not inhibited by heparin, nor did they compete for entry in a transduction assay, indicating that AAV6 and AAV2 capsid bind different receptors. In vivo analysis of vectors showed that AAV2 pseudotype vectors gave high transduction rates in alveolar cells but much lower rates in the airway epithelium. In contrast, the AAV6 pseudotype vectors exhibited much more efficient transduction of epithelial cells in large and small airways, showing up to 80% transduction in some airways. These results, combined with our previous results showing lower immunogenicity of AAV6 than of AAV2 vectors, indicate that AAV6 vectors may provide significant advantages over AAV2 for gene therapy of lung diseases like cystic fibrosis.